Found 9 matching records:
Displaying record number 631
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MAb ID |
F105 (F-105) |
HXB2 Location |
Env |
Env Epitope Map
|
Author Location |
gp120 |
Research Contact |
Marshall Posner, Boston MA |
Epitope |
(Discontinuous epitope)
|
Ab Type |
gp120 CD4bs |
Neutralizing |
L View neutralization details |
Contacts and Features |
View contacts and features |
Species
(Isotype)
|
human(IgG1κ) |
Patient |
|
Immunogen |
HIV-1 infection |
Keywords |
adjuvant comparison, antibody binding site, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autologous responses, binding affinity, brain/CSF, chimeric antibody, co-receptor, complement, computational prediction, dendritic cells, effector function, enhancing activity, escape, genital and mucosal immunity, glycosylation, HAART, ART, immunoprophylaxis, immunotherapy, immunotoxin, isotype switch, kinetics, mimics, mother-to-infant transmission, neutralization, polyclonal antibodies, rate of progression, review, SIV, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity |
Notes
Showing 181 of
181 notes.
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F105: The study describes the generation, crystal structure, and immunogenic properties of a native-like Env SOSIP trimer based on a group M consensus (ConM) sequence. A crystal structure of ConM SOSIP.v7 trimer together with nAbs PGT124 and 35O22 revealed that ConM SOSIP.v7 is structurally similar to other Env trimers. In rabbits, the ConM SOSIP trimer induced serum nAbs that neutralized the autologous Tier 1A virus (ConM from 2004) and a related Tier 1B ConS virus (ConM from 2001). These responses target the trimer apex and were enhanced when the trimers were presented on ferritin nanoparticles. The neutralization of ConM and ConS pseudoviruses was tested against a large panel of nAbs and non-nAbs (2219, 2557, 3074, 3869, 447-52D, 830A, 654-30D, 1008-30D, 1570D, 729-30D, F105, 181D, 246D, 50-69D, sCD4, VRC01, 3BNC117, CH31, PG9, PG16, CH01, PGDM1400, PGT128, PGT121, 10-1074, PGT151, VRC43.01, 2G12, DH511.2_K3, 10E8, 2F5, 4E10); most nAbs were able to neutralize these pseudoviruses. Soluble ConM trimers were able to weakly activate B cells expressing PGT121 and PG16 BCRs but were inactive against those expressing VRC01 and PGT145. In contrast, at the same molar amount of trimers, the ConM SOSIP.v7-ferritin nanoparticles activated all 4 B cells efficiently. Binding of bnAbs 2G12 and PGT145 and non-nAbs F105 and 19b to ConM SOSIP.v7 trimer and SOSIP showed that the ferritin-bound trimer bound more avidly than the soluble trimer. This study shows that native-like HIV-1 Env trimers can be generated from consensus sequences, and such immunogens might be suitable vaccine components to prime and/or boost desirable nAb responses.
Sliepen2019
(neutralization, vaccine antigen design, binding affinity)
-
F105: Membrane-bound mRNA-encoded BG505-based Apex GT Env trimer vaccine candidates, which bind to inferred germline variants of bnAbs PCT64 and PG9, were developed through directed evolution and characterized. All assessed ApexGT constructs, as well as BG505 SOSIP.MD39 (background for Apex constructs), in soluble or membrane-bound forms (encoded by DNA or RNA), had generally similar antigenic profiles and had absent to low binding to mAb F105.
Willis2022
(antibody binding site)
-
F105: This study explored the basis of the neutralization resistance of tier 3 virus 253-11 (subtype CRF02_AG). Virus 253-11 was resistant to neutralization by 17b, b12, VRC03, F105, SCD4, CH12, Z13e1, PG16, PGT145, 2G12, PGT121, PGT126, PGT128, PGT130, 39F, F240, and 35O22; the virus was sensitive to 3BNC117, NIH45-46G54W, VRC01, 10E8, 2F5, 4E10, PG9, VRC26.26, 10-1074, and PGT151. Virus 253-11 was strikingly resistant to most tested antibodies that target V3/glycans, despite possessing key potential N-linked glycosylation sites, especially N301 and N332, needed for the recognition of this class of antibodies. The resistance of 253-11 was not associated with an unusually long V1/V2 loop, nor with polymorphisms in the V3 loop and N-linked glycosylation sites. The 253-11 MPER was rarely recognized by sera, but was more often recognized in a chimera consisting of a HIV-2 backbone with the 253-11 MPER, suggesting steric or kinetic hindrance of the MPER. Mutations in the 253-11 MPER previously reported to increase the lifetime of the prefusion Env conformation (Y681H, L669S), decreased the resistance of 253-11 to several mAbs, presumably destabilizing its otherwise stable, closed trimer structure. A crystal structure of a recombinant 253-11 SOSIP trimer revealed that the heptad repeat helices in gp41 are drawn in close proximity to the trimer axis and that gp120 protomers also showed a relatively compact form around the trimer axis.
Moyo2018
(neutralization, structure)
-
F105: Reduction in exposure of non-neutralizing Ab (nnAb) epitopes on native-like Env trimer immunogens results in bnAbs being elicited that have autologous tier 2 neutralization instead of tier 1. The design of trimer modifications to silence nnAb reactivity were directed towards (1) the V3 loop (2) epitopes exposed through CD4-induced conformational changes (CD4i epitopes) and (3) the exposed SOSIP trimer base that is usually buried within virus membrane. (1) In Steichen2016 2 Env variants of BG505 SOSIP.664 with reduced V3 nnAb-generating activity were created, one using mammalian display screens, BG505 MD39, and the other with an engineered disulfide bond, BG505 SOSIP.DS21. MD39's trimer design was improved by using the Rosetta Design platform and inserting 6 buried mutations to form BG505 Olio6, and both this trimer as well as the DS21 were shown to have reduced antigenicity for nnAb generation in a rabbit vaccine model. (2) To reduce CD4i epitope elicitation of nnAbs, saturation mutagenesis of Olio6 was performed, in search of the trimer that binds VRC01-class bnAbs but not CD4. BG505 Olio6.CD4KO containing the G473T mutation was identified. In addition, for the purposes of nucleic acid-based vaccine platform designs, the natural furin cleavage site between gp120 and gp41 was removed to abolish protease cleavage, by swapping the order of gp14 and gp120 in the gp160 gene, giving the trimer BG505 MD39.CP (circular permutation). (3) The exposed trimer base was masked with glycan in 3 under-glycosylated regions in order to direct bnAb responses to the distal regions (CD4bs, V2 apex, N332 superset) of the trimer instead, generating the GRSF (glycan resurfaced) MD39 and GRSF MD39.CP variants. Furthermore, variants with improved thermostability over MD39 were created, MD37 and MD64. All of these stabilizing mutations were transferred to diverse HIV isolates from different subtypes. Finally 3 subtype C (isolate 327c) trimers were assessed for binding to bnAbs, VRC01, PGT121, PGT151, PGT145, PG9 and to nnAbs, F105 and 17b - F105 did not bind to any of these. nnAb F105 discriminates between non-native and native trimers by binding non-native subtype B Env immunogens like AD8 SOSIP and not native AD8 MD64.
Kulp2017
(antibody binding site, antibody generation, antibody interactions, assay or method development, autologous responses, vaccine antigen design, structure)
-
F105: DS-SOSIP.4mut (4mut) was identified as the most immunogenic and stable of 4 engineered, soluble, closed prefusion HIV-1 Env trimers. 4mut contained 4 mutations (M154, M300, M302 and L320) designed to form hydrophobic interactions between V1V1 and V3 loops. Before V3-negative selection, mAb F105 recognized DS-SOSIP and BG505 SOSIP.664 but failed to recognize 4mut or the other 3 designed trimers (DS-SOSIP.6mut containing 4mut mutations, Y177W and I420M, DS-SOSIP.I423F and DS-SOSIP.A316W). After V3-negative selection, F105 also failed to recognize DS-SOSIP and BG505 SOSIP.664. Each DS-SOSIP variant was able to elicit trimer-specific responses, comparable to BG505 SOSIP.664, in guinea pigs after 4 immunizations, but none elicited heterologous neutralizing activity. Crystal structures were generated for 4mut and 6mut.
Chuang2017
(vaccine antigen design, vaccine-induced immune responses)
-
F105: Using subtype A BG505 Env structural information, improved variants of subtype B JRFL and subtype C 16055 Env native flexibly linked (NFL) trimers were generated. The trimer-derived (TD) residues that increased well-ordered, homogeneous, stable, and soluble trimers did not require positive or negative selection as previously needed [Guenaga2015, PLoS Pathos. 11(1):e1004570]. ELISA binding to the two CD4bs-targeting nnAbs, F105 and b6 was inefficient as desired, for the NFL TD as well as NFL TD CC (disulfide link stabilized) trimers, indicating that these trimers were probably in the desired, closed conformation.
Guenaga2015a
(antibody interactions, assay or method development, vaccine antigen design, structure)
-
F105: Most published structures of bnAbs, yet none of non- or poorly-neutralizing mAbs, were structurally compatible with a newly generated crystal structure of a mature ligand-free endoglycosidase H-treated BG505 SOSIP.664 Env trimer. Robust binding of the structurally incompatible V3- and CD4-bs targeting nAbs could be induced with CD4. A “DS” variant of BG505 SOSIP.664, containing a stabilizing disulfide bond between 201C and 433C mutations, was developed and appeared to represent an obligate intermediate in that it only bound a single CD4 and remained in a prefusion closed conformation. CD4bs-targeting mAb F105 was author-defined as ineffective due to its neutralization breadth of 7.65% on a panel of 170 diverse HIV-1 pseudoviruses. This was consistent with structural modeling which suggested that F105 was incompatible with BG505 SOSIP.664 when considering antibody-antigen-volume overlap yet compatible when considering epitope r.m.s deviation. Some mutations that stabilized the closed prefusion state of BG505 SOSIP.664 increased F105 binding modestly to moderately, compared to the lack of binding seen with wildtype SOSIP.664. Soluble CD4 did not have an effect on F105 binding of Env trimers.
Kwon2015
(neutralization, vaccine antigen design, structure)
-
F105: Cryo-electron microscopy (EM) of the cleaved, soluble SOSIP gp140 trimer complexed with CD4bs-binding bnAb PGV04 was studied at 5.8Å, facilitating study of Env V1/V2, V3, HR1 and HR2 domains and some shielding glycans. This provides further information on trimer assembly, gp120-gp41 interactions and the three-dimensional CD4bs epitope cluster. For instance, bnAb F105, like b13, does not neutralize the BG505 virus or bind trimer BG505 SOSIP.664 - it has extensive clashes with V1/V2 (same protomer), glycans, and V3 from the adjacent protomer, which differs from another CD4bs bnAbs that also does not neutralize BG505, b12, but which has minimal clashing with these regions of the Env trimer.
Lyumkis2013
(vaccine antigen design, structure)
-
F105: Native, well-ordered, soluble mimetics of the Env trimer from subtypes B (JRFL) and C (16055) were obtained from genetically identical samples of heterogeneous mixture of disordered Env SOSIPs. Negative selection by non-nAbs was used to remove disordered oligomers, leaving well-ordered trimers that were able to bind sCD4, a panel of bnAbs that bind CD4bs, and PGT15 which is a bnAb that binds only cleavage-dependent, well-ordered, Env trimer. Several biophysical techniques were used to interrogate the structure of the purified subtype B and C trimers. Trimer antigenicity was assessed by bio-layer interferometry against F105-like non-neutralizing Abs, and some bnAbs in solution. CD4bs-binding, non-nAb F105 inefficiently recognized the negatively selected trimers.
Guenaga2015
(vaccine antigen design, subtype comparisons, structure)
-
F105: REVIEW: This review discusses isotype switching. Several anti-HIV mAbs are mentioned as having isotype switch variants: F105, F425 B4e8, F240, 2F5, and PGT121.
Janda2016
(isotype switch, review)
-
F105: This study examined whether HIV-1-specific bnAbs are capable of cross-neutralizing simian immunodeficiency viruses (SIVs) from chimpanzees (n=11) or western gorillas (n=1). BnAbs directed against the epitopes at the CD4 binding site (VRC01, VRC03, VRC-PG04, VRC-CH03, VRC-CH31, F105, b13, NIH45-46G54W, 45-46m2, 45-46m7), V3 (10-1074, PGT121, PGT128, PGT135, and 2G12), and gp41-gp120 interface (8ANC195, 35O22, PGT151, PGT152, PGT158) failed to neutralize SIVcpz and SIVgor strains. V2-directed bNabs (PG9, PG16, PGT145) as well as llama-derived heavy-chain only antibodies recognizing the CD4 binding site or gp41 epitopes (JM4, J3, 3E3, 2E7, 11F1F, Bi-2H10) were either completely inactive or neutralized only a fraction of SIVcpz strains. In contrast, neutralization of SIVcpz and SIVgor strains was achieved with low-nanomolar potency by one antibody targeting the MPER region of gp41 (10E8), as well as functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Igmim2, CD4-218.3-E51, CD4-218.3-E51-mim2), mono- and bispecific anti-human CD4 mAbs (iMab, PG9-iMab, PG16-iMab, LM52, LM52-PGT128), and CCR5 receptor mAbs (PRO140, PRO140-10E8). Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5, and neutralized SIVcpz in chimpanzee CD4+ T cells. These findings provide new insight into the protective capacity of anti-HIV-1 bnAbs and identify candidates for further development to combat SIV infection.
Barbian2015
(neutralization, SIV, binding affinity)
-
F105: To understand early bnAb responses, 51 HIV-1 clade C infected infants were assayed for neutralization of a 12-virus multi-clade panel. Plasma bnAbs targeting V2-apex on Env were predominant in infant elite and broad neutralizers. In infant elite neutralizers, multi-variant infection was associated with plasma bnAbs targeting diverse autologous viruses. A panel of mAbs (PG9, PG16, PGT145, PGDM1400, VRC26.25, 10-1074, BG18, AIIMS-P01, PGT121, PGT128, PGT135, VRC01, N6, 3BNC117, PGT151, 35O22, 10E8, 4E10, F105, 17b, A32, 48d, b6, 447-52d) was assayed for their ability to neutralize Env clones from infant elite neutralizers; circulating viral variants in infant elite neutralizers were most susceptible to V2-apex bnAbs.
Mishra2020a
(neutralization, polyclonal antibodies)
-
F105: Soluble versions of HIV-1 Env trimers (sgp140 SOSIP.664) stabilized by a gp120-gp41 disulfide bond and a change (I559P) in gp41 have been structurally characterized. Cross-linking/mass spectrometry to evaluate the conformations of functional membrane Env and sgp140 SOSIP.664 has been reported. Differences were detected in the gp120 trimer association domain and C terminus and in the gp41 HR1 region which can guide the improvement of Env glycoprotein preparations and potentially increase their effectiveness as a vaccine. The CD4bs Ab F105 exhibited poor neutralization against HIV-1AD8 full-length and cytoplasmic tail-deleted Envs.
Castillo-Menendez2019
(vaccine antigen design, structure)
-
F105: Two conserved tyrosine (Y) residues within the V2 loop of gp120, Y173 and Y177, were mutated individually or in combination, to either phenylalanine (F) or alanine (A) in several strains of diverse subtypes. In general, these mutations increased neutralization sensitivity, with a greater impact of Y177 over Y173 single mutations, of double over single mutations, and of A over F substitutions. The Y173A Y177A double mutation in HIV-1 BaL increased sensitivity to most of the weakly neutralizing MAbs tested (2158, 447-D, 268-D, B4e8, D19, 17b, 48d, 412d) and even rendered the virus sensitive to non-neutralizing antibodies against the CD4 binding site (F105, 654-30D, and b13). In the case of V2 mAb 697-30D, residue Y173 is part of its epitope, and thus abrogates its binding and has no effect on neutralization; the Y177A mutant alone did increase neutralization sensitivity to this mAb. When the double mutant was tested against bnAbs, there was a large decrease in neutralization sensitivity compared to WT for many bnAbs that target V1, V2, or V3 (PG9, PG16, VRC26.08, VRC38, PGT121, PGT122, PGT123, PGT126, PGT128, PGT130, PGT135, VRC24, CH103). The double mutation had lesser or no effect on neutralization by one V3 bnAb (2G12) and by most bnAbs targeting the CD4 binding site (VRC01, VRC07, VRC03, VRC-PG04, VRC-CH31, 12A12, 3BNC117, N6), the gp120-gp41 interface (35O22, PGT151), or the MPER (2F5, 4E10, 10E8).
Guzzo2018
(antibody binding site, neutralization)
-
F105: The influence of a V2 State 2/3-stabilizing Env mutation, L193A, on ADCC responses mediated by sera from HIV-1-infected individuals was evaluated. Conformations spontaneously sampled by the Env trimer at the surface of infected cells had a significant impact on ADCC. State 2/3 preferring ligand F105 recognized L193A variants of CH58 and CH77 IMCs with a significant increase compared to the WT.
Prevost2018
(effector function)
-
F105: A systems glycobiology approach was applied to reverse engineer the relationship between bNAb binding and glycan effects on Env proteins. Glycan occupancy was interrogated across every potential N-glycan site in 94 recombinant gp120 antigens. Using a Bayesian machine learning algorithm, bNAb-specific glycan footprints were identified and used to design antigens that selectively alter bNAb antigenicity. The novel synthesized antigens unsuccessfully bound to target bNAbs with enhanced and selective antigenicity.
Yu2018
(glycosylation, vaccine antigen design)
-
F105: The first cryo-EM structure of a cross-linked vaccine antigen was solved. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a bNAb PGV04 Fab fragment revealed how cross-linking affects key properties of the trimer. SOSIP and GLA-SOSIP trimers were compared for antigenicity by ELISA, using a large panel of mAbs previously determined to react with BG505 Env. Non-NAbs globally lost reactivity (7-fold median loss of binding), likely because of covalent stabilization of the cross-linked ‘closed’ form of the GLA-SOSIP trimer that binds non-nAbs weakly or not at all. V3-specific non-NAbs showed 2.1–3.3-fold reduced binding. Three autologous rabbit monoclonal NAbs to the N241/N289 ‘glycan-hole’ surface, showed a median ˜1.5-fold reduction in binding. V3 non-nAb 4025 showed residual binding to the GLA-SOSIP trimer. By contrast, bNAbs like F105 broadly retained reactivity significantly better than non-NAbs, with exception of PGT145 (3.3-5.3 fold loss of binding in ELISA and SPR).
Schiffner2018
(vaccine antigen design, binding affinity, structure)
-
F105: This study reports host tolerance mechanisms that limit the development of CD4bs and HCDR3-binder bNAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs bNAbs recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice Env + B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env- upon receptor editing. Stepwise immunization initiates CD4bs-bNAb responses, but immune tolerance mechanisms restrict their development. The Val-Phe-Tyr hydrophobic tip of the F105 HCDR3 was reported to interact with the same hydrophobic pocket on gp120 (PDB: 3HI1).
Williams2017a
(glycosylation, structure, antibody lineage, chimeric antibody)
-
F105: To understand HIV neutralization mediated by the MPER, antibodies and viruses were studied from CAP206, a patient known to produce MPER-targeted neutralizing mAbs. 41 human mAbs were isolated from CAP206 at various timepoints after infection, and 4 macaque mAbs were isolated from animals immunized with CAP206 Env proteins. Two rare, naturally-occuring single-residue changes in Env were identified in transmitted/founder viruses (W680G in CAP206 T/F and Y681D in CH505 T/F) that made the viruses less resistant to neutralization. The results point to the role of the MPER in mediating the closed trimer state, and hence the neutralization resistance of HIV. CH58 was one of several mAbs tested for neutralization of transmitted founder viruses isolated from clade C infected individuals CAP206 and CH505, compared to T/F viruses containing MPER mutations that confer enhanced neutralization sensitivity.
Bradley2016a
(neutralization)
-
F105: This study performed cyclical permutation of the V1 loop of JRFL in order to develop better gp120 trimers to elicit neutralizing antibodies. Some mutated trimers showed improved binding to several mAbs, including VRC01, VRC03, VRC-PG04, PGT128, PGT145, PGDM1400, b6, and F105. Guinea pigs immunized with prospective trimers showed improved neutralization of a panel of HIV-1 pseudoviruses.
Kesavardhana2017
(vaccine antigen design, vaccine-induced immune responses)
-
F105: This study investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit NAbs. Rabbits were immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). N197 glycan- and residue 230- removal conferred sensitivity to Trimer VLP sera and DNA trimer sera respectively, showing for the first time that strain-specific holes in the "glycan fence" can allow the development of tier 2 NAbs to native spikes. All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. N197 glycan mutants were tested against F105 showing a loss of tier 2 phenotype. The results are in Table S5.
Crooks2015
(glycosylation, neutralization)
-
F105: Env residue N197 on the BG505-SOSIP trimer was mutated to test the effect of its glycosylation on the binding kinetics of CD4BS and other mAbs. Removal of the glycan had little effect on the overall structure of the molecule. Its removal resulted in increased binding of CD4 and CD4BS antibodies (VRC01, VRC03, V3-3074), but little effect on bNAbs targeting other epitopes (PG9, PG16, PGT145, 17b, A32, 2G12, PGT121, PGT126). Two CD4BS-binding antibodies tested (b12, F105) had insufficient breadth to bind the BG505-SOSIP trimer. Removal of the N197 glycan may allow for the development of better SOSIP immunogens, particularly to elicit CD4BS-specific Abs.
Liang2016
(glycosylation, vaccine antigen design)
-
F105: PGT145 was used to positively isolate a subtype B Env trimer immunogen, B41 SOSIP.664, that exists in two conformations, closed and partially open. bNAbs tested against the trimer were able to neutralize the B41 pseudovirus with a wide range of potencies. Among non-nAbs to CD4bs (b6, F91, F105); to CD4i (17b); to gp41ECTO (F240); and to V3 (447-52D, 39F, CO11, 19b and 14e), none neutralized B41 (IC50 >50µg/ml).
Pugach2015
-
F105: Two clade C recombinant Env glycoprotein trimers, DU422 and ZM197M, with native-like structural and antigenic properties involving epitopes against all known classes of bNAbs, were produced and characterized. These Clade C trimers (10-15% of which are in a partially open form) were more like B41 Clade B trimers which have 50-75% trimers in the partially open configuration than like B505 Clade B trimers, almost 100% in the closed, prefusion state. The Clade C trimers have no affinity for the CD4bs non-nAb, F105, and F105 was unable to neutralize the equivalent pseudotyped viruses for either trimer.
Julien2015
(assay or method development, structure)
-
F105: Env trimer BG505 SOSIP.664 as well as the clade B trimer B41 SOSIP.664 were stabilized using a bifunctional aldehyde (glutaraldehye, GLA) or a heterobifunctional cross-linker, EDC/NHS with modest effects on antigenicity and barely any on biochemistry or structural morphology. ELISA, DSC and SPR were used to test recognition of the trimers by bNAbs, which was preserved and by weakly NAbs or non-NAbs, which was reduced. Cross-linking partially preserves quaternary morphology so that affinity chromatography by positive selection using quaternary epitope-specific bNAabs, and negative selection using non-nAbs, enriched antigenic characteristics of the trimers. Anti-CD4bs epitope, non-nAb F105 showed reduced binding to cross-linked trimers.
Schiffner2016
(assay or method development, binding affinity, structure)
-
F105: A new trimeric immunogen, BG505 SOSIP.664 gp140, was developed that bound and activated most known neutralizing antibodies but generally did not bind antibodies lacking neuralizing activity. This highly stable immunogen mimics the Env spike of subtype A transmitted/founder (T/F) HIV-1 strain, BG505. Anti-CD4bs non-nAb F105 did not neutralize BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, and did not recognize or bind the immunogen either.
Sanders2013
(assay or method development, neutralization, binding affinity)
-
F105: This study examined the development and co-evolution of autologous antibodies and viruses in two patients. Antibodies with limited heterologous breadth were able to potently neutralize autologous viruses, and such antibodies could select for neutralization-resistant autologous viruses implicated in transmission. Viruses from subject CH0457 were largely susceptible to neutralization by CD4bs-binding heterologous nAbs CH31 and CH106. The CD4bs CH27 lineage mAbs from subject CH0457 were similar to HJ16, which neutralizes multiple tier 2 but not tier 1 viruses. Narrow neutralizing CD4bs mAb F105 weakly neturalized 2.8% of an 84-psuedoviral panel amplified from CH0457.
Moody2015
(neutralization)
-
F105: CD4-binding site Abs are reviewed. New insights from donor-serum responses, atomic-level structures of antibody-Env complexes, and next-generation sequencing of B-cell transcripts are invigorating vaccine-design efforts to elicit effective CD4-binding site Abs. Analysis of the epitopes recognized by CD4-binding Abs reveals substantial similarity in the recognized region of gp120. The non-potent F105 induces conformations of the bridging sheet which is incompatible with the functional viral spike.
Georgiev2013a
(review)
-
F105: A computational method to predict Ab epitopes at the residue level, based on structure and neutralization panels of diverse viral strains has been described. This method was evaluated using 19 Env-Abs, including F105, against 181 diverse HIV-1 strains with available Ab-Ag complex structures
Chuang2013
(computational prediction)
-
F105: The complexity of the epitopes recognized by ADCC responses in HIV-1 infected individuals and candidate vaccine recipients is discussed in this review. F105 is discussed as the CD4bs-targeting, neutralizing anti-gp120 mAb exhibiting ADCC activity and having a discontinuous epitope.
Pollara2013
(effector function, review)
-
F105: Systematic computational analyses of gp120 plasticity and conformational transition in complexes with CD4 binding fragments, mimetic proteins and Ab fragments are described to explain the molecular mechanisms by which gp120 interacts with the CD4bs at local and subdomain levels. An isotopic elastic network analysis, a full atomic normal mode analysis and simulation of conformational transitions were used to compare the gp120 structures in CD4 bound and F105 Ab-bound states.
Korkut2012
(structure)
-
F105: Isolation of VRC06 and VRC06b mAbs from a slow progressor donor 45 is reported. This is the same donor from whom bNmAbs VRC01, VRC03 and NIH 45-46 were isolated and the new mAbs are clonal variants of VRC03. F105 was used as a CD4bs mAb to compare neutralizing specificity of VRC06.
Li2012
-
F105: Somatic hypermutations are preferably found in CDR loops, which alter the Ab combining sites, but not the overall structure of the variable domain. FWR of CDR are usually resistant to and less tolerant of mutations. This study reports that most bnAbs require somatic mutations in the FWRs which provide flexibility, increasing Ab breadth and potency. To determine the consequence of FWR mutations the framework residues were reverted to the Ab's germline counterpart (FWR-GL) and binding and neutralizing properties were then evaluated. Fig S4C described the comparison of Ab framework amino acid replacement vs. interactive surface area on F105.
Klein2013
(neutralization, structure, antibody lineage)
-
F105: Intrinsic reactivity of HIV-1, a new property regulating the level of both entry and sensitivity to Abs has been reported. This activity dictates the level of responsiveness of Env protein to co-receptor, CD4 engagement and Abs. HIV-1 has developed steric constraints on the Abs binding to CD4BS. Role of F105 has been discussed as a CD4BS binding Ab. The sensitivity of HIV-1 to F105 was enhanced by the altered gp41, J1Hx(66, 197).
Haim2011
(antibody interactions)
-
F105: This study reports the isolation of a panel of Env vaccine elicited CD4bs-directed macaque mAbs and genetic and functional features that distinguish these Abs from CD4bs mAbs produced during chronic HIV-1 infection. F105 was used as a Non-bNAb which was similar in function to non human primates mAbs.
Sundling2012
(vaccine-induced immune responses)
-
F105: Crystal structures of unliganded core gp120 from HIV-1 clade B, C, and E were determined to understand the mechanism of CD4 binding capacity of unliganded HIV-1. The results suggest that the CD4 bound conformation represents "a ground state" for the gp120 core with variable loop. F105 was used as a control to prove whether the purified and crystallized gp120 is in the CD4 bound conformational state or not.
Kwon2012
(structure)
-
F105:The rational design of vaccines to elicit broadly neutralizing antibodies to HIV-1 is discussed in relation to understanding of vaccine recognition sites, the structural basis of interaction with HIV-1 env and vaccine developmental pathways. F105 has been mentioned to describe the sites of HIV-1 vulnerability to neutralizing antibody.
Kwong2011
(antibody binding site, neutralization, vaccine antigen design, review)
-
F105: A panel of glycan deletion mutants was created by point mutation into HIV gp160, showing that glycans are important targets on HIV-1 glycoproteins for broad neutralizing responses in vivo. Enrichment of high mannose N-linked glycan(HM-glycan) of HIV-1 glycoprotein enhanced neutralizing activity of sera from 8/9 patients. F105 was used as a control to compare the neutralizing activity of patients' sera.
Lavine2012
(neutralization)
-
F105: In order to increase recognition of CD4 by Env and to elicit stronger neutralizing antibodies against it, two Env probes were produced and tested - monomeric Env was stabilized by pocket filling mutations in the CD4bs (PF2) and trimeric Env was formed by appending trimerization motifs to soluble gp120/gp14. PF2-containing proteins were better recognized by bNMAb against CD4bs and more rapidly elicited neutralizing antibodies against the CD4bs. Trimeric Env, however, elicited a higher neutralization potency that mapped to the V3 region of gp120.
Feng2012
(neutralization)
-
F105: The sera of 113 HIV-1 seroconverters from three cohorts were analyzed for binding to a set of well-characterized gp120 core and resurfaced stabilized core (RSC3) protein probes, and their cognate CD4bs knockout mutants. F105 bound very strongly to the gp120 core but did not bind to the gp120 core D368R, RSC3, RSC3/G367R, RSC3 Δ3711, and RSC3 Δ3711/P363N.
Lynch2012
(binding affinity)
-
F105: The strategy of incorporating extra glycans onto gp120 was explored, with the goal to occlude the epitopes of non-neutralizing mAbs while maintaining exposure of the b12 site. The focus was on the head-to-head comparison of the ability of 2 adjuvants, monophosphoryl lipid A (MPL) and Quil A, to promote CD4-specific Ab responses in mice immunized with the engineered mutant Q105N compared to gp120wt. Neutralizing and non-neutralizing antibodies targeting three areas on gp120 – the CD4bs (F105, b6, b12, b13, VRC01, VRC03 and CD4- IgG2), the glycosylated ‘silent face’ (2G12) and the V3 loop (B4e8) – were assessed for binding. The antibodies b6, b12, b13, VRC01 and 2G12 bound best to mutant Q105N, albeit with lower affinities than to gp120wt. Retention of b6 and b13 binding was not expected, but can be explained by their very similar mode of interaction with the CD4bs compared to b12. Abs F105 and VRC03 did not bind Q105N at all. The V3-specific antibody B4e8 did not bind to Q105N.
Ahmed2012
(adjuvant comparison, antibody binding site, glycosylation, neutralization, escape)
-
F105: gp120 was cyclically permuted and new N- and C-termini were created within the V1, V3, and V4 loop regions to reduce the length of the linker joining gp120 and M9. The cyclic permutant V1cyc were used to incorporate the trimerization domains. In contrast to monomeric gp120, h-CMP-V1cyc (a covalently linked trimer) interacted with similar affinities to both b12 and F105. SUMO2a-V1cyc (a mixture of a trimer, a dimer, and a monomer) binds approximately 5-10-fold weaker than gp120 to b12 and F105. Monomeric and both trimeric versions of V1cyc bound less well to F105 than wt-gp120. It has been shown that V1 cyclic permutants of gp120 with an appropriate trimerization domain can fold into a conformation that shows poorer affinity for F105 relative to gp120.
Saha2012
(binding affinity)
-
F105: Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies was studied by isolation of VRC01-like neutralizers with CD4bs probe; structural definition of gp120 recognition by RSC3-identified antibodies from different donors; functional complementation of heavy and light chains among VRC01-like antibodies; identification of VRC01 antibodies by 454 pyrosequencing; and cross-donor phylogenetic analysis of sequences derived from the same precursor germline gene. F105 had 37-69% sequence identity of its heavy and light chains to respective chains of VRC-PG04 and VRC-CH31.
Wu2011
(structure)
-
F105: A strategy is described for eliciting antibodies in mice against selected cryptic, conformationally dependent conserved epitopes of gp120 by immunizing with multiple identical copies of covalently linked multiple copy peptides (MCPs) representing 3 different domains of gp120. MAb F105 bound to oligomeric gp120 on cells infected with viruses from clade B with similar affinity as mAb 11A8 but with a very low affinity from clade A and D.
Kelker2010
(binding affinity)
-
F105: Crystal structures of gp120 and gp41 in complex with CD4 and/or mAbs 17b, 48d, b12, b13, 412d, X5, 211C, C11, 15e, m6, m9 and F105 were used to determine the structure and the mobility of the gp41-interactive region of gp120. Elements determined to maintain the gp120-gp41 interaction were the gp120 termini and a newly described invariant 7-stranded β-sandwich. Structurally plastic elements of gp120 responsible for the various gp120 conformation changes due to receptor- or Ab-binding were structured into 3 layers, with the V1/V2 loops emanating from layer 2 and the highly glycosylated outer domain from layer 3.
Pancera2010a
(antibody binding site)
-
F105: A mathematical framework is designed to determine the number of Abs required to neutralize a single trimer called the stoichiometry of trimer neutralization (N). 15 different virus antibody combinations divided into five groups based on antibody binding sites were used in the designed model. F105 was classified into CD4BS group as it interferes with CD4 binding site. The number of F105 Abs needed to neutralize a single trimer was determined to equal 1.
Magnus2010
-
F105: Unlike the MPER mAbs tested, F105 did not show any Env-independent virus capture. MAb competition assays revealed that F105 did not compete with b12 or b6 for virion capture.
Leaman2010
-
F105: Impact of in vivo Env-CD4 interactions was studied during vaccinations of Rhesus macaques with two Env trimer variants rendered CD4 binding defective (368D/R and 423/425/431 trimers) and wild-type (WT) trimers. Ab binding profiles of the three trimer variants were assessed by binding analyses to different MAbs. CD4bs-directed mAb F105 bound similarly to WT and 423/425/431 trimers but did not bind to 368D/R trimers.
Douagi2010
(binding affinity)
-
F105: Expression of gp120 was shown to lead to the accumulation of both monomeric gp120 and aberrant dimeric gp120 forms. Dimeric forms of gp120 were recognized by CD4BS mAbs, such as F105, but were not recognized by CD4i MAbs or MAbs to the gp120 inner domain. It is suggested that gp120 dimerization occludes or disrupts the inner domain and/or the co-receptor binding site. Formation of gp120 dimers was reduced by removal of the V1/V2 loops or the N and C termini.
Finzi2010
(antibody binding site)
-
F105: Crystal structure of the D7 llama heavy chain antibody fragment V(HH) was resolved and compared to other CD4bs Abs (b12, b13, F105 and m18). Unlike for F105, CDR2 of D7 did not have aromatic residues at the tip and does not play a prominent role in gp120 interactions. As F105 and the other CD4bs Abs, D7 had aromatic residues at the tip of its CDR3. Other than that, there was no significant structural homology between D7 and other CD4bs Ab loops, underlining the differences in mode of gp120 interaction.
Hinz2010
(structure)
-
F105: A set of Env variants with deletions in V1/V2 was constructed. Replication competent Env variants with V1/V2 deletions were obtained using virus evolution of V1/V2 deleted variants. Sensitivity of the evolved ΔV1V2 viruses was evaluated to study accessibility of their neutralization epitopes. F105 bound better to the ΔV1V2 variants than to the full-length trimer, indicating better exposure of F105 epitope when the V1V2 domain is removed.
Bontjer2010
(binding affinity)
-
F105: An outer domain (ODec) based immunogen including the whole outer domain and most of the CD4 binding residues was designed and expressed in E-coli bacterial cells. The ODec lacked V1V2 and V3, incorporated 11 designed mutations at the interface of the inner and outer domains of gp120, and was unglycosylated. F105 bound to monomeric gp120 but did not bind to ODec. Structural analyses showed that 5/10 residues required for F105 binding were absent in the ODec construct. Sera from rabbits immunized with ODec neutralized 4/5 clade B and 1/2 clade C viruses.
Bhattacharyya2010
(kinetics, binding affinity)
-
F105: The crystal structure for VRC01 in complex with an HIV-1 gp120 core from a clade A/E recombinant strain was analyzed to understand the structural basis for its neutralization breadth and potency. F105 bound with high affinity to non-CD4-bound gp120 but not to CD4-bound conformation. F105 covered 79% of the contact site for CD4 receptor on gp120, its heavy chain contacting CDR1, CDR2 and CDR3 regions. The number of mutations from the germline and the number of mutated contact residues for F105 were smaller than those for VRC01. Unlike VRC01, variation of V5 conformation of gp120 with F105 spanned over the whole range of V5.
Zhou2010
(antibody binding site, neutralization, binding affinity, structure)
-
F105: Resurfaced stabilized core 3 (RSC3) protein was designed to preserve the antigenic structure of the gp120 CD4bs neutralizing surface but eliminate other antigenic regions of HIV-1. RSC3 did not show binding to F105. Memory B cells were selected that bound to RSC3 and full IgG mAbs were expressed. Three newly detected mAbs (VRC1, VRC2 and VRC3) competed with F105 for binding to gp120. Addition of RSC3 had no effect on F105 neutralization of HXB2.
Wu2010
(antibody interactions, neutralization, binding affinity)
-
F105: OD (GSL)(δβ20-21)(hCD4-TM) glycoprotein variant was constructed by eliminating V1 and V2 regions, truncating V3, and deleting cleavage, fusion, and interhelical domains from Env derivatives from R3A TA1 virus. In addition, the variant was membrane-anchored, the β20-β21 hairpin was truncated, and the central 20 amino acids of the V3 loop were replaced with a basic hexapeptide. Although this variant showed increased binding to b12 and 2G12, it did not bind to F105.
Wu2009a
(binding affinity)
-
F105: A panel of clade B and C viruses from early infections was used to analyze F105 neutralization resistance. Removal of a glycan at position 301 at the base of the V3 loop rendered PVO.4 strain sensitive to neutralization by F105. In addition, point mutations T569A and I675V in the gp41 region increased viral neutralization sensitivity to F105, indicating their effect on viral spike accessibility.
Wu2009
(glycosylation, neutralization)
-
F105: The Ig usage for variable heavy chain of this Ab was as follows: IGHV:4-59*01, IGHD:4-17, D-RF:2, IGHJ:5. Non-V3 mAbs preferentially used the VH1-69 gene segment. In contrast to V3 mAbs, these non-V3 mAbs used several VH4 gene segments and the D3-9 gene segment. Similarly to the V3 mAbs, the non-V3 mAbs used the VH3 gene family in a reduced manner.
Gorny2009
(antibody sequence)
-
F105: The Fab' fragment of F105 was linked to sterically stabilized pegylated liposomes containing a protease inhibitor. The complex was specifically taken up by HIV-1 infected cells, indicating preservation of F105 specific binding after conjugation and incorporation into liposomes. The inhibitor that was derived intracellularly by F105-liposome complex showed greater and longer antiviral activity than the free drug, indicating that F105 can be used in targeted delivery of antiretroviral compounds.
Clayton2009
(HAART, ART)
-
F105: IgG and Fab F105 neutralized Tier 1 viruses but not Tier 2 viruses. Crystal structure of F105 in complex with gp120 revealed small differences in recognition of gp120 by F105 compared to CD4, where all four strands of the bridging sheet were displaced to uncover a hydrophobic region which served for F105 binding. A monomeric disulfide gp120 variant was not bound by F105, suggesting that F105 relies on access to the hydrophobic surface for binding. Structure analyses revealed that F105, and other CD4BS Abs that access this hydrophobic region, induce conformation changes in gp120 that are poorly compatible with functional viral spike. F105 was not able to bind to cleavage-defective envelope glycoproteins.
Chen2009
(antibody binding site, neutralization, kinetics, binding affinity, structure)
-
F105: F105 neutralized infection of PBLs with various HIV-1 strains. However, F105 did not inhibit transcytosis of cell-free or cell-associated virus across a monolayer of epithelial cells, in contrast, it somewhat increased the passage of cell-free HIV-1 through the epithelial cells. A mixture of 13 mAbs directed to well-defined epitopes of the HIV-1 envelope, including F105, did not inhibit HIV-1 transcytosis, indicating that envelope epitopes involved in neutralization are not involved in mediating HIV-1 transcytosis. When the mixture of 13 mAbs and HIV-1 was incubated with polyclonal anti-human γ chain, the transcytosis was partially inhibited, indicating that agglutination of viral particles at the apical surface of cells may be critical for HIV transcytosis inhibition by HIV-specific Abs.
Chomont2008
(enhancing activity, neutralization)
-
F105: 5 loop structures surrounding the CD4 binding site in the gp120 liganded conformation were identified that may protect gp120 from Abs. Loops A, B, C and E were located in the C2, C3, C4 and C5 regions respectively, and loop D was situated in the V5 region. F105 MAb bound gp120 of the IIIB wild type virus 8- to 16-fold better than gp120 of the 89.6 wild type. Deletion of loop C resulted in greater than 100-fold increase in F105 binding to 89.6 gp120. Deletions of loops A, D or three amino acids in loop E resulted in gp120 mutants that failed to bind F105.
Berkower2008
(antibody binding site, binding affinity)
-
F105: A chimeric protein entry inhibitor, L5, was designed consisting of an allosteric peptide inhibitor 12p1 and a carbohydrate-binding protein cyanovirin (CNV) connected via a flexible linker. The L5 chimera inhibited F105-gp120 interaction, but the CNV alone did not, indicating that the chimera has the high affinity binding property of the CNV molecule and the inhibitory property of the 12p1 peptide.
McFadden2007
-
F105: This review provides information on the HIV-1 glycoprotein properties that make it challenging to target with neutralizing Abs. F105 neutralization properties and binding to HIV-1 envelope, and current strategies to develop versions of the Env spike with functional trimer properties for elicitation of broadly neutralizing Abs, are discussed. In addition, approaches to target cellular molecules, such as CD4, CCR5, CXCR4, and MHC molecules, with therapeutic Abs are reviewed.
Phogat2007
(review)
-
F105: F105 structure, binding and neutralization are reviewed in detail. Molecules designed to eliminate binding by F105 while preserving epitopes of other neutralizing Abs are discussed.
Lin2007
(review, structure)
-
F105: This review summarizes F105 Ab epitope, properties and neutralization activity. F105 use in passive immunization studies in primates and possible mechanisms explaining protection against infection are discussed.
Kramer2007
(immunotherapy, review)
-
F105: gp120 proteins with double mutation T257S+S375W, which alters the cavity at the epicenter of the CD4 binding region, decreased F105 recognition to an undetectable level. The S375W single mutation also disrupted the binding surface of the F105 Ab.
Dey2007a
(binding affinity)
-
F105: A significantly higher level of anti-V3 Ab (694/98D) and anti-C1 mAb (EH21) bound to gp120 complexed with F105 mAb than to gp120 alone or in complex with other non-CD4bs Abs, indicating that binding of F105 to gp120 increases exposure of specific V3 and C1 mAb epitopes.
Visciano2008
-
F105: A series of peptide conjugates were constructed via click reaction of both aryl and alkyl acetylenes with an internally incorporated azidoproline 6 derived from parent peptide RINNIPWSEAMM. Many of these conjugates exhibited increase in both affinity for gp120 and inhibition potencies at both the CD4 and coreceptor binding sites. All high affinity peptides inhibited the interactions of YU2 gp120 with F105 Ab. The aromatic, hydrophobic, and steric features in the residue 6 side-chain were found important for the increased affinity and inhibition of the high-affinity peptides.
Gopi2008
-
F105: F105 was tested for its ability to induce conformational changes similar to those induced by CD4. Although presence of sCD4 increased neutralization of JRFL by 447-52D and immune sera rich in V3-Abs from guinea pigs, the presence of F105 did not, indicating that F105 does not induce a conformation alternation in Env that exposes the V3 loop to neutralizing Abs.
Wu2008
-
F105: Neutralization of HIV-1 IIIB LAV isolate by F105 was within the same range as the neutralization of the virus by natural antibodies from human sera against the gal(α1,3)gal disaccaride linked to CD4 gp120-binding peptides, indicating that the activity of natural antibodies can be re-directed to neutralize HIV-1.
Perdomo2008
(neutralization)
-
F105: Two HIV-1 isolates, NL4-3 and KB9, were adapted to replicate in cells using the common marmoset receptors CD4 and CXCR4. The adaptation resulted in a small number of changes of env sequences in both isolates. The adapted NL4-3 variants were generally more sensitive to neutralization by F105 than the adapted KB9 variants. All of the NL4-3 exhibited similar sensitivity to neutralization by F105 except for the viruses containing the V242I change, which exhibited a slight increase in neutralization sensitivity to F105. Wildtype KB9 is resistant to neutralization by F105 but the changes associated with adaptation to marmoset receptors resulted in variants with increased sensitivity to neutralization by F105. Thus, adaptation to marmoset receptors resulted in an increase in sensitivity to neutralization by F105 for KB9 but not for NL4-3.
Pacheco2008
(neutralization)
-
F105: A new purification method was developed using a high affinity peptide mimicking CD4 as a ligand in affinity chromatography. This allowed the separation in one step of HIV envelope monomer from cell supernatant and capture of pre-purified trimer. Binding of F105 to gp120SF162 purified by the miniCD4 affinity chromatography and a multi-step method was comparable, suggesting that the miniCD4 allows the separation of HIV-1 envelope with an intact F105 epitope. gp140DF162ΔV2 was purified by the miniCD4 method to assess its ability to capture gp140 trimers. Binding of F105 to gp140DF162ΔV2 purified by the miniCD4 affinity chromatography and a multi-step method was comparable, suggesting that the SF162 trimer antigenicity was preserved.
Martin2008
(assay or method development, binding affinity)
-
F105: 32 human HIV-1 positive sera neutralized most viruses from clades A, B, and C. Two of the sera stood out as particularly potent and broadly reactive. IgG eluted from gp120 wildtype and core protein from the sera were reabsorbed with the gp120-D368R mutant protein to remove non-CD4-binding site Abs. Binding of the resulting flow-through core eluate/368ft IgG to gp120 was completely blocked by Fab F105. Fab F105 also blocked most of the binding of the gp120WT eluate/368ft IgG, indicating that these Ab fractions were highly enriched with CD4-binding site Abs.
Li2007a
(neutralization)
-
F105: A recombinant gp120-Fc, used in an assay to determine 2G12 epitope contribution to DC-SIGN binding to gp120, bound to F105, indicating it was conformationally intact.
Hong2007
(binding affinity)
-
F105: A D386N change in the V4 region, which results in restoration of N-glycosylation at this site, did not have any impact on the neutralization of a mutant virus by F105 compared to wildtype. Also, there was no association between increased sensitivity to F105 neutralization and enhanced macrophage tropism.
Dunfee2007
(neutralization)
-
F105: The crystal structure of this Ab was compared to the high resolution crystal structure of Fab m18. Although the variable domains of m18 and F105 showed sequence similarity, the H3s of these Abs showed distinct conformations. Similarly, the H2s conformations of these Abs differed.
Prabakaran2006
(antibody binding site, mimics, antibody sequence, structure)
-
F105: This Ab was used to determine the degree to which fixation of gp120 in its CD4-bound conformation restricts antigenic recognition. F105 was not able to bind well to the stabilized gp120.
Zhou2007
-
F105: F105 bound exclusively to cells expressing gp120 in a co-receptor-independent manner. Although binding and uptake of F105 was increased with increased expression of gp120 on the cell surface, efficient internalization in short amount of time was possible even in cells expressing low levels of gp120. Internalized F105 was localized to the Golgi compartment. Kinetic analyses of F105 binding to gp120 demonstrated a heterogeneous mode of binding that did not trigger a conformational change in the formed complex. Compared to sCD4, F105 had a higher gp120 affinity, due to slower dissociation.
Clayton2007
(co-receptor, kinetics, binding affinity)
-
F105: Compared to the full-length Con-S gp160, chimeric VLPs containing Con-S ΔCFI gp145 with transmembrane (TM) and cytoplasmic tail (CT) sequences derived from the mouse mammary tumor virus (MMTV), showed higher binding capacity to F105. Chimeric VLPs with only CT derived from MMTV also showed higher binding capacity to F105 than the full-length Con-S gp160, however, not as high as the chimeric CT-TM VLPs.
Wang2007a
(binding affinity)
-
F105: This Ab was used to select phages from two different peptide libraries. Synthetic peptides corresponding to the selected phage sequences showed slight inhibition of F105 binding to gp120. F105 did not bind to synthetic peptides to 5145A MAb fused to phage pIII protein. Sera from rabbits immunized with 5145A peptide-phage pIII protein did not inhibit binding of F105 to gp120.
Wilkinson2007
(antibody polyreactivity)
-
F105: The major infectivity and neutralization differences between a PBMC-derived HIV-1 W61D strain and its T-cell line adapted counterpart were conferred by the interactions of three Env amino acid substitutions, E440G, D457G and H564N. Chimeric Env-pseudotyped virus Ch5, containing all three of the mutations, was more neutralization sensitive to F105 than Ch2, which did not contain any of these mutations. Neutralization sensitivity to F105 by Env-pseudotyped viruses containing D457G mutation alone, or in combination with E440G or H564N, was unaffected compared to mutants lacking this mutation. Binding of F105 to gp120 derived from Env-pseudotyped viruses was unaffected by any of these mutations.
Beddows2005a
(neutralization, binding affinity)
-
F105: All clones derived from biopanning using IgG1b12 bound to this Ab but not to the control Ab F105.
Dorgham2005
(antibody binding site)
-
F105: Point mutations in the highly conserved structural motif LLP-2 within the intracytoplasmic tail of gp41 resulted in conformational alternations of both gp41 and gp120. The alternations did not affect virus CD4 binding, coreceptor binding site exposure, or infectivity of the virus, but did result in decreased binding and neutralization by certain mAbs and human sera. F105 exhibited similar levels of binding to both the LLP-2 mutant and wildtype viruses, indicating that its epitope was not altered by the mutation.
Kalia2005
(antibody binding site, binding affinity)
-
F105: A series of genetically modified Env proteins were generated and expressed in both insect and animal cells to be monitored for their antigenic characteristics. For F105, modified protein 3G (mutations in 3 glycosylation sites) showed the highest binding to this Ab compared to the other Env proteins.
Kang2005
(antibody binding site, binding affinity)
-
F105: A stable trimerization motif, GCN4, was appended to the C terminus of YU2gp120 to obtain stable gp120 trimers (gp120-GCN4). Each trimer subunit was capable of binding IgG1b12, indicating that they were at least 85% active. D457V mutation in the CD4 binding site resulted in a decreased affinity of the gp120-GCN4 for CD4, but the mutation did not affect binding of F105. F105 was able to bind to both wildtype gp120, gp120-GCN4, and to the respective corresponding mutant molecules D457Vgp120 and D457Vgp120-GCN4.
Pancera2005a
(binding affinity)
-
F105: JR-FL and YU2 HIV-1 strains were not neutralized by F105. F105 and other non-neutralizing Abs only recognized JR-FL cleavage-defective glycoproteins, while the neutralizing Abs (2G12 and IgG1b12) recognized both cleavage competent and cleavage-defective glycoproteins. It is suggested that an inefficient env glycoprotein precursor cleavage exposes non-neutralizing determinants, while only neutralizing regions remain accessible on efficiently cleaved spikes. For YU2, both cleavage-competent and -defective glycoproteins were recognized by both neutralizing and non-neutralizing Abs. F105, along with other Abs able to neutralize lab-adapted isolates, displayed enhanced viral entry at higher Ab concentrations, whereas the Abs that cannot neutralize any virus did not display such enhancement.
Pancera2005
(antibody binding site, enhancing activity, neutralization, binding affinity)
-
F105: This review summarizes data on the role of nAb in HIV-1 infection and the mechanisms of Ab protection, data on challenges and strategies to design better immunogens that may induce protective Ab responses, and data on structure and importance of mAb epitopes targeted for immune intervention. The importance of standardized assays and standardized virus panels in neutralization and vaccine studies is also discussed.
Srivastava2005
(antibody binding site, neutralization, vaccine antigen design, immunotherapy, mother-to-infant transmission, review)
-
F105: Ab neutralization of viruses with mixtures of neutralization-sensitive and neutralization-resistant envelope glycoproteins was measured. It was concluded that binding of a single Ab molecule is sufficient to inactivate function of an HIV-1 glycoprotein trimer. The inhibitory effect of the Ab was similar for neutralization-resistant and -sensitive viruses indicating that the major determinant of neutralization potency of an Ab is the efficiency with which it binds to the trimer. It was also indicated that each functional trimer on the virus surface supports HIV-1 entry independently, meaning that every trimer on the viral surface must be bound by an Ab for neutralization of the virus to be achieved.
Yang2005b
(neutralization)
-
F105: A substantial fraction of soluble envelope glycoprotein trimers contained inter-subunit disulfide bonds. Reduction of these disulfide bonds had little effect on binding of the F105 to the glycoprotein indicating that the inter-S-S bonds had no impact on the exposure of F105 epitope.
Yuan2005
(antibody binding site)
-
F105: This review focuses on the importance of neutralizing Abs in protecting against HIV-1 infection, including mechanisms of Ab interference with the viral lifecycle, Ab responses elicited during natural HIV infection, and use of monoclonal and polyclonal Abs in passive immunization. In addition, vaccine design strategies for eliciting of protective broadly neutralizing Abs are discussed. MAbs included in this review are: 2F5, Clone 3 (CL3), 4E10, Z13, IgG1b12, 2G12, m14, 447-52D, 17b, X5, m16, 47e, 412d, E51, CM51, F105, F425, 19b, 2182, DO142-10, 697-D, 448D, 15e and Cβ1.
McCann2005
(antibody binding site, antibody interactions, neutralization, variant cross-reactivity, immunotherapy, review)
-
F105: A chimeric cell surface receptor (105TCR) was designed consisting of the single chain Fv domain of F105, CD8α hinge and the transmembrane, and the cytoplasmic domains of TCRζ. 105TCR was successfully expressed on the surface of T-cells. It mediated full activation of T-cells leading to cytokine production when bound to gp120 on the surface of an infected cell. It did not bind to soluble gp120. Retrovirally transduced CD8+ cells expressed high levels of 105TCR and were able to lyse HIV-1 envelope expressing cells specifically in an MHC-unrestricted manner.
Masiero2005
(immunotherapy)
-
F105: A T-cell line adapted strain (TCLA) of CRF01_AE primary isolate DA5 (PI) was more neutralization sensitive to F105 than the primary isolate. Mutant virus derived from the CRF01_AE PI strain, that lacked N-linked glycosylation at position 197 in the C2 region of gp120, was significantly more sensitive to neutralization by F105 then the PI strain. Deglycosylated subtype B mutants at positions 197 and 234 were significantly more neutralizable by F105 than the parental strain.
Teeraputon2005
(antibody binding site, neutralization, subtype comparisons)
-
F105: Macaques were immunized with SF162gp140, ΔV2gp140, ΔV2ΔV3gp140 and ΔV3gp140 constructs and their antibody responses were compared to the broadly reactive NAb responses in a macaque infected with SHIV SF162P4, and with pooled sera from humans infected with heterologous HIV-1 isolates (HIVIG). F105 bound to SF162gp140 but a deletion of V2 or V3 loops from the gp140 construct reduced the binding.
Derby2006
(antibody binding site)
-
F105: This Ab did not inhibit HIV-1 BaL replication in macrophages or in PHA-stimulated PBMCs.
Holl2006
(neutralization, dendritic cells)
-
F105: The ability of F105 to neutralize R5, R5X4 and X4 primary isolates was compared to that of mAbs 17b, E51 and 412d. F105 neutralized the R5 ADA virus more efficiently than 17b, comparable to 412d, however, it neutralized R5X4 isolate 89.6 less efficiently than 412d and E51. F105 was, on the other hand, more efficient in neutralizing the X4 isolate HXBc2 than the other mAbs.
Choe2003
(neutralization)
-
F105: The crystal structure of the Fab fragment from F105 was solved. It has an extended CDR H3 loop, with a Phe at the apex that may recognize the binding pocket of gp120 used by the Phe-42 residue of CD4. The potent nAb IgG1b12 recognizes an overlapping binding site, the main difference is that F105 extends across the interface of the inner and outer domains of gp120 while b12 does not. IgG1b12 also has undergone extensive affinity maturation (45 mutations) while F105 has not (13 mutations) -- an average for gp120 mAbs is 22 mutations.
Wilkinson2005
(antibody sequence, structure)
-
F105: Antigens were designed to attempt to target immune responses toward the IgG1b12 epitope, while minimizing antibody responses to less desirable epitopes. One construct had a series of substitutions near the CD4 binding site (GDMR), the other had 7 additional glycans (mCHO). The 2 constructs did not elicit b12-like neutralizing antibodies, but both antigens successfully dampened other responses that were intended to be dampened while not obscuring b12 binding. CD4BS mAbs except Fab b12 (b6, b3, F105) did not bind to either GDMR or mCHO.
Selvarajah2005
(vaccine antigen design, vaccine-induced immune responses)
-
F105: The HIV-1 Bori-15 variant was adapted from the Bori isolate for replication microglial cells. Bori-15 had increased replication in microglial cells and a robust syncytium-forming phenotype, ability to use low levels of CD4 for infection, and increased sensitivity to neutralization by sCD4 and 17b. Four amino acid changes in gp120 V1-V2 were responsible for this change. Protein functionality and integrity of soluble, monomeric gp120-molecules derived from parental HIV-1 Bori and microglia-adapted HIV-1 Bori-15 was assessed in ELISA binding assays using CD4BS MAbs F105 and IgG1b12, glycan-specific 2G12, and V3-specific 447-52D, and were unchanged. Association rates of sCD4 and 17b were not changed, but dissociation rates were 3-fold slower for sCD4 and 14-fold slower for 17b.
Martin-Garcia2005
(antibody binding site)
-
F105: By adding N-linked glycosylation sites to gp120, epitope masking of non-neutralizing epitopes can be achieved leaving the IgG1b12 binding site intact. This concept was originally tested with the addition of four glycosylation sites, but binding to b12 was reduced. It was modified here to exclude the C1 N-terminal region, and to include only three additional glycosylation sites. This modified protein retains full b12 binding affinity and it masks other potentially competing epitopes, and does not bind to 21 other mAbs to 7 epitopes on gp120, including F105.
Pantophlet2004
(vaccine antigen design)
-
F105: NAbs against HIV-1 M group isolates were tested for their ability to neutralize 6 randomly selected HIV-1 O group strains. F105 was not particularly effective at neutralizing HIV-1 group O strains.
Ferrantelli2004a
(variant cross-reactivity)
-
F105: The role of serine proteases on HIV infection was explored. Trypsin decreased the binding of most Env mAb tested and diminished cell fusion of H9 cells infected with HIV-1 LAI virus (H9/IIIB) to MAGI cells. In contrast, thrombin increased the binding of mAbs to gp120 epitopes near the CD4 and CCR5 binding sites, and increased cell fusion. Binding of CD4BS mAb F105 was decreased by trypsin, but increased by thrombin. Thrombin may increase HIV-induced cell fusion in blood by causing a conformational activating shift in gp120.
Ling2004
(antibody binding site)
-
F105: A pseudotyping assay showed that an X4 V3 loop peptide could enhance infectivity of X4 virus, R5 and R5X4 V3 loops peptides could enhance infectivity of an R5 virus, and R5X4 peptides could enhance infectivity of an R5X4 virus. Neither R5 nor R5X4 peptides influenced binding of CD4BS mAbs F105 and Ig1Gb12, but did increase binding of CD4i mAb 17b.
Ling2002
(antibody binding site, co-receptor)
-
F105: The peptide 12p1 (RINNIPWSEAMM) inhibits direct binding of YU2 gp120 or Env trimer to CD4, CCR5 and mAb 17b in a concentration-dependent allosteric manner. 12p1 is thought to bind to unbound gp120 near the CD4 binding site, with a 1:1 stoichiometry. 12p1 also inhibited mAb F105 binding; presumably because F105 favors an unactivated conformation, but not mAbs 2G12 or b12. The 1:1 stoichiometry, the fact that the peptide binding site is accessible on the trimer, the non-CD4 like aspect of the binding, and an ability to inhibit viral infection in cell cultures make 12p1 a promising lead for therapeutic design.
Biorn2004
-
F105: This review summarizes mAbs directed to HIV-1 Env. There are 51 CD4BS MAbs and Fabs in the database; most, like this mAb, neutralize TCLA strains only.
Gorny2003
(review)
-
F105: A gp120 molecule was designed to focus the immune response onto the IgG1b12 epitope. Ala substitutions that enhance the binding of IgG1b12 and reduce the binding of non-neutralizing mAbs were combined with additional N-linked glycosylation site sequons inhibiting binding of non-neutralizing mAbs; b12 bound to the mutated gp120. C1 and C5 were also removed, but this compromised b12 binding.
Pantophlet2003b
(vaccine antigen design)
-
F105: scFv 4KG5 reacts with a conformational epitope that is formed by the V1V2 and V3 loops and the bridging sheet (C4) region of gp120 and is influenced by carbohydrates. Of a panel of mAbs tested, only nAb b12 enhanced 4KG5 binding to gp120 JRFL. MAbs to the following regions diminished 4KG5 binding: V2 loop, V3 loop, V3-C4 region, CD4BS. MAbs directed against C1, CD4i, C5 regions didn't impact 4KG5 binding. These results suggest that the orientation or dynamics of the V1/V2 and V3 loops restricts CD4BS access on the envelope spike, and IgG1b12 can uniquely remain unaffected by these loops. This was one of the CD4BS MAbs used.
Zwick2003a
(antibody interactions)
-
F105: Env genes derived from uncultured brain biopsy samples from four HIV-1 infected patients with late-stage AIDS were compared to env genes from PBMC samples. Brain isolates did not differ in the total number or positions of N-glycosylation sites, patterns of coreceptor usage, or ability to be recognized by gp160 and gp41 MAbs. F105 recognized most variants, some from each of the four individuals by gp120 immunoprecipitation.
Ohagen2003
(brain/CSF, variant cross-reactivity)
-
F105: Thermodynamics of binding to gp120 was measured using isothermal titration calorimetry for sCD4, 17b, b12, 48d, F105, 2G12 and C11 to intact YU2 and the HXBc2 core. The free energy of binding was similar. Enthalpy and entropy changes were divergent, but compensated. Not only CD4 but mAb ligands induced thermodynamic changes in gp120 that were independent of whether the core or the full gp120 protein was used. Non-neutralizing CD4BS and CD4i mAbs (17b, 48d, 1.5e, b6, F105 and F91) had large entropy contributions to free energy (mean: 26.1 kcal/mol) of binding to the gp120 monomer, but the potent CD4BS neutralizing MAb b6 had a much smaller value of 5.7 kcal/mol. The high values suggest surface burial or protein folding and ordering of amino acids. These results suggest that while the trimeric Env complex has four surfaces, a non-neutralizing face (occluded on the oligomer), a variable face, a neutralizing face and a silent face (protected by carbohydrate masking), gp120 monomers further protect receptor binding sites by conformational or entropic masking, requiring a large energy handicap for Ab binding not faced by other anti-gp120 Abs.
Kwong2002
(antibody binding site)
-
F105: This paper shows that binding of CD4BS mAbs to Env blocks the conformational shift that allows co-receptor CCR5 binding and CD4-independent mediated cell fusion. CD4BS MAbs F105, 15e, and IgG1b12 as well as their Fab fragments inhibited CD4-independent binding of the V1/V2 loop-deleted gp120 glycoproteins of R5 HIV-1 isolates ADA, YU2 and JR-FL and to CCR5 in a concentration dependent manner. CD4BS MAbs IgG1b12, F91 and F105 and their Fab counterparts (except for C11, used as a negative control) inhibited CD4-independent JR-FL and YU-2 gp120-CCR5 binding to CCR5-expressing Cf2Th cells and syncytium formation.
Raja2003
(antibody binding site, co-receptor)
-
F105: 17b: This paper describes the generation of CD4i MAb E51, that like CD4i mAb 17b, blocks CCR5 binding to sCD4-bound gp120. The substitutions E381R, F383S, R419D I420R, K421D, Q422L, I423S, and Y435S (HXB2 numbering) all severely reduce 17b and E51 binding. All but I423S also diminish CCR5 binding by more than 50%. The mutation F383S also inhibits sCD4 binding and F105 binding, and K421D inhibits F105 binding, but not sCD4.
Xiang2003
(antibody binding site)
-
F105: This study examined Ab interactions, binding and neutralization with a B clade R5 isolate (92US660) and R5X4 isolate (92HT593). Abs generally bound and neutralized the R5X4 isolate better than the R5 isolate. Anti-gp41 mAb F240 enhanced the binding of CD4BS MAbs IgG1b12 and F105 to both R5X4 and R5 isolates, but had no effect on neutralization. Anti-V3 MAb B4a1 increased CD4BS MAbs IgG1b12 and F105 to R5X4 virions, but only IgG1b12 binding was increased by B4a1 to the R5 isolate, and neutralization was not impacted.
Cavacini2002
(co-receptor)
-
F105: NIH AIDS Research and Reference Reagent Program: 857.
-
F105: Alanine scanning mutagenesis was used to compare substitutions that affected anti-CD4BS nAb b12 -- rec gp120s were engineered to contain combinations of Alanine substitutions that enhanced b12 binding, and while binding of b12 to these gp120 monomers was generally maintained or increased, binding by five non-neutralizing anti-CD4bs MAbs (b3, b6, F105, 15e, and F91) was reduced or completely abolished.
Pantophlet2003
(antibody binding site)
-
F105: Virion capture assays are not a good predictor of neutralization, and the presentation of epitopes using this assay seems to be different from that of functional Envelope spikes on primary isolates -- F105 and b6 could efficiently block the b12-mediated capture of infectious virions in a virus capture, but did not inhibit b12 neutralization -- while b12 was potent at neutralizing the three primary virions JR-CSF, ADA, and 89.6, the Abs F105, 19b, and Fab b6 were overall very poor neutralizers.
Poignard2003
(antibody interactions)
-
F105: Review of nAbs that discusses mechanisms of neutralization, passive transfer of nAbs and protection in animal studies, and vaccine strategies.
Liu2002
(immunoprophylaxis, review)
-
F105: Review of nAbs that notes that F105 binds the CD4BS, in combination with other mAbs it can protect some macaques against SHIV infection, and that it has strong ADCC activity.
Ferrantelli2002
(antibody interactions, effector function, immunoprophylaxis, review)
-
F105: A rare mutation in the neutralization sensitive R2-strain in the proximal limb of the V3 region caused Env to become sensitive to neutralization by MAbs directed against the CD4 binding site (CD4BS), CD4-induced (CD4i) epitopes, soluble CD4 (sCD4), and HNS2, a broadly neutralizing sera -- 2/12 anti-V3 mAbs tested (19b and 694/98-D) neutralized R2, as did 2/3 anti-CD4BS MAbs (15e and IgG1b12), 2/2 CD4i mAbs (17b and 4.8D), and 2G12 and 2F5 -- thus multiple epitopes on R2 are functional targets for neutralization and the neutralization sensitivity profile of R2 is intermediate between the highly sensitive MN-TCLA strain and the typically resistant MN-primary strain.
Zhang2002
(antibody binding site)
-
F105: gp120 mutants were used to define the CXCR4 binding site using CXCR4 displayed on paramagnetic proteoliposomes (PMPLs) to reduce non-specific gp120 binding---basic residues in the V3 loop and the β19 strand (RIKQ, positions 419-422) were involved, and deletion of the V1-V2 loops allowed CD4-independent CXCR4 binding---mAbs 17b (CD4i) and F105 (CD4BS) were used to study conformational changes in the mutants---the affinity of ΔV1 and ΔV1-V2 mutants for F105 was comparable to the wildtype---V3 mutants did not affect F105 binding---the K421A mutation in the β19 strand dramatically reduced F105 affinity, consistent with what is known about the F105 epitope.
Basmaciogullar2002
(antibody binding site)
-
F105: HIV-1 gp160δCT (cytoplasmic tail-deleted) proteoliposomes (PLs) containing native, trimeric envelope glycoproteins from R5 strains YU2 and JRFL, and X4 strain HXBc2, were made in a physiologic membrane setting as candidate immunogens for HIV vaccines---2F5 bound to gp160δCT with a reconstituted membrane ten-fold better than the same protein on beads, while such an affinity difference was not seen with F105 and 2G12---anti-CD4BS MAbs IgG1b12 and F105, A32 (C1-C4), C11 (C1-C5), and 39F (V3) mAbs bound gp160δCT PLs indistinguishably from gp160δCT expressed on the cell surface.
Grundner2002
(antibody binding site)
-
F105: A series of mutational changes were introduced into the YU2 gp120 that favored different conformations -- 375 S/W seems to favor a conformation of gp120 closer to the CD4-bound state, and is readily bound by sCD4 and CD4i MAbs (17b, 48d, 49e, 21c and 23e) but binding of anti-CD4BS MAbs (F105, 15e, IgG1b12, 21h and F91 was markedly reduced -- IgG1b12 failed to neutralize this mutant, while neutralization by 2G12 was enhanced -- 2F5 did not neutralize either WT or mutant, probably due to polymorphism in the YU2 epitope -- another mutant, 423 I/P, disrupted the gp120 bridging sheet, favored a different conformation and did not bind CD4, CCR5, or CD4i antibodies, but did bind to CD4BS MAbs.
Xiang2002
(antibody binding site)
-
F105: A modified gp140 (gp140deltaCFI), with C-term mutations intended to mimic a fusion intermediate and stabilize trimer formation, retained antigenic conformational determinants as defined by binding to CD4 and to mAbs 2F5, 2G12, F105, and b12, and enhanced humoral immunity without diminishing the CTL response in mice injected with a DNA vaccine.
Chakrabarti2002
(vaccine antigen design)
-
F105: Passive immunization of neonate macaques with a combination of F105+2G12+2F5 conferred complete protection against oral challenge with SHIV-vpu+ or -- the combination b12+2G12+2F5 conferred partial protection against SHIV89.6 -- such combinations may be useful for prophylaxis at birth and against milk born transmission -- the synergistic combination of IgG1b12, 2G12, 2F5, and 4E10 neutralized a collection of HIV clade C primary isolates.
Xu2002
(immunoprophylaxis, mother-to-infant transmission)
-
F105: Uncleaved soluble gp140 (YU2 strain, R5 primary isolate) can be stabilized in an oligomer by fusion with a C-term trimeric GCN4 motif or using a T4 trimeric motif derived from T4 bacteriophage fibritin---stabilized oligomer gp140δ683(-FT) showed strong preferential recognition by NAbs IgG1b12 and 2G12 relative to the gp120 monomer, in contrast to poorly neutralizing MAbs F105, F91, 17b, 48d, and 39F which showed reduced levels of binding, and C11, A32, and 30D which did not bind the stabilized oligomer.
Yang2002
(vaccine antigen design)
-
F105: Abs against the V3 loop (50.1, 58.2, 59.1, 257-D, 268-D, 447-52D), CD4BS (IgG1b12, 559-64D, F105), CD4i (17b), and to gp41 (2F5, F240) each showed similar binding efficiency to Env derived from related pairs of primary and TCLA lines (primary: 168P and 320SI, and TCLA: 168C and 320SI-C3.3), but the TCLA lines were much more susceptible to neutralization suggesting that the change in TCLA lines that make them more susceptible to NAbs alters some step after binding.
York2001
(antibody binding site)
-
F105: Mutations in two glycosylation sites in the V2 region of HIV-1 ADA at positions 190 and 197 (187 DNTSYRLINCNTS 199) cause the virus to become CD4-independent and able to enter cells through CCR5 alone -- these same mutations tended to increase the neutralization sensitivity of the virus, including to F105.
Kolchinsky2001
(antibody binding site)
-
F105: SHIV-HXBc2 is a neutralization sensitive non-pathogenic virus, and several in vivo passages through monkeys yielded highly pathogenic SHIV KU-1---HXBc2 and the KU-1 clone HXBc2P3.2 differ in 12 amino acids in gp160---substitutions in both gp120 and gp41 reduced the ability of sCD4, IgG1b12, F105 and AG1121 to Env achieve saturation and full occupancy, and neutralize KU-1---17b and 2F5 also bound less efficiently to HXBc2P3.2, although 2G12 was able to bind both comparably.
Si2001
(antibody binding site)
-
F105: A combination of gp41 fusion with the GNC4 trimeric sequences and disruption of the YU2 gp120-gp41 cleavage site resulted in stable gp140 trimers (gp140-GNC4) that preserve and expose some neutralizing epitopes while occluding some non-neutralizing epitopes -- CD4BS MAbs (F105 and F91) and CD4i (17b and 48d) recognized gp140-GNC4 as well as gp120 or gp140 -- non-neutralizing mAbs C11, A32, 522-149, M90, and #45 bound to the gp140-GNC4 glycoprotein at reduced levels compared to gp120 -- mAbs directed at the extreme termini of gp120 C1 (135/9 and 133/290) and C5 (CRA-1 and M91) bound efficiently to gp140-GNC4.
Yang2000
(vaccine antigen design)
-
F105: Six mutations in MN change the virus from a high-infectivity neutralization resistant phenotype to low-infectivity neutralization sensitive -- V3, CD4BS, and CD4i MAbs are 20-100 fold more efficient at neutralizing the sensitive form, although F105 was an exception and cannot neutralize either form of MN -- the mutation L544P reduced binding of all mAbs against gp120 by causing conformational changes.
Park2000
-
F105: Host encoded intercellular adhesion molecule (ICAM-1) is incorporated by the HIV-1 virion and enhances viral infectivity -- ICAM-1 does not modify virus sensitivity to antibodies 0.5beta or 4.8D or sCD4, but neutralizing ability of F105 was diminished in ICAM bearing virions in the presence of lymphocyte function-association antigen-1 (LFA-1) Ab.
Fortin2000
-
F105: A triple combination of 2F5, F105 and 2G12 effectively neutralized perinatal infection of macaque infants when challenged with SHIV-vpu+ -- the plasma half-life was 7.2 +/- 2.2 days.
Baba2000
(immunoprophylaxis, mother-to-infant transmission)
-
F105: A mini-review of observations of passive administration of IgG NAbs conferring protection against intervenous or vaginal SHIV challenge, that considers why IgG mAbs might protect against mucosal challenge. Database note: First author "RobertGuroff" is also found as "Robert-Guroff" on annotated papers in this database.
RobertGuroff2000
(genital and mucosal immunity, immunoprophylaxis, review)
-
F105: Anti-C1 region mAb 87-135/9 blocks gp120 interaction with CD4+ cells -- blocking activity is additive when combined with antibodies which bind in the C4 region of gp120 (F105, 388/389, and b12).
Kropelin1998
(antibody interactions)
-
F105: F105 enhances viral entry of viruses carrying the YU2 envelope glycoproteins, but neutralizes HXBc2.
Sullivan1998b
(enhancing activity)
-
F105: A comparison of 25 gp120 specific, conformation dependent mAbs was done and F105 was used for competition studies -- F105 did cross-compete with multiple CD4BS specific MAbs, however most could not neutralize even the autologous NL4-3 strains.
Sugiura1999
(antibody interactions)
-
F105: Immunoprecipitation of gp120 and gp160 expressed from a rec Semliki Forest virus by F105 and IgG1b12 indicated that the SFV expressed HIV-1 Env was folded appropriately -- and SVF-HIV-1 Env vaccine gave the strongest anti-HIV-1 Env response in mice, when compared to an HIV-1 Env DNA vaccine and a rgp160 protein.
Brand1998
(vaccine antigen design)
-
F105: The mAb F240 binds to the immunodominant region of gp41 and enhances infection in the presence of complement -- reactivity of F240 is enhanced by preincubation of cells with sCD4 or anti-CD4BS MAb F105.
Cavacini1998a
(antibody interactions)
-
F105: Neutralization synergy was observed when the mAbs 694/98-D (V3), 2F5 (gp41), and 2G12 (gp120 discontinuous) were used in combination, and even greater neutralizing potential was seen with the addition of a fourth MAb, F105 (CD4 BS).
Li1998
(antibody interactions)
-
F105: Phase I dose escalation study, single dose of 100 or 500 mg/m2 was given to 4 HIV+ patients -- sustained levels, no immune response against F105, no toxicity, infused Ab retained function -- there was no evidence of anti-HIV-1 activity and virus was not diminished at day 1 or 7, by culture or plasma RNA.
Cavacini1998
(kinetics, immunotherapy)
-
F105: Summary of the implications of the crystal structure of the core of gp120 bound to CD4 and 17b with what is known about mutations that reduce nAb binding -- probable mechanism of neutralization by CD4BS Ab is direct interference with CD4 binding.
Wyatt1998
(antibody binding site, structure)
-
F105: Binds both gp120 and soluble gp120+gp41 complex efficiently, suggesting its gp120 epitope is not blocked by gp41 binding -- does not bind to HXBc2 gp120 if the 19 C-term amino acids, in conjunction with C1 positions 31-93, are deleted.
Wyatt1997
(antibody binding site)
-
F105: Virus with the V1-V2 loop deleted was viable and more susceptible to neutralization by CD4i MAb 17b, and anti-V3 mAbs 1121, 9284, and 110.4, but not to a CD4BS mAb, F105 or sCD4.
Cao1997
(antibody binding site)
-
F105: One of 14 human mAbs tested for ability to neutralize a chimeric SHIV-vpu+, which expressed HIV-1 IIIB env -- F105 could only achieve 50% neutralization alone -- all Ab combinations tested showed synergistic neutralization -- F105 has synergistic response with mAbs 694/98-D (anti-V3), 48d, 2F5, and 2G12, and also with HIVIG.
Li1997
(antibody interactions, variant cross-reactivity)
-
F105: In a multilaboratory blinded study, failed to neutralize any of nine B clade primary isolates.
DSouza1997
(variant cross-reactivity)
-
F105: Neutralizes TCLA strains, but not primary isolates.
Parren1997
(variant cross-reactivity)
-
F105: Intracellular co-expression of heavy and light chains of the Fab105 fragment MAb F105 was enhanced by inclusion of an internal ribosome entry site (IRES) sequence -- the Fab105 IRES expression cassette was cloned into an adeno-associated virus (AAV) shuttle vector, and transduced into human lymphocytes which were able to produce and secrete the Fab105 fragments while maintaining normal growth -- several primary HIV-1 patient isolates were effectively blocked.
Chen1996
(immunotherapy)
-
F105: Binding of F105 to oligomeric gp120 occurs despite the fact it cannot neutralize primary isolates.
Litwin1996
-
F105: A panel of immunotoxins were generated by linking Env MAbs to ricin A -- immunotoxins mediated cell killing, but killing was not directly proportional to binding.
Pincus1996
(immunotoxin)
-
F105: F105 is V H4 -- V-region heavy chain usage was examined and a bias of enhanced V H1 and V H4, and reduced V H3, was noted among HIV infected individuals.
Wisnewski1996
(antibody sequence)
-
F105: Neutralizes HIV-1 LAI less potently than V3 specific mAbs.
McDougal1996
-
F105: Phase I study -- mAb clearance in plasma has a 13 day half-life.
Wolfe1996
(kinetics, immunotherapy)
-
F105: The sulfated polysaccharide curdlan sulfate (CRDS) binds to the Envelope of T-tropic viruses and neutralizes virus -- deletion of the V3 loop results in less potent inhibition of F105 binding by CRDS -- binding site of F105 described as 256-257 ST, 368-370 DPE, 421 K, and 470-484 PGGGDMRDNWRSELY.
Jagodzinski1996
(antibody binding site)
-
F105: Changing heavy chain from IgG1 to IgG3 increased neutralization efficiency.
Cavacini1995
-
F105: Biotinylated F105 was used for competition studies with Ab derived from pregnant HIV-1+ women -- a correlation between maternal anti-CD4 BS Abs overlapping the F105 binding site and lack of HIV-1 transmission to infants was noted.
Khouri1995
(mother-to-infant transmission)
-
F105: Efficient neutralization of T-cell adapted lines HXBc2 and MN, no neutralization of primary isolates 89.6, ADA and YU2 -- even some enhancement of infection of ADA and YU2 was observed.
Sullivan1995
(enhancing activity, variant cross-reactivity)
-
F105: Eight patient phase Ia trial for use as an immunotherapeutic -- no clinical or biochemical side effects observed, plasma levels of 10 ug/ml maintained for 21 days.
Posner1995
(immunotherapy)
-
F105: An immunoassay for titrating CD4BS serum antibody was developed using a gp120-coated solid phase and competition with mAb F105 -- 109/110 French HIV-1+ sera and 51/56 HIV-1+ African sera had detectable CD4BS Abs using this assay, demonstrating CD4 binding site conservation among diverse subtypes -- CD4BS Abs were detected soon after seroconversion and persisted -- 0/21 HIV-2+ sera reacted, indicating that the HIV-1 and HIV-2 CD4BS Abs are not cross-reactive.
Turbica1995
(assay or method development, subtype comparisons)
-
F105: A human CD4+ T lymphocyte line was transduced to express Fab fragments of F105 -- heavy and light chains are joined by an inter-chain linker -- in the transduced cells infected with HIV-1, the Fab binds intracellularly to the envelope protein and inhibits HIV-1 production -- secreted Fab fragments neutralize cell-free HIV-1 -- combined intra- and extracellular binding activities of the expressed Fab make transduced cells resistant to HIV-1 infection and also can protect surrounding lymphocytes by secreting neutralizing antibodies.
Marasco1993,Chen1994a
(variant cross-reactivity)
-
F105: Used as a positive control for CD4 BS antibodies in a study of the influence of oligomeric structure of Env in determining the repertoire of the Ab response.
Earl1994
(antibody binding site)
-
F105: Fab fragments show reduced capacity to neutralize IIIB, MN, and RF compared to intact IgG1, suggesting bivalent interaction may be important in binding and neutralization.
Cavacini1994a
(variant cross-reactivity)
-
F105: Administered intravenously to four cynomologus monkeys, plasma pharmacokinetics and biological activity tested.
Cavacini1994
(kinetics)
-
F105: MAbs against the glycosphingolipid GalCer block HIV infection of normally susceptible CD4 negative cells from the brain and colon -- anti-CD4 mAbs moderately inhibit gp120 binding to GalCer, possibly through steric hindrance -- binding of GalCer to gp120 inhibited but did not completely block F105 binding.
Cook1994
(brain/CSF)
-
F105: A mutation in gp41, 582 A/T, confers resistance to neutralization (also confers resistance to mAbs 48d, 21h, 15e and 17b).
Thali1994
(antibody binding site)
-
F105: Comparison of mAb F105 sequences with those of mAbs 21h and 15e.
Bagley1994
(antibody sequence)
-
F105: A neutralization escape mutant (HXB2 A281V) was selected by growth of HXB2 in the presence of broadly neutralizing sera -- F105 neutralization was not affected by this mutation.
Watkins1993
(escape)
-
F105: Ab response in IIIB lab workers was compared to gp160 LAI vaccine recipients -- F105 was used as a control -- infected lab workers and some of the gp160 vaccinees had a mAb response that could inhibit gp120-CD4 binding, at lower titers than the infected lab workers.
Pincus1993a
(vaccine-induced immune responses)
-
F105: The gp41 mutation 582(Ala to Thr) results in conformational changes in gp120 that confer neutralization resistance to a class of conformation sensitive neutralizing mAbs -- required >81 fold higher concentrations to neutralize the mutant than wild type.
Klasse1993b
(antibody interactions)
-
F105: Study of synergy of neutralization and binding comparing F105 and sCD4 with the V3 mAbs: 50.1, 59.1, 83.1, and 58.2 -- synergy was observed, and the data suggest that binding of one ligand (F105) can increase the binding of the second (e. g. V3 loop mAbs) due to conformational changes.
Potts1993
(antibody interactions)
-
F105: Study of synergy between F105 and sera from vaccinated volunteers with V3-loop specific neutralization activity -- 2/3 sera demonstrated neutralization synergy, and 3/3 binding/fusion-inhibition synergy.
Montefiori1993
(antibody interactions)
-
F105: Binding to Delta V1/2 and Delta V1/2/3 mutant glycoproteins is 2.4- and 13-fold greater, respectively, than binding to wildtype gp120.
Wyatt1993
(antibody binding site)
-
F105: Serum from all asymptomatic HIV-1 positive people tested block F105 binding, but only from 27% of symptomatic individuals.
Cavacini1993a
(rate of progression)
-
F105: Additive MN or SF2 neutralization when combined with anti-V3 mAbs 447-52D and 257-D.
Cavacini1993
(antibody interactions)
-
F105: No neutralization of primary isolates observed (John Moore, pers comm), laboratory strains could be neutralized though.
-
F105: F105 binds to and neutralizes selected lab strains and 3/9 HIV-1 primary isolates -- synergistic enhancement of neutralization by seropositive sera.
Posner1993
(antibody interactions, variant cross-reactivity)
-
F105: Called F-105 -- neutralizes IIIB -- strong inhibition of HIV+ human sera binding to IIIB gp120.
Moore1993a
-
F105: Significant enhancement of F105 binding to RF infected cells preincubated with V3-specific mAbs V3-2 and V3-1.
Posner1992a
(antibody interactions)
-
F105: F105 mediates ADCC against SF2 through the CD16+ population of PBMC -- does not mediate complement-dependent cytotoxicity.
Posner1992
(complement, effector function)
-
F105: Precipitation of Delta 297-329 env glycoprotein, which has a deleted V3 loop, is much more efficient than precipitation of wild type.
Wyatt1992
(antibody binding site)
-
F105: MAb cDNA sequence -- V H4 V71-4 rearranged with a D H D-D fusion product of dlr4 and da4, and with J H5 -- V kappa is from the Humvk325 germline gene joined with Jkappa 2.
Marasco1992
(antibody sequence)
-
F105: Amino acid substitutions that impair F105 neutralization inhibit gp120-CD4 interaction.
Thali1992a
(antibody binding site)
-
F105: F105 neutralization escape mutants result from changes in amino acids in discontinuous regions: C2, 256-262 and C3, 386-370.
Thali1991
(antibody binding site)
-
F105: First description of F105, binds topographically near the CD4-binding site -- inhibits binding of free, infectious virions to uninfected HT-H9 cells, but does not react with virus adsorbed to uninfected HT-H9 cells -- soluble rCD4 pre-bound to infected cells inhibits F105 binding -- F105 inhibits infection of HT-H9 cells in standard neutralization assays with HIV-1 and MN strains.
Posner1991
(antibody binding site, antibody generation)
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Posner1991
M. R. Posner, T. Hideshima, T. Cannon, M. Mukherjee, K. H. Mayer, and R. A. Byrn. An IgG Human Monoclonal Antibody That Reacts with HIV-I/gp120, Inhibits Virus Binding to Cells, and Neutralizes Infection. J. Immunol., 146:4325-4332, 1991. Original paper describing the neutralizing MAb F105. PubMed ID: 1710248.
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Ahmed2012
Fatima K. Ahmed, Brenda E. Clark, Dennis R. Burton, and Ralph Pantophlet. An Engineered Mutant of HIV-1 gp120 Formulated with Adjuvant Quil A Promotes Elicitation of Antibody Responses Overlapping the CD4-Binding Site. Vaccine, 30(5):922-930, 20 Jan 2012. PubMed ID: 22142583.
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Baba2000
T. W. Baba, V. Liska, R. Hofmann-Lehmann, J. Vlasak, W. Xu, S. Ayehunie, L. A. Cavacini, M. R. Posner, H. Katinger, G. Stiegler, B. J. Bernacky, T. A. Rizvi, R. Schmidt, L. R. Hill, M. E. Keeling, Y. Lu, J. E. Wright, T. C. Chou, and R. M. Ruprecht. Human neutralizing monoclonal antibodies of the IgG1 subtype protect. Nat. Med., 6:200-6, 2000. PubMed ID: 10655110.
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Bagley1994
J. Bagley, P. J. Dillon, C. Rosen, J. Robinson, J. Sodroski, and W. A. Marasco. Structural Characterization of Broadly Neutralizing Human Monoclonal Antibodies Against the CD4 Binding Site of HIV-1 gp120. Mol. Immunol., 31(15):1149-1160, 1994. This paper is a detailed study of the V-D-J heavy chain usage and V-J light chain usage for the three monoclonals that bind to the HIV-1 envelope CD4 binding site: F105, 15e and 21h. Different germline genes were used, and there was evidence for antigen-drive clonal selection of somatic mutations. Eight positions in the heavy chain and two in the light chain complementarity determining positions were identical in the three Mabs. PubMed ID: 7935503.
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Barbian2015
Hannah J. Barbian, Julie M. Decker, Frederic Bibollet-Ruche, Rachel P. Galimidi, Anthony P. West, Jr., Gerald H. Learn, Nicholas F. Parrish, Shilpa S. Iyer, Yingying Li, Craig S. Pace, Ruijiang Song, Yaoxing Huang, Thomas N. Denny, Hugo Mouquet, Loic Martin, Priyamvada Acharya, Baoshan Zhang, Peter D. Kwong, John R. Mascola, C. Theo Verrips, Nika M. Strokappe, Lucy Rutten, Laura E. McCoy, Robin A. Weiss, Corrine S. Brown, Raven Jackson, Guido Silvestri, Mark Connors, Dennis R. Burton, George M. Shaw, Michel C. Nussenzweig, Pamela J. Bjorkman, David D. Ho, Michael Farzan, and Beatrice H. Hahn. Neutralization Properties of Simian Immunodeficiency Viruses Infecting Chimpanzees and Gorillas. mBio, 6(2), 21 Apr 2015. PubMed ID: 25900654.
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Basmaciogullar2002
Stéphane Basmaciogullari, Gregory J. Babcock, Donald Van Ryk, Woj Wojtowicz, and Joseph Sodroski. Identification of Conserved and Variable Structures in the Human Immunodeficiency Virus gp120 Glycoprotein of Importance for CXCR4 Binding. J. Virol., 76(21):10791-800, Nov 2002. PubMed ID: 12368322.
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Beddows2005a
Simon Beddows, Natalie N. Zheng, Carolina Herrera, Elizabeth Michael, Kelly Barnes, John P. Moore, Rod S. Daniels, and Jonathan N. Weber. Neutralization Sensitivity of HIV-1 Env-Pseudotyped Virus Clones is Determined by Co-Operativity between Mutations Which Modulate the CD4-Binding Site and Those That Affect gp120-gp41 Stability. Virology, 337(1):136-148, 20 Jun 2005. PubMed ID: 15914227.
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Berkower2008
Ira Berkower, Chiraag Patel, Yisheng Ni, Konstantin Virnik, Zhexin Xiang, and Angelo Spadaccini. Targeted Deletion in the beta20--beta21 Loop of HIV Envelope Glycoprotein gp120 Exposes the CD4 Binding Site for Antibody Binding. Virology, 377(2):330-338, 1 Aug 2008. PubMed ID: 18519142.
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Bhattacharyya2010
Sanchari Bhattacharyya, Roshan Elizabeth Rajan, Yalla Swarupa, Ujjwal Rathore, Anjali Verma, Ranga Udaykumar, and Raghavan Varadarajan. Design of a Non-Glycosylated Outer Domain-Derived HIV-1 gp120 Immunogen That Binds to CD4 and Induces Neutralizing Antibodies. J. Biol. Chem., 285(35):27100-27110, 27 Aug 2010. PubMed ID: 20558728.
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Biorn2004
Alyssa C. Biorn, Simon Cocklin, Navid Madani, Zhihai Si, Tijana Ivanovic, James Samanen, Donald I. Van Ryk, Ralph Pantophlet, Dennis R. Burton, Ernesto Freire, Joseph Sodroski, and Irwin M. Chaiken. Mode of Action for Linear Peptide Inhibitors of HIV-1 gp120 Interactions. Biochemistry, 43(7):1928-1938, 24 Feb 2004. PubMed ID: 14967033.
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Bontjer2010
Ilja Bontjer, Mark Melchers, Dirk Eggink, Kathryn David, John P. Moore, Ben Berkhout, and Rogier W. Sanders. Stabilized HIV-1 Envelope Glycoprotein Trimers Lacking the V1V2 Domain, Obtained by Virus Evolution. J. Biol. Chem, 285(47):36456-36470, 19 Nov 2010. PubMed ID: 20826824.
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Bradley2016a
Todd Bradley, Ashley Trama, Nancy Tumba, Elin Gray, Xiaozhi Lu, Navid Madani, Fatemeh Jahanbakhsh, Amanda Eaton, Shi-Mao Xia, Robert Parks, Krissey E. Lloyd, Laura L. Sutherland, Richard M. Scearce, Cindy M. Bowman, Susan Barnett, Salim S. Abdool-Karim, Scott D. Boyd, Bruno Melillo, Amos B. Smith, 3rd., Joseph Sodroski, Thomas B. Kepler, S. Munir Alam, Feng Gao, Mattia Bonsignori, Hua-Xin Liao, M Anthony Moody, David Montefiori, Sampa Santra, Lynn Morris, and Barton F. Haynes. Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity. EBioMedicine, 12:196-207, Oct 2016. PubMed ID: 27612593.
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Brand1998
D. Brand, F. Lemiale, I. Turbica, L. Buzelay, S. Brunet, and F. Barin. Comparative Analysis of Humoral Immune Responses to HIV Type 1 Envelope Glycoproteins in Mice Immunized with a DNA Vaccine, Recombinant Semliki Forest Virus RNA, or Recombinant Semliki Forest Virus Particles. AIDS Res. Hum. Retroviruses, 14:1369-1377, 1998. PubMed ID: 9788678.
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Cao1997
J. Cao, N. Sullivan, E. Desjardin, C. Parolin, J. Robinson, R. Wyatt, and J. Sodroski. Replication and Neutralization of Human Immunodeficiency Virus Type 1 Lacking the V1 and V2 Variable Loops of the gp120 Envelope Glycoprotein. J. Virol., :9808-9812, 1997. An HIV-1 mutant lacking the V1-V2 loops can replicate in Jurkat cells and revertants that replicate with wild-type efficiency rapidly evolve in culture. These viruses exhibited increased neutralization susceptibility to V3 loop or CD4i MAbs, but not to sCD4 or anti-CD4BS MAbs. Thus the gp120 V1 and V2 loops protect HIV-1 from some subsets of neutralizing antibodies. PubMed ID: 9371651.
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Castillo-Menendez2019
Luis R. Castillo-Menendez, Hanh T. Nguyen, and Joseph Sodroski. Conformational Differences between Functional Human Immunodeficiency Virus Envelope Glycoprotein Trimers and Stabilized Soluble Trimers. J. Virol., 93(3), 1 Feb 2019. PubMed ID: 30429345.
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Cavacini1993
L. A. Cavacini, C. L. Emes, J. Power, A. Buchbinder, S. Zolla-Pazner, and M. R. Posner. Human Monoclonal Antibodies to the V3 Loop of HIV-1 gp120 Mediate Variable and Distinct Effects on Binding and Viral Neutralization by a Human Monoclonal Antibody to the CD4 Binding Site. J. Acquir. Immune Defic. Syndr., 6:353-358, 1993. PubMed ID: 8455141.
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Cavacini1993a
L. A. Cavacini, C. L. Emes, J. Power, J. Underdalh, R. Goldstein, K. Mayer, and M. R. Posner. Loss of Serum Antibodies to a Conformational Epitope of HIV-1/gp120 Identified by a Human Monoclonal Antibody Is Associated with Disease Progression. J. Acquir. Immune Defic. Syndr., 6:1093-1102, 1993. Serum from 100\% of asymptomatic HIV-positive people blocked F105 binding, while serum samples from 27\% of ARC/AIDS patients blocked F105 binding. PubMed ID: 7692037.
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Cavacini1994
L. A. Cavacini, J. Power, C. L. Emes, K. Mace, G. Treacy, and M. R. Posner. Plasma Pharmacokinetics and Biological Activity of a Human Immunodeficiency Virus Type 1 Neutralizing Human Monoclonal Antibody, F105, in Cynomolgus Monkeys. Tumor Immunol., 15:251-256, 1994. MAb F105 was administered intravenously to four cynomolgus monkeys. At 15 days post-dose, total serum F105 was 230 +/- 79 $\mu$g/ml and F105 was immunoreactive with cells infected with the MN and IIIB strains of HIV-1 as determined by flow cytometry. PubMed ID: 8061897.
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Cavacini1994a
L. A. Cavacini, C. L. Emes, J. Power, M. Duval, and M. R. Posner. Effect of Antibody Valency on Interaction with Cell-Surface Expressed HIV-1 and Viral Neutralization. J. Immunol., 152:2538-2545, 1994. PubMed ID: 7510748.
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Cavacini1995
L. A. Cavacini, C. L. Emes, J. Power, F. D. Desharnais, M. Duval, D. Montefiori, and M. R. Posner. Influence of Heavy Chain Constant Regions on Antigen Binding and HIV-1 Neutralization by a Human Monoclonal Antibody. J. Immunol., 155:3638-3644, 1995. By changing the IgG1 constant region of MAb F105 from IgG$_1\kappa$ to IgG$_3\kappa$, dramatic strain specific increases in neutralization efficiency were obtained. PubMed ID: 7561063.
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Cavacini1998
L. A. Cavacini, M. H. Samore, J. Gambertoglio, B. Jackson, M. Duval, A. Wisnewski, S. Hammer, C. Koziel, C. Trapnell, and M. R. Posner. Phase I Study of a Human Monoclonal Antibody Directed against the CD4-Binding Site of HIV Type 1 Glycoprotein 120. AIDS Res. Hum. Retroviruses, 14:545-550, 1998. In an immunotherapeutic study, administration of a single dose of F105 was non-toxic and the Ab persisted, yet no benefit was observed in 4 individuals. The authors suggest it may be more helpful in other settings, for example, patients with no pre-existing anti-CD4 BS Abs, or in combination with other MAbs. PubMed ID: 9591708.
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Cavacini1998a
L. A. Cavacini, C. L. Emes, A. V. Wisnewski, J. Power, G. Lewis, D. Montefiori, and M. R. Posner. Functional and molecular characterization of human monoclonal antibody. AIDS Res. Hum. Retroviruses, 14:1271-80, 1998. PubMed ID: 9764911.
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Cavacini1999
L. A. Cavacini, A. Wisnewski, J. E. Peterson, D. Montefiori, C. Emes, M. Duval, G. Kingsbury, A. Wang, D. Scadden, and M. R. Posner. A Human Anti-HIV Autoantibody Enhances EBV Transformation and HIV infection. Clin. Immunol., 93:263-273, 1999. PubMed ID: 10600338.
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Cavacini2002
Lisa A. Cavacini, Mark Duval, James Robinson, and Marshall R. Posner. Interactions of Human Antibodies, Epitope Exposure, Antibody Binding and Neutralization of Primary Isolate HIV-1 Virions. AIDS, 16(18):2409-2417, 6 Dec 2002. Erratum in AIDS. 2003 Aug 15;17(12):1863. PubMed ID: 12461414.
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Chakrabarti2002
Bimal K. Chakrabarti, Wing-pui Kong, Bei-yue Wu, Zhi-Yong Yang, Jacques Friborg, Xu Ling, Steven R. King, David C. Montefiori, and Gary J. Nabel. Modifications of the Human Immunodeficiency Virus Envelope Glycoprotein Enhance Immunogenicity for Genetic Immunization. J. Virol., 76(11):5357-5368, Jun 2002. PubMed ID: 11991964.
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Chen1994a
S. Y. Chen, Y. Khouri, J. Bagley, and W. A. Marasco. Combined intra- and extracellular immunization against human immunodeficiency virus type 1 infection with a human anti-gp120 antibody. Proc. Natl. Acad. Sci. U.S.A., 91:5932-5936, 1994. PubMed ID: 8016092.
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Chen1996
J. D. Chen, Q. Yang, W. A. Marasco, and S. Y. Chen. Intra- and Extra-Cellular Immunization against HIV-1 Infection with Lymphocytes Transduced with an AAV Vector Expressing a Human Anti-gp120 Antibody. Hum. Gene Ther., 7:1515-1525, 1996. PubMed ID: 8864752.
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Chen2009
Lei Chen, Young Do Kwon, Tongqing Zhou, Xueling Wu, Sijy O'Dell, Lisa Cavacini, Ann J. Hessell, Marie Pancera, Min Tang, Ling Xu, Zhi-Yong Yang, Mei-Yun Zhang, James Arthos, Dennis R. Burton, Dimiter S. Dimitrov, Gary J. Nabel, Marshall R. Posner, Joseph Sodroski, Richard Wyatt, John R. Mascola, and Peter D. Kwong. Structural Basis of Immune Evasion at the Site of CD4 Attachment on HIV-1 gp120. Science, 326(5956):1123-1127, 20 Nov 2009. PubMed ID: 19965434.
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Choe2003
Hyeryun Choe, Wenhui Li, Paulette L. Wright, Natalya Vasilieva, Miro Venturi, Chih-Chin Huang, Christoph Grundner, Tatyana Dorfman, Michael B. Zwick, Liping Wang, Eric S. Rosenberg, Peter D. Kwong, Dennis R. Burton, James E. Robinson, Joseph G. Sodroski, and Michael Farzan. Tyrosine Sulfation of Human Antibodies Contributes to Recognition of the CCR5 Binding Region of HIV-1 gp120. Cell, 114(2):161-170, 25 Jul 2003. PubMed ID: 12887918.
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Chomont2008
Nicolas Chomont, Hakim Hocini, Jean-Chrysostome Gody, Hicham Bouhlal, Pierre Becquart, Corinne Krief-Bouillet, Michel Kazatchkine, and Laurent Bélec. Neutralizing Monoclonal Antibodies to Human Immunodeficiency Virus Type 1 Do Not Inhibit Viral Transcytosis Through Mucosal Epithelial Cells. Virology, 370(2):246-254, 20 Jan 2008. PubMed ID: 17920650.
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Chuang2013
Gwo-Yu Chuang, Priyamvada Acharya, Stephen D. Schmidt, Yongping Yang, Mark K. Louder, Tongqing Zhou, Young Do Kwon, Marie Pancera, Robert T. Bailer, Nicole A. Doria-Rose, Michel C. Nussenzweig, John R. Mascola, Peter D. Kwong, and Ivelin S. Georgiev. Residue-Level Prediction of HIV-1 Antibody Epitopes Based on Neutralization of Diverse Viral Strains. J. Virol., 87(18):10047-10058, Sep 2013. PubMed ID: 23843642.
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Chuang2017
Gwo-Yu Chuang, Hui Geng, Marie Pancera, Kai Xu, Cheng Cheng, Priyamvada Acharya, Michael Chambers, Aliaksandr Druz, Yaroslav Tsybovsky, Timothy G. Wanninger, Yongping Yang, Nicole A. Doria-Rose, Ivelin S. Georgiev, Jason Gorman, M. Gordon Joyce, Sijy O'Dell, Tongqing Zhou, Adrian B. McDermott, John R. Mascola, and Peter D. Kwong. Structure-Based Design of a Soluble Prefusion-Closed HIV-1 Env Trimer with Reduced CD4 Affinity and Improved Immunogenicity. J. Virol., 91(10), 15 May 2017. PubMed ID: 28275193.
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Clayton2007
Reginald Clayton, Asa Ohagen, Olivia Goethals, Alexandra Smets, Marnix Van Loock, Lieve Michiels, Erin Kennedy-Johnston, Mark Cunningham, Haiyan Jiang, Sharon Bola, Lester Gutshall, George Gunn, Alfred Del Vecchio, Robert Sarisky, Sabine Hallenberger, and Kurt Hertogs. Binding Kinetics, Uptake and Intracellular Accumulation of F105, an Anti-gp120 Human IgG1kappa Monoclonal Antibody, in HIV-1 Infected Cells. J. Virol. Methods, 139(1):17-23, Jan 2007. PubMed ID: 17034868.
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Clayton2009
Reginald Clayton, Asa Ohagen, Francois Nicol, Alfred M. Del Vecchio, Tim H. M. Jonckers, Olivia Goethals, Marnix Van Loock, Lieve Michiels, John Grigsby, Zheng Xu, Yuan Peng Zhang, Lester L. Gutshall, Mark Cunningham, Haiyan Jiang, Sharon Bola, Robert T. Sarisky, and Kurt Hertogs. Sustained and Specific In Vitro Inhibition of HIV-1 Replication by a Protease Inhibitor Encapsulated in gp120-Targeted Liposomes. Antiviral Res., 84(2):142-149, Nov 2009. PubMed ID: 19699239.
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Cook1994
D. G. Cook, J. Fantini, S. L. Spitalnik, and F. Gonzalez-Scarano. Binding of Human Immunodeficiency Virus Type 1 HIV-1 gp120 to Galactosylceramide (GalCer): Relationship to the V3 Loop. Virol., 201:206-214, 1994. Antibodies against GalCer can block infection of CD4-negative cells from the brain and colon that are susceptible to HIV infection. This paper explores the ability of a panel of MAbs to inhibit binding of gp120 to GalCer, and also of the binding of GalCer to inhibit MAb-gp120 interaction. MAbs to the V3 loop and GalCer showed mutual inhibition of binding to gp120, and anti-CD4 binding site MAbs showed reduced inhibition. N- and C-terminal MAbs didn't influence GalCer binding. PubMed ID: 8184533.
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Crooks2015
Ema T. Crooks, Tommy Tong, Bimal Chakrabarti, Kristin Narayan, Ivelin S. Georgiev, Sergey Menis, Xiaoxing Huang, Daniel Kulp, Keiko Osawa, Janelle Muranaka, Guillaume Stewart-Jones, Joanne Destefano, Sijy O'Dell, Celia LaBranche, James E. Robinson, David C. Montefiori, Krisha McKee, Sean X. Du, Nicole Doria-Rose, Peter D. Kwong, John R. Mascola, Ping Zhu, William R. Schief, Richard T. Wyatt, Robert G. Whalen, and James M. Binley. Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site. PLoS Pathog, 11(5):e1004932, May 2015. PubMed ID: 26023780.
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Derby2006
Nina R. Derby, Zane Kraft, Elaine Kan, Emma T. Crooks, Susan W. Barnett, Indresh K. Srivastava, James M. Binley, and Leonidas Stamatatos. Antibody Responses Elicited in Macaques Immunized with Human Immunodeficiency Virus Type 1 (HIV-1) SF162-Derived gp140 Envelope Immunogens: Comparison with Those Elicited during Homologous Simian/Human Immunodeficiency Virus SHIVSF162P4 and Heterologous HIV-1 Infection. J. Virol., 80(17):8745-8762, Sep 2006. PubMed ID: 16912322.
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Dey2007a
Barna Dey, Marie Pancera, Krisha Svehla, Yuuei Shu, Shi-Hua Xiang, Jeffrey Vainshtein, Yuxing Li, Joseph Sodroski, Peter D Kwong, John R Mascola, and Richard Wyatt. Characterization of Human Immunodeficiency Virus Type 1 Monomeric and Trimeric gp120 Glycoproteins Stabilized in the CD4-Bound State: Antigenicity, Biophysics, and Immunogenicity. J Virol, 81(11):5579-5593, Jun 2007. PubMed ID: 17360741.
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Dorgham2005
Karim Dorgham, Ismaïl Dogan, Natacha Bitton, Christophe Parizot, Valerie Cardona, Patrice Debré, Oliver Hartley, and Guy Gorochov. Immunogenicity of HIV Type 1 gp120 CD4 Binding Site Phage Mimotopes. AIDS Res. Hum. Retroviruses, 21(1):82-92, Jan 2005. PubMed ID: 15665647.
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Douagi2010
Iyadh Douagi, Mattias N. E. Forsell, Christopher Sundling, Sijy O'Dell, Yu Feng, Pia Dosenovic, Yuxing Li, Robert Seder, Karin Loré, John R. Mascola, Richard T. Wyatt, and Gunilla B. Karlsson Hedestam. Influence of Novel CD4 Binding-Defective HIV-1 Envelope Glycoprotein Immunogens on Neutralizing Antibody and T-Cell Responses in Nonhuman Primates. J. Virol., 84(4):1683-1695, Feb 2010. PubMed ID: 19955308.
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DSouza1997
M. P. D'Souza, D. Livnat, J. A. Bradac, S. H. Bridges, the AIDS Clinical Trials Group Antibody Selection Working Group, and Collaborating Investigators. Evaluation of monoclonal antibodies to human immunodeficiency virus type 1 primary isolates by neutralization assays: performance criteria for selecting candidate antibodies for clinical trials. J. Infect. Dis., 175:1056-1062, 1997. Five laboratories evaluated neutralization of nine primary B clade isolates by a coded panel of seven human MAbs to HIV-1 subtype B envelope. IgG1b12, 2G12, 2F5 showed potent and broadly cross-reactive neutralizing ability; F105, 447/52-D, 729-D, 19b did not neutralize the primary isolates. PubMed ID: 9129066.
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Dunfee2007
Rebecca L. Dunfee, Elaine R. Thomas, Jianbin Wang, Kevin Kunstman, Steven M. Wolinsky, and Dana Gabuzda. Loss of the N-Linked Glycosylation Site at Position 386 in the HIV Envelope V4 Region Enhances Macrophage Tropism and Is Associated with Dementia. Virology, 367(1):222-234, 10 Oct 2007. PubMed ID: 17599380.
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Earl1994
P. L. Earl, C. C. Broder, D. Long, S. A. Lee, J. Peterson, S. Chakrabarti, R. W. Doms, and B. Moss. Native oligomeric human immunodeficiency virus type 1 Envelope glycoprotein elicits diverse monoclonal antibody reactivities. J. Virol., 68:3015-3026, 1994. In a study of the repertoire of response to oligomeric versus monomeric Env protein, 138 murine MAbs were generated in response to an immunogen that was a gp120/bp41 oligomeric molecule that was not cleaved due to a mutation in the cleavage site. The oligomeric molecule was found to elicit a response that was very different than the monomer. Most MAbs were conformational, many were to gp41 or if in gp120, to the CD4 BS. Few MAbs to linear V3 epitopes were produced in response to oligomeric protein, though this was a common specificity in response to immunization with gp120 monomeric protein. PubMed ID: 7512157.
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EdwardsBH2002
Bradley H. Edwards, Anju Bansal, Steffanie Sabbaj, Janna Bakari, Mark J. Mulligan, and Paul A. Goepfert. Magnitude of Functional CD8+ T-Cell Responses to the Gag Protein of Human Immunodeficiency Virus Type 1 Correlates Inversely with Viral Load in Plasma. J. Virol., 76(5):2298-2305, Mar 2002. PubMed ID: 11836408.
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Feng2012
Yu Feng, Krisha McKee, Karen Tran, Sijy O'Dell, Stephen D. Schmidt, Adhuna Phogat, Mattias N. Forsell, Gunilla B. Karlsson Hedestam, John R. Mascola, and Richard T. Wyatt. Biochemically Defined HIV-1 Envelope Glycoprotein Variant Immunogens Display Differential Binding and Neutralizing Specificities to the CD4-Binding Site. J. Biol. Chem., 287(8):5673-5686, 17 Feb 2012. PubMed ID: 22167180.
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Ferrantelli2002
Flavia Ferrantelli and Ruth M. Ruprecht. Neutralizing Antibodies Against HIV --- Back in the Major Leagues? Curr. Opin. Immunol., 14(4):495-502, Aug 2002. PubMed ID: 12088685.
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Ferrantelli2004a
Flavia Ferrantelli, Moiz Kitabwalla, Robert A. Rasmussen, Chuanhai Cao, Ting-Chao Chou, Hermann Katinger, Gabriela Stiegler, Lisa A. Cavacini, Yun Bai, Joseph Cotropia, Kenneth E. Ugen, and Ruth M. Ruprecht. Potent Cross-Group Neutralization of Primary Human Immunodeficiency Virus Isolates with Monoclonal Antibodies--Implications for Acquired Immunodeficiency Syndrome Vaccine. J. Infect. Dis., 189(1):71-74, 1 Jan 2004. PubMed ID: 14702155.
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Finzi2010
Andrés Finzi, Beatriz Pacheco, Xin Zeng, Young Do Kwon, Peter D. Kwong, and Joseph Sodroski. Conformational Characterization of Aberrant Disulfide-Linked HIV-1 gp120 Dimers Secreted from Overexpressing Cells. J Virol Methods, 168(1-2):155-161, Sep 2010. PubMed ID: 20471426.
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Fortin2000
J. F. Fortin, R. Cantin, M. G. Bergeron, and M. J. Tremblay. Interaction between Virion-Bound Host Intercellular Adhesion Molecule-1 and the High-Affinity State of Lymphocyte Function-Associated Antigen-1 on Target Cells Renders R5 and X4 Isolates of Human Immunodeficiency Virus Type 1 More Refractory to Neutralization. Virology, 268:493-503, 2000. PubMed ID: 10704357.
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Georgiev2013a
Ivelin S. Georgiev, M. Gordon Joyce, Tongqing Zhou, and Peter D. Kwong. Elicitation of HIV-1-Neutralizing Antibodies against the CD4-Binding Site. Curr. Opin. HIV AIDS, 8(5):382-392, Sep 2013. PubMed ID: 23924998.
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Giraud1999
A. Giraud, Y. Ataman-Onal, N. Battail, N. Piga, D. Brand, B. Mandrand, and B. Verrier. Generation of Monoclonal Antibodies to Native Human Immunodeficiency Virus Type 1 Envelope Glycoprotein by Immunization of Mice with Naked RNA. J. Virol. Methods, 79:75-84, 1999. PubMed ID: 10328537.
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Gopi2008
Hosahudya Gopi, M. Umashankara, Vanessa Pirrone, Judith LaLonde, Navid Madani, Ferit Tuzer, Sabine Baxter, Isaac Zentner, Simon Cocklin, Navneet Jawanda, Shendra R. Miller, Arne Schön, Jeffrey C. Klein, Ernesto Freire, Fred C. Krebs, Amos B. Smith, Joseph Sodroski, and Irwin Chaiken. Structural Determinants for Affinity Enhancement of a Dual Antagonist Peptide Entry Inhibitor of Human Immunodeficiency Virus Type-1. J. Med. Chem., 51(9):2638-2647, 8 May 2008. PubMed ID: 18402432.
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Gorny2003
Miroslaw K. Gorny and Susan Zolla-Pazner. Human Monoclonal Antibodies that Neutralize HIV-1. In Bette T. M. Korber and et. al., editors, HIV Immunology and HIV/SIV Vaccine Databases 2003. pages 37--51. Los Alamos National Laboratory, Theoretical Biology \& Biophysics, Los Alamos, N.M., 2004. URL: http://www.hiv.lanl.gov/content/immunology/pdf/2003/zolla-pazner_article.pdf. LA-UR 04-8162.
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Gorny2009
Miroslaw K. Gorny, Xiao-Hong Wang, Constance Williams, Barbara Volsky, Kathy Revesz, Bradley Witover, Sherri Burda, Mateusz Urbanski, Phillipe Nyambi, Chavdar Krachmarov, Abraham Pinter, Susan Zolla-Pazner, and Arthur Nadas. Preferential Use of the VH5-51 Gene Segment by the Human Immune Response to Code for Antibodies against the V3 Domain of HIV-1. Mol. Immunol., 46(5):917-926, Feb 2009. PubMed ID: 18952295.
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Grundner2002
Christoph Grundner, Tajib Mirzabekov, Joseph Sodroski, and Richard Wyatt. Solid-Phase Proteoliposomes Containing Human Immunodeficiency Virus Envelope Glycoproteins. J. Virol., 76(7):3511-3521, Apr 2002. PubMed ID: 11884575.
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Guenaga2015
Javier Guenaga, Natalia de Val, Karen Tran, Yu Feng, Karen Satchwell, Andrew B. Ward, and Richard T. Wyatt. Well-Ordered Trimeric HIV-1 Subtype B and C Soluble Spike Mimetics Generated by Negative Selection Display Native-Like Properties. PLoS Pathog., 11(1):e1004570, Jan 2015. PubMed ID: 25569572.
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Guenaga2015a
Javier Guenaga, Viktoriya Dubrovskaya, Natalia de Val, Shailendra K. Sharma, Barbara Carrette, Andrew B. Ward, and Richard T. Wyatt. Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers. J. Virol., 90(6):2806-2817, 30 Dec 2015. PubMed ID: 26719252.
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Guzzo2018
Christina Guzzo, Peng Zhang, Qingbo Liu, Alice L. Kwon, Ferzan Uddin, Alexandra I. Wells, Hana Schmeisser, Raffaello Cimbro, Jinghe Huang, Nicole Doria-Rose, Stephen D. Schmidt, Michael A. Dolan, Mark Connors, John R. Mascola, and Paolo Lusso. Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation. mBio, 9(6), 11 Dec 2018. PubMed ID: 30538178.
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Haim2011
Hillel Haim, Bettina Strack, Aemro Kassa, Navid Madani, Liping Wang, Joel R. Courter, Amy Princiotto, Kathleen McGee, Beatriz Pacheco, Michael S. Seaman, Amos B. Smith, 3rd., and Joseph Sodroski. Contribution of Intrinsic Reactivity of the HIV-1 Envelope Glycoproteins to CD4-Independent Infection and Global Inhibitor Sensitivity. PLoS Pathog., 7(6):e1002101, Jun 2011. PubMed ID: 21731494.
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Hinz2010
Andreas Hinz, David Lutje Hulsik, Anna Forsman, Willie Wee-Lee Koh, Hassan Belrhali, Andrea Gorlani, Hans de Haard, Robin A. Weiss, Theo Verrips, and Winfried Weissenhorn. Crystal Structure of the Neutralizing Llama V(HH) D7 and Its Mode of HIV-1 gp120 Interaction. PLoS One, 5(5):e10482, 2010. PubMed ID: 20463957.
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Vincent Holl, Maryse Peressin, Thomas Decoville, Sylvie Schmidt, Susan Zolla-Pazner, Anne-Marie Aubertin, and Christiane Moog. Nonneutralizing Antibodies Are Able To Inhibit Human Immunodeficiency Virus Type 1 Replication in Macrophages and Immature Dendritic Cells. J. Virol., 80(12):6177-6181, Jun 2006. PubMed ID: 16731957.
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Patrick W.-P. Hong, Sandra Nguyen, Sophia Young, Stephen V. Su, and Benhur Lee. Identification of the Optimal DC-SIGN Binding Site on Human Immunodeficiency Virus Type 1 gp120. J. Virol., 81(15):8325-8336, Aug 2007. PubMed ID: 17522223.
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P. P. Jagodzinski, J. Wustner, D. Kmieciak, T. J. Wasik, A. Fertala, A. L. Sieron, M. Takahashi, T. Tsuji, T. Mimura, M. S. Fung, M. K. Gorny, M. Kloczewiak, Y. Kaneko, and D. Kozbor. Role of the V2, V3, and CD4-Binding Domains of GP120 in Curdlan Sulfate Neutralization Sensitivity of HIV-1 during Infection of T Lymphocytes. Virology, 226:217-227, 1996. PubMed ID: 8955041.
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Janda2016
Alena Janda, Anthony Bowen, Neil S. Greenspan, and Arturo Casadevall. Ig Constant Region Effects on Variable Region Structure and Function. Front. Microbiol., 7:22, 4 Feb 2016. PubMed ID: 26870003.
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Jean-Philippe Julien, Jeong Hyun Lee, Gabriel Ozorowski, Yuanzi Hua, Alba Torrents de la Peña, Steven W. de Taeye, Travis Nieusma, Albert Cupo, Anila Yasmeen, Michael Golabek, Pavel Pugach, P. J. Klasse, John P. Moore, Rogier W. Sanders, Andrew B. Ward, and Ian A. Wilson. Design and Structure of Two HIV-1 Clade C SOSIP.664 Trimers That Increase the Arsenal of Native-Like Env Immunogens. Proc. Natl. Acad. Sci. U.S.A., 112(38):11947-11952, 22 Sep 2015. PubMed ID: 26372963.
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Vandana Kalia, Surojit Sarkar, Phalguni Gupta, and Ronald C. Montelaro. Antibody Neutralization Escape Mediated by Point Mutations in the Intracytoplasmic Tail of Human Immunodeficiency Virus Type 1 gp41. J. Virol., 79(4):2097-2107, Feb 2005. PubMed ID: 15681412.
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Sang-Moo Kang, Fu Shi Quan, Chunzi Huang, Lizheng Guo, Ling Ye, Chinglai Yang, and Richard W. Compans. Modified HIV Envelope Proteins with Enhanced Binding to Neutralizing Monoclonal Antibodies. Virology, 331(1):20-32, 5 Jan 2005. PubMed ID: 15582650.
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Hanna C. Kelker, Vincenza R. Itri, and Fred T. Valentine. A Strategy for Eliciting Antibodies against Cryptic, Conserved, Conformationally Dependent Epitopes of HIV Envelope Glycoprotein. PLoS One, 5(1):e8555, 2010. PubMed ID: 20052405.
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Sannula Kesavardhana, Raksha Das, Michael Citron, Rohini Datta, Linda Ecto, Nonavinakere Seetharam Srilatha, Daniel DiStefano, Ryan Swoyer, Joseph G. Joyce, Somnath Dutta, Celia C. LaBranche, David C. Montefiori, Jessica A. Flynn, and Raghavan Varadarajan. Structure-Based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies. J. Biol. Chem., 292(1):278-291, 6 Jan 2017. PubMed ID: 27879316.
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Y. F. Khouri, K. McIntosh, L. Cavacini, M. Posner, M. Pagano, R. Tuomala, and W. A. Marasco. Vertical Transmission of HIV-1. Correlation with Maternal Viral Load and Plasma Levels of CD4 Binding Site Anti-gp120 Antibodies. J. Clin. Invest., 95:732-737, 1995. Differences in levels of Abs directed against the monomeric gp120 and against the V3 loop region of gp120 were not significantly different between transmitting and non-transmitting mothers. Differences were observed in the levels of CD4 binding site antibodies, as determined by the ability of diluted maternal plasma to inhibit binding of the CD4 binding site monoclonal antibody F105 (MAb F105) to monomeric gp120. PubMed ID: 7860754.
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P. Klasse, J. A. McKeating, M. Schutten, M. S. Reitz, Jr., and M. Robert-Guroff. An Immune-Selected Point Mutation in the Transmembrane Protein of Human Immunodeficiency Virus Type 1 (HXB2-Env:Ala 582(--> Thr)) Decreases Viral Neutralization by Monoclonal Antibodies to the CD4-Binding Site. Virology, 196:332-337, 1993. PubMed ID: 8356803.
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Klein2013
Florian Klein, Ron Diskin, Johannes F. Scheid, Christian Gaebler, Hugo Mouquet, Ivelin S. Georgiev, Marie Pancera, Tongqing Zhou, Reha-Baris Incesu, Brooks Zhongzheng Fu, Priyanthi N. P. Gnanapragasam, Thiago Y. Oliveira, Michael S. Seaman, Peter D. Kwong, Pamela J. Bjorkman, and Michel C. Nussenzweig. Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization. Cell, 153(1):126-138, 28 Mar 2013. PubMed ID: 23540694.
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P. Kolchinsky, E. Kiprilov, P. Bartley, R. Rubinstein, and J. Sodroski. Loss of a single N-linked glycan allows CD4-independent human immunodeficiency virus type 1 infection by altering the position of the gp120 V1/V2 variable loops. J. Virol., 75(7):3435--43, Apr 2001. URL: http://jvi.asm.org/cgi/content/full/75/7/3435. PubMed ID: 11238869.
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Anil Korkut and Wayne A. Hendrickson. Structural Plasticity and Conformational Transitions of HIV Envelope Glycoprotein gp120. PLoS One, 7(12):e52170, 2012. PubMed ID: 23300605.
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Victor G. Kramer, Nagadenahalli B. Siddappa, and Ruth M. Ruprecht. Passive Immunization as Tool to Identify Protective HIV-1 Env Epitopes. Curr. HIV Res., 5(6):642-55, Nov 2007. PubMed ID: 18045119.
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M. Kropelin, C. Susal, V. Daniel, and G. Opelz. Inhibition of HIV-1 rgp120 Binding to CD4+ T Cells by Monoclonal Antibodies Directed against the gp120 C1 or C4 Region. Immunol. Lett., 63:19-25, 1998. PubMed ID: 9719434.
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Daniel W. Kulp, Jon M. Steichen, Matthias Pauthner, Xiaozhen Hu, Torben Schiffner, Alessia Liguori, Christopher A. Cottrell, Colin Havenar-Daughton, Gabriel Ozorowski, Erik Georgeson, Oleksandr Kalyuzhniy, Jordan R. Willis, Michael Kubitz, Yumiko Adachi, Samantha M. Reiss, Mia Shin, Natalia de Val, Andrew B. Ward, Shane Crotty, Dennis R. Burton, and William R. Schief. Structure-Based Design of Native-Like HIV-1 Envelope Trimers to Silence Non-Neutralizing Epitopes and Eliminate CD4 Binding. Nat. Commun., 8(1):1655, 21 Nov 2017. PubMed ID: 29162799.
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Kwon2012
Young Do Kwon, Andrés Finzi, Xueling Wu, Cajetan Dogo-Isonagie, Lawrence K. Lee, Lucas R. Moore, Stephen D. Schmidt, Jonathan Stuckey, Yongping Yang, Tongqing Zhou, Jiang Zhu, David A. Vicic, Asim K. Debnath, Lawrence Shapiro, Carole A. Bewley, John R. Mascola, Joseph G. Sodroski, and Peter D. Kwong. Unliganded HIV-1 gp120 Core Structures Assume the CD4-Bound Conformation with Regulation by Quaternary Interactions and Variable Loops. Proc. Natl. Acad. Sci. U.S.A., 109(15):5663-5668, 10 Apr 2012. PubMed ID: 22451932.
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Kwon2015
Young Do Kwon, Marie Pancera, Priyamvada Acharya, Ivelin S. Georgiev, Emma T. Crooks, Jason Gorman, M. Gordon Joyce, Miklos Guttman, Xiaochu Ma, Sandeep Narpala, Cinque Soto, Daniel S. Terry, Yongping Yang, Tongqing Zhou, Goran Ahlsen, Robert T. Bailer, Michael Chambers, Gwo-Yu Chuang, Nicole A. Doria-Rose, Aliaksandr Druz, Mark A. Hallen, Adam Harned, Tatsiana Kirys, Mark K. Louder, Sijy O'Dell, Gilad Ofek, Keiko Osawa, Madhu Prabhakaran, Mallika Sastry, Guillaume B. E. Stewart-Jones, Jonathan Stuckey, Paul V. Thomas, Tishina Tittley, Constance Williams, Baoshan Zhang, Hong Zhao, Zhou Zhou, Bruce R. Donald, Lawrence K. Lee, Susan Zolla-Pazner, Ulrich Baxa, Arne Schön, Ernesto Freire, Lawrence Shapiro, Kelly K. Lee, James Arthos, James B. Munro, Scott C. Blanchard, Walther Mothes, James M. Binley, Adrian B. McDermott, John R. Mascola, and Peter D. Kwong. Crystal Structure, Conformational Fixation and Entry-Related Interactions of Mature Ligand-Free HIV-1 Env. Nat. Struct. Mol. Biol., 22(7):522-531, Jul 2015. PubMed ID: 26098315.
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Kwong2002
Peter D. Kwong, Michael L. Doyle, David J. Casper, Claudia Cicala, Stephanie A. Leavitt, Shahzad Majeed, Tavis D. Steenbeke, Miro Venturi, Irwin Chaiken, Michael Fung, Hermann Katinger, Paul W. I. H. Parren, James Robinson, Donald Van Ryk, Liping Wang, Dennis R. Burton, Ernesto Freire, Richard Wyatt, Joseph Sodroski, Wayne A. Hendrickson, and James Arthos. HIV-1 Evades Antibody-Mediated Neutralization through Conformational Masking of Receptor-Binding Sites. Nature, 420(6916):678-682, 12 Dec 2002. Comment in Nature. 2002 Dec 12;420(6916):623-4. PubMed ID: 12478295.
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Peter D. Kwong, John R. Mascola, and Gary J. Nabel. Rational Design of Vaccines to Elicit Broadly Neutralizing Antibodies to HIV-1. Cold Spring Harb. Perspect. Med., 1(1):a007278, Sep 2011. PubMed ID: 22229123.
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Christy L. Lavine, Socheata Lao, David C. Montefiori, Barton F. Haynes, Joseph G. Sodroski, Xinzhen Yang, and NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI). High-Mannose Glycan-Dependent Epitopes Are Frequently Targeted in Broad Neutralizing Antibody Responses during Human Immunodeficiency Virus Type 1 Infection. J. Virol., 86(4):2153-2164, Feb 2012. PubMed ID: 22156525.
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Daniel P. Leaman, Heather Kinkead, and Michael B. Zwick. In-Solution Virus Capture Assay Helps Deconstruct Heterogeneous Antibody Recognition of Human Immunodeficiency Virus Type 1. J. Virol., 84(7):3382-3395, Apr 2010. PubMed ID: 20089658.
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A. Li, T. W. Baba, J. Sodroski, S. Zolla-Pazner, M. K. Gorny, J. Robinson, M. R. Posner, H. Katinger, C. F. Barbas III, D. R. Burton, T.-C. Chou, and R. M Ruprecht. Synergistic Neutralization of a Chimeric SIV/HIV Type 1 Virus with Combinations of Human Anti-HIV Type 1 Envelope Monoclonal Antibodies or Hyperimmune Globulins. AIDS Res. Hum. Retroviruses, 13:647-656, 1997. Multiple combinations of MAbs were tested for their ability to synergize neutralization of a SHIV construct containing HIV IIIB env. All of the MAb combinations tried were synergistic, suggesting such combinations may be useful for passive immunotherapy or immunoprophylaxis. Because SHIV can replicate in rhesus macaques, such approaches can potentially be studied in an it in vivo monkey model. PubMed ID: 9168233.
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A. Li, H. Katinger, M. R. Posner, L. Cavacini, S. Zolla-Pazner, M. K. Gorny, J. Sodroski, T. C. Chou, T. W. Baba, and R. M. Ruprecht. Synergistic Neutralization of Simian-Human Immunodeficiency Virus SHIV-vpu+ by Triple and Quadruple Combinations of Human Monoclonal Antibodies and High-Titer Anti-Human Immunodeficiency Virus Type 1 Immunoglobulins. J. Virol., 72:3235-3240, 1998. PubMed ID: 9525650.
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Yuxing Li, Stephen A. Migueles, Brent Welcher, Krisha Svehla, Adhuna Phogat, Mark K. Louder, Xueling Wu, George M. Shaw, Mark Connors, Richard T. Wyatt, and John R. Mascola. Broad HIV-1 Neutralization Mediated by CD4-Binding Site Antibodies. Nat. Med., 13(9):1032-1034, Sep 2007. PubMed ID: 17721546.
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Li2012
Yuxing Li, Sijy O'Dell, Richard Wilson, Xueling Wu, Stephen D. Schmidt, Carl-Magnus Hogerkorp, Mark K. Louder, Nancy S. Longo, Christian Poulsen, Javier Guenaga, Bimal K. Chakrabarti, Nicole Doria-Rose, Mario Roederer, Mark Connors, John R. Mascola, and Richard T. Wyatt. HIV-1 Neutralizing Antibodies Display Dual Recognition of the Primary and Coreceptor Binding Sites and Preferential Binding to Fully Cleaved Envelope Glycoproteins. J. Virol., 86(20):11231-11241, Oct 2012. PubMed ID: 22875963.
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Liang2016
Yu Liang, Miklos Guttman, James A. Williams, Hans Verkerke, Daniel Alvarado, Shiu-Lok Hu, and Kelly K. Lee. Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan. J. Virol., 90(20):9224-9236, 15 Oct 2016. PubMed ID: 27489265.
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George Lin and Peter L. Nara. Designing Immunogens to Elicit Broadly Neutralizing Antibodies to the HIV-1 Envelope Glycoprotein. Curr. HIV Res., 5(6):514-541, Nov 2007. PubMed ID: 18045109.
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Hong Ling, Xiao-Yan Zhang, Osamu Usami, and Toshio Hattori. Activation of gp120 of Human Immunodeficiency Virus by Their V3 Loop-Derived Peptides. Biochem. Biophys. Res. Commun., 297(3):625-631, 27 Sep 2002. PubMed ID: 12270140.
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Hong Ling, Peng Xiao, Osamu Usami, and Toshio Hattori. Thrombin Activates Envelope Glycoproteins of HIV Type 1 and Enhances Fusion. Microbes Infect., 6(5):414-420, Apr 2004. PubMed ID: 15109955.
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V. Litwin, K. A. Nagashima, A. M. Ryder, C. H. Chang, J. M. Carver, W. C. Olson, M. Alizon, K. W. Hasel, P. J. Maddon, and G. P. Allaway. Human immunodeficiency virus type 1 membrane fusion mediated by a laboratory-adapted strain and a primary isolate analyzed by resonance energy transfer. J. Virol., 70:6437-6441, 1996. Fusion of primary (JRFL) and TCLA (LAI) strains of the virus were studied. The degree, kinetics, neutral pH and divalent cations requirements were similar for membrane fusion for both viruses. However, the inhibition of fusion by sCD4 and CD4-IgG2 occurred at virus neutralization concentrations for JRFL, but higher concentrations were required to inhibit LAI fusion than to neutralize LAI, suggesting that viral neutralization and fusion-inhibition are distinct. PubMed ID: 8709277.
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Xiao Song Liu, Wen Jun Liu, Kong Nan Zhao, Yue Hua Liu, Graham Leggatt, and Ian H. Frazer. Route of Administration of Chimeric BPV1 VLP Determines the Character of the Induced Immune Responses. Immunol. Cell Biol., 80(1):21-9, Feb 2002. PubMed ID: 11869359.
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Rebecca M. Lynch, Lillian Tran, Mark K. Louder, Stephen D. Schmidt, Myron Cohen, CHAVI 001 Clinical Team Members, Rebecca DerSimonian, Zelda Euler, Elin S. Gray, Salim Abdool Karim, Jennifer Kirchherr, David C. Montefiori, Sengeziwe Sibeko, Kelly Soderberg, Georgia Tomaras, Zhi-Yong Yang, Gary J. Nabel, Hanneke Schuitemaker, Lynn Morris, Barton F. Haynes, and John R. Mascola. The Development of CD4 Binding Site Antibodies during HIV-1 Infection. J. Virol., 86(14):7588-7595, Jul 2012. PubMed ID: 22573869.
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Dmitry Lyumkis, Jean-Philippe Julien, Natalia de Val, Albert Cupo, Clinton S. Potter, Per-Johan Klasse, Dennis R. Burton, Rogier W. Sanders, John P. Moore, Bridget Carragher, Ian A. Wilson, and Andrew B. Ward. Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV-1 Envelope Trimer. Science, 342(6165):1484-1490, 20 Dec 2013. PubMed ID: 24179160.
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Carsten Magnus and Roland R. Regoes. Estimating the Stoichiometry of HIV Neutralization. PLoS Comput. Biol., 6(3):e1000713, Mar 2010. PubMed ID: 20333245.
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W. A. Marasco, J. Bagley, C. Zani, M. Posner, L. Cavacini, W. A. Haseltine, and J. Sodroski. Characterization of the cDNA of a Broadly Reactive Neutralizing Human anti-gp120 Monoclonal Antibody. J. Clin. Invest., 90:1467-1478, 1992. PubMed ID: 1401079.
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W. A. Marasco, W. A. Haseltine, and S. Y. Chen SY. Design, intracellular expression, and activity of a human anti-human immunodeficiency virus type 1 gp120 single-chain antibody. Proc. Natl. Acad. Sci. U.S.A., 90:7889-7893, 1993. Comment in Proc Natl Acad Sci USA 1993 90:7427-8. PubMed ID: 8356098.
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Grégoire Martin, Yide Sun, Bernadette Heyd, Olivier Combes, Jeffrey B Ulmer, Anne Descours, Susan W Barnett, Indresh K Srivastava, and Loïc Martin. A Simple One-Step Method for the Preparation of HIV-1 Envelope Glycoprotein Immunogens Based on a CD4 Mimic Peptide. Virology, 381(2):241-250, 25 Nov 2008. PubMed ID: 18835005.
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Julio Martín-García, Simon Cocklin, Irwin M. Chaiken, and Francisco González-Scarano. Interaction with CD4 and Antibodies to CD4-Induced Epitopes of the Envelope gp120 from a Microglial Cell-Adapted Human Immunodeficiency Virus Type 1 Isolate. J. Virol., 79(11):6703-6713, Jun 2005. PubMed ID: 15890908.
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S. Masiero, C. Del Vecchio, R. Gavioli, G. Mattiuzzo, M. G. Cusi, L. Micheli, F. Gennari, A. Siccardi, W. A. Marasco, G. Palu, and C. Parolin. T-Cell Engineering by a Chimeric T-Cell Receptor with Antibody-Type Specificity for the HIV-1 gp120. Gene Ther., 12(4):299-310, Feb 2005. PubMed ID: 15496956.
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C. M. Mc Cann, R. J. Song, and R. M. Ruprecht. Antibodies: Can They Protect Against HIV Infection? Curr. Drug Targets Infect. Disord., 5(2):95-111, Jun 2005. PubMed ID: 15975016.
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J. S. McDougal, M. S. Kennedy, S. L. Orloff, J. K. A. Nicholson, and T. J. Spira. Mechanisms of Human Immunodeficiency Virus Type 1 (HIV-1) Neutralization: Irreversible Inactivation of Infectivity by Anti-HIV-1 Antibody. J. Virol., 70:5236-5245, 1996. Studies of polyclonal sera autologous virus inactivation indicates that in individuals over time, viral populations emerge that are resistant to inactivating effects of earlier sera. PubMed ID: 8764033.
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Karyn McFadden, Simon Cocklin, Hosahudya Gopi, Sabine Baxter, Sandya Ajith, Naheed Mahmood, Robin Shattock, and Irwin Chaiken. A Recombinant Allosteric Lectin Antagonist of HIV-1 Envelope gp120 Interactions. Proteins, 67(3):617-629, 15 May 2007. PubMed ID: 17348010.
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Nitesh Mishra, Shaifali Sharma, Ayushman Dobhal, Sanjeev Kumar, Himanshi Chawla, Ravinder Singh, Muzamil Ashraf Makhdoomi, Bimal Kumar Das, Rakesh Lodha, Sushil Kumar Kabra, and Kalpana Luthra. Broadly Neutralizing Plasma Antibodies Effective against Autologous Circulating Viruses in Infants with Multivariant HIV-1 Infection. Nat. Commun., 11(1):4409, 2 Sep 2020. PubMed ID: 32879304.
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D. C. Montefiori, B. S. Graham, J. Zhou, J. Zhou, R. A. Bucco, D. H. Schwartz, L. A. Cavacini, M. R. Posner, and the NIH-NIAID AIDS Vaccine Clinical Trials Network. V3-Specific Neutralizing Antibodies in Sera From HIV-1 gp160-Immunized Volunteers Block Virus Fusion and Act Synergistically with Human Monoclonal Antibody to the Conformation-dependent CD4 Binding Site of gp120. J. Clin. Invest., 92:840-847, 1993. PubMed ID: 8349820.
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Moody2015
M. Anthony Moody, Feng Gao, Thaddeus C. Gurley, Joshua D. Amos, Amit Kumar, Bhavna Hora, Dawn J. Marshall, John F. Whitesides, Shi-Mao Xia, Robert Parks, Krissey E. Lloyd, Kwan-Ki Hwang, Xiaozhi Lu, Mattia Bonsignori, Andrés Finzi, Nathan A. Vandergrift, S. Munir Alam, Guido Ferrari, Xiaoying Shen, Georgia D. Tomaras, Gift Kamanga, Myron S. Cohen, Noel E. Sam, Saidi Kapiga, Elin S. Gray, Nancy L. Tumba, Lynn Morris, Susan Zolla-Pazner, Miroslaw K. Gorny, John R. Mascola, Beatrice H. Hahn, George M. Shaw, Joseph G. Sodroski, Hua-Xin Liao, David C. Montefiori, Peter T. Hraber, Bette T. Korber, and Barton F. Haynes. Strain-Specific V3 and CD4 Binding Site Autologous HIV-1 Neutralizing Antibodies Select Neutralization-Resistant Viruses. Cell Host Microbe., 18(3):354-362, 9 Sep 2015. PubMed ID: 26355218.
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J. P. Moore and D. D. Ho. Antibodies to discontinuous or conformationally sensitive epitopes on the gp120 glycoprotein of human immunodeficiency virus type 1 are highly prevalent in sera of infected humans. J. Virol., 67:863-875, 1993. CD4BS antibodies are prevalent in HIV-1-positive sera, while neutralizing MAbs to C4, V2, and V3 and MAbs to linear epitopes are less common. Most linear epitope MAbs in human sera are directed against the V3 region, and cross-reactive MAbs tend to be directed against discontinuous epitopes. PubMed ID: 7678308.
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Moyo2018
Thandeka Moyo, June Ereño-Orbea, Rajesh Abraham Jacob, Clara E. Pavillet, Samuel Mundia Kariuki, Emily N. Tangie, Jean-Philippe Julien, and Jeffrey R. Dorfman. Molecular Basis of Unusually High Neutralization Resistance in Tier 3 HIV-1 Strain 253-11. J. Virol., 92(14), 15 Jul 2018. PubMed ID: 29618644.
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Asa Ohagen, Amy Devitt, Kevin J. Kunstman, Paul R. Gorry, Patrick P. Rose, Bette Korber, Joann Taylor, Robert Levy, Robert L. Murphy, Steven M. Wolinsky, and Dana Gabuzda. Genetic and Functional Analysis of Full-Length Human Immunodeficiency Virus Type 1 env Genes Derived from Brain and Blood of Patients with AIDS. J. Virol., 77(22):12336-12345, Nov 2003. PubMed ID: 14581570.
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J. Oscherwitz, F. M. Gotch, K. B. Cease, and J. A. Berzofsky. New Insights and Approaches Regarding B- and T-Cell Epitopes in HIV Vaccine Design. AIDS, 13(Suppl A):S163-174, 1999. PubMed ID: 10885773.
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Beatriz Pacheco, Stephane Basmaciogullari, Jason A. Labonte, Shi-Hua Xiang, and Joseph Sodroski. Adaptation of the Human Immunodeficiency Virus Type 1 Envelope Glycoproteins to New World Monkey Receptors. J. Virol., 82(1):346-357, Jan 2008. PubMed ID: 17959679.
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Marie Pancera and Richard Wyatt. Selective Recognition of Oligomeric HIV-1 Primary Isolate Envelope Glycoproteins by Potently Neutralizing Ligands Requires Efficient Precursor Cleavage. Virology, 332(1):145-156, 5 Feb 2005. PubMed ID: 15661147.
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Marie Pancera, Jacob Lebowitz, Arne Schön, Ping Zhu, Ernesto Freire, Peter D. Kwong, Kenneth H. Roux, Joseph Sodroski, and Richard Wyatt. Soluble Mimetics of Human Immunodeficiency Virus Type 1 Viral Spikes Produced by Replacement of the Native Trimerization Domain with a Heterologous Trimerization Motif: Characterization and Ligand Binding Analysis. J. Virol., 79(15):9954-9969, Aug 2005. PubMed ID: 16014956.
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Pancera2010a
Marie Pancera, Shahzad Majeed, Yih-En Andrew Ban, Lei Chen, Chih-chin Huang, Leopold Kong, Young Do Kwon, Jonathan Stuckey, Tongqing Zhou, James E. Robinson, William R. Schief, Joseph Sodroski, Richard Wyatt, and Peter D. Kwong. Structure of HIV-1 gp120 with gp41-Interactive Region Reveals Layered Envelope Architecture and Basis of Conformational Mobility. Proc. Natl. Acad. Sci. U.S.A., 107(3):1166-1171, 19 Jan 2010. PubMed ID: 20080564.
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Ralph Pantophlet, Erica Ollmann Saphire, Pascal Poignard, Paul W. H. I. Parren, Ian A. Wilson, and Dennis R. Burton. Fine Mapping of the Interaction of Neutralizing and Nonneutralizing Monoclonal Antibodies with the CD4 Binding Site of Human Immunodeficiency Virus Type 1 gp120. J. Virol., 77(1):642-658, Jan 2003. PubMed ID: 12477867.
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Ralph Pantophlet, Ian A. Wilson, and Dennis R. Burton. Hyperglycosylated Mutants of Human Immunodeficiency Virus (HIV) Type 1 Monomeric gp120 as Novel Antigens for HIV Vaccine Design. J. Virol., 77(10):5889-8901, May 2003. PubMed ID: 12719582.
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R. Pantophlet, I. A. Wilson, and D. R. Burton. Improved Design of an Antigen with Enhanced Specificity for the Broadly HIV-Neutralizing Antibody b12. Protein Eng. Des. Sel., 17(10):749-758, Oct 2004. PubMed ID: 15542540.
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E. J. Park, M. K. Gorny, S. Zolla-Pazner, and G. V. Quinnan. A global neutralization resistance phenotype of human immunodeficiency virus type 1 is determined by distinct mechanisms mediating enhanced infectivity and conformational change of the envelope complex. J. Virol., 74:4183-91, 2000. PubMed ID: 10756031.
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P. W. Parren, M. C. Gauduin, R. A. Koup, P. Poignard, Q. J. Sattentau, P. Fisicaro, and D. R. Burton. Erratum to Relevance of the Antibody Response against Human Immunodeficiency Virus Type 1 Envelope to Vaccine Design. Immunol. Lett., 58:125-132, 1997. corrected and republished article originally printed in Immunol. Lett. 1997 Jun;57(1-3):105-112. PubMed ID: 9271324.
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Perdomo2008
Maria F. Perdomo, Michael Levi, Matti Sällberg, and Anders Vahlne. Neutralization of HIV-1 by Redirection of Natural Antibodies. Proc. Natl. Acad. Sci. U.S.A., 105(34):12515-12520, 26 Aug 2008. PubMed ID: 18719129.
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Phogat2007
S. Phogat, R. T. Wyatt, and G. B. Karlsson Hedestam. Inhibition of HIV-1 Entry by Antibodies: Potential Viral and Cellular Targets. J. Intern. Med., 262(1):26-43, Jul 2007. PubMed ID: 17598813.
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Pincus1993a
S. H. Pincus, K. G. Messer, D. H. Schwartz, G. K. Lewis, B. S. Graham, W. A. Blattner, and G. Fisher. Differences in the Antibody Response to Human Immunodeficiency Virus-1 Envelope Glycoprotein (gp160) in Infected Laboratory Workers and Vaccinees. J. Clin. Invest., 91:1987-1996, 1993. PubMed ID: 7683694.
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Pincus1996
S. H. Pincus, K. Wehrly, R. Cole, H. Fang, G. K. Lewis, J. McClure, A. J. Conley, B. Wahren, M. R. Posner, A. L. Notkins, S. A. Tilley, A. Pinter, L. Eiden, M. Teintze, D. Dorward, and V. V. Tolstikov. In Vitro Effects of Anti-HIV Immunotoxins Directed against Multiple Epitopes on HIV Type 1 Envelope Glycoprotein 160. AIDS Res. Hum. Retroviruses, 12:1041-1051, 1996. A panel of anti-gp160 MAbs to was used to construct anti-HIV immunotoxins by coupling antibodies to ricin A chain (RAC). The ability of the immunotoxins to kill HIV-1-infected cells was tested in tissue culture. Immunotoxins that bind epitopes on the cell surface killed infected cells, although killing was not directly proportional to binding. The activity of anti-gp41 immunotoxins was markedly enhanced in the presence of sCD4. PubMed ID: 8827220.
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Poignard2003
Pascal Poignard, Maxime Moulard, Edwin Golez, Veronique Vivona, Michael Franti, Sara Venturini, Meng Wang, Paul W. H. I. Parren, and Dennis R. Burton. Heterogeneity of Envelope Molecules Expressed on Primary Human Immunodeficiency Virus Type 1 Particles as Probed by the Binding of Neutralizing and Nonneutralizing Antibodies. J. Virol., 77(1):353-365, Jan 2003. PubMed ID: 12477840.
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Pollara2013
Justin Pollara, Mattia Bonsignori, M. Anthony Moody, Marzena Pazgier, Barton F. Haynes, and Guido Ferrari. Epitope Specificity of Human Immunodeficiency Virus-1 Antibody Dependent Cellular Cytotoxicity (ADCC) Responses. Curr. HIV Res., 11(5):378-387, Jul 2013. PubMed ID: 24191939.
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Posner1992
M. R. Posner, H. S. Elboim, T. Cannon, L. Cavicini, and T. Hideshima. Functional Activity of an HIV-1 Neutralizing IgG Human Monoclonal Antibody: ADCC and Complement-Mediated Lysis. AIDS Res. Hum. Retroviruses, 8:553-558, 1992. PubMed ID: 1381201.
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Posner1992a
M. Posner, L. Cavacini, C. Emes, J. Power, M. Gorny, and S. Zolla-Pazner. Human Monoclonal Antibodies to the V3 Loop of gp120 Mediate Variable and Distinct Effects on Binding and Viral Neutralization by a Human Monoclonal Antibody to the CD4 Binding Site. J. Cell Biochem., Suppl O(16 part E):69, 1992.
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Posner1993
M. R. Posner, L. A. Cavacini, C. L. Emes, J. Power, and R. Byrn. Neutralization of HIV-1 by F105, a Human Monoclonal Antibody to the CD4 Binding Site of gp120. J. Acquir. Immune Defic. Syndr., 6:7-14, 1993. PubMed ID: 8417177.
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Posner1995
M. R. Posner, L. A. Cavacini, J. Gambertoglio, C. Spino, E. Wolfe, C. Trapnell, N. Ketter, S. Hammer, and M. Samore. An ACTG Phase Ia Safety and Pharmacokinetic Trial of Immunotherapy with the Anti-CD4 Binding Site Human Monoclonal Antibody F105. Natl. Conf. Hum. Retroviruses Relat. Infect. (2nd), 1995:150, 1995. Aidsline: 95920546 Abstract: Eight HIV-positive asymptomatic individuals were given F105 by intravenous infusion. There were no clinical side effects or changes in biochemical tests among the eight volunteers. The plasma half life of F105 had a range of 8.7-18.6 days.
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Potts1993
B. J. Potts, K. G. Field, Y. Wu, M. Posner, L. Cavacini, and M. White-Scharf. Synergistic Inhibition of HIV-1 by CD4 Binding Domain Reagents and V3-Directed Monoclonal Antibodies. Virology, 197:415-419, 1993. Four anti-V3 loop MAbs, (59.1, 83.1, 50.1, and 58.2), were evaluated for their affinity, neutralization potencies, and their ability to synergize F105 or sCD4 neutralization. The most important parameter for synergy was the capacity to neutralize a given virus independently. PubMed ID: 8212576.
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Prabakaran2006
Ponraj Prabakaran, Jianhua Gan, You-Qiang Wu, Mei-Yun Zhang, Dimiter S. Dimitrov, and Xinhua Ji. Structural Mimicry of CD4 by a Cross-Reactive HIV-1 Neutralizing Antibody with CDR-H2 and H3 Containing Unique Motifs. J. Mol. Biol., 357(1):82-99, 17 Mar 2006. PubMed ID: 16426633.
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Prevost2018
Jérémie Prévost, Jonathan Richard, Shilei Ding, Beatriz Pacheco, Roxanne Charlebois, Beatrice H Hahn, Daniel E Kaufmann, and Andrés Finzi. Envelope Glycoproteins Sampling States 2/3 Are Susceptible to ADCC by Sera from HIV-1-Infected Individuals. Virology, 515:38-45, Feb 2018. PubMed ID: 29248757.
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Pugach2015
Pavel Pugach, Gabriel Ozorowski, Albert Cupo, Rajesh Ringe, Anila Yasmeen, Natalia de Val, Ronald Derking, Helen J. Kim, Jacob Korzun, Michael Golabek, Kevin de Los Reyes, Thomas J. Ketas, Jean-Philippe Julien, Dennis R. Burton, Ian A. Wilson, Rogier W. Sanders, P. J. Klasse, Andrew B. Ward, and John P. Moore. A Native-Like SOSIP.664 Trimer Based on an HIV-1 Subtype B env Gene. J. Virol., 89(6):3380-3395, Mar 2015. PubMed ID: 25589637.
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Raja2003
Aarti Raja, Miro Venturi, Peter Kwong, and Joseph Sodroski. CD4 Binding Site Antibodies Inhibit Human Immunodeficiency Virus gp120 Envelope Glycoprotein Interaction with CCR5. J. Virol., 77(1):713-718, Jan 2003. PubMed ID: 12477875.
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RobertGuroff2000
Marjorie Robert-Guroff. IgG Surfaces as an Important Component in Mucosal Protection. Nat. Med., 6(2):129-130, Feb 2000. PubMed ID: 10655090.
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Saha2012
Piyali Saha, Sanchari Bhattacharyya, Sannula Kesavardhana, Edward Roshan Miranda, P. Shaik Syed Ali, Deepak Sharma, and Raghavan Varadarajan. Designed Cyclic Permutants of HIV-1 gp120: Implications for Envelope Trimer Structure and Immunogen Design. Biochemistry, 51(9):1836-1847, 6 Mar 2012. PubMed ID: 22329717.
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Sanders2013
Rogier W. Sanders, Ronald Derking, Albert Cupo, Jean-Philippe Julien, Anila Yasmeen, Natalia de Val, Helen J. Kim, Claudia Blattner, Alba Torrents de la Peña, Jacob Korzun, Michael Golabek, Kevin de los Reyes, Thomas J. Ketas, Marit J. van Gils, C. Richter King, Ian A. Wilson, Andrew B. Ward, P. J. Klasse, and John P. Moore. A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but not Non-Neutralizing Antibodies. PLoS Pathog., 9(9):e1003618, Sep 2013. PubMed ID: 24068931.
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Schiffner2016
Torben Schiffner, Natalia de Val, Rebecca A. Russell, Steven W. de Taeye, Alba Torrents de la Peña, Gabriel Ozorowski, Helen J. Kim, Travis Nieusma, Florian Brod, Albert Cupo, Rogier W. Sanders, John P. Moore, Andrew B. Ward, and Quentin J. Sattentau. Chemical Cross-Linking Stabilizes Native-Like HIV-1 Envelope Glycoprotein Trimer Antigens. J. Virol., 90(2):813-828, 28 Oct 2015. PubMed ID: 26512083.
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Schiffner2018
Torben Schiffner, Jesper Pallesen, Rebecca A. Russell, Jonathan Dodd, Natalia de Val, Celia C. LaBranche, David Montefiori, Georgia D. Tomaras, Xiaoying Shen, Scarlett L. Harris, Amin E. Moghaddam, Oleksandr Kalyuzhniy, Rogier W. Sanders, Laura E. McCoy, John P. Moore, Andrew B. Ward, and Quentin J. Sattentau. Structural and Immunologic Correlates of Chemically Stabilized HIV-1 Envelope Glycoproteins. PLoS Pathog., 14(5):e1006986, May 2018. PubMed ID: 29746590.
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Selvarajah2005
Suganya Selvarajah, Bridget Puffer, Ralph Pantophlet, Mansun Law, Robert W. Doms, and Dennis R. Burton. Comparing Antigenicity and Immunogenicity of Engineered gp120. J. Virol., 79(19):12148-12163, Oct 2005. PubMed ID: 16160142.
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Si2001
Zhihai Si, Mark Cayabyab, and Joseph Sodroski. Envelope Glycoprotein Determinants of nEutralization Resistance in a Simian-Human Immunodeficiency Virus (SHIV-HXBc2P 3.2) Derived by Passage in Monkeys. J. Virol., 75(9):4208-4218, May 2001. PubMed ID: 11287570.
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Srivastava2005
Indresh K. Srivastava, Jeffrey B. Ulmer, and Susan W. Barnett. Role of Neutralizing Antibodies in Protective Immunity Against HIV. Hum. Vaccin., 1(2):45-60, Mar-Apr 2005. PubMed ID: 17038830.
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Sugiura1999
W. Sugiura, C. C. Broder, B. Moss, and P. L. Earl. Characterization of conformation-dependent anti-gp120 murine monoclonal antibodies produced by immunization with monomeric and oligomeric human immunodeficiency virus type 1 envelope proteins. Virology, 254:257-67, 1999. PubMed ID: 9986792.
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Sullivan1995
N. Sullivan, Y. Sun, J. Li, W. Hofmann, and J. Sodroski. Replicative Function and Neutralization Sensitivity of Envelope Glycoproteins from Primary and T-Cell Line-Passaged Human Immunodeficiency Virus Type 1 Isolates. J. Virol., 69:4413-4422, 1995. Three gp120 molecules derived from primary isolates were compared to T-cell adapted lines HXBc2 and MN. Complementation experiments showed viral entry into peripheral blood mononuclear cell targets was five-fold less efficient for primary isolates. Anti-CD4 binding site neutralizing MAbs were far less potent against primary isolates, and the single anti-V3 MAb tested was 3-fold less potent. The differences in neutralization efficiency could not be attributed to differences in affinity for monomeric gp120, but were related to binding to the oligomeric complex. Enhanced infectivity of primary isolates was observed using sCD4 and MAb F105, which can neutralize T-cell adapted strains. PubMed ID: 7769703.
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Sullivan1998b
N. Sullivan, Y. Sun, J. Binley, J. Lee, C. F. Barbas III, P. W. H. I. Parren, D. R. Burton, and J. Sodroski. Determinants of human immunodeficiency virus type 1 envelope glycoprotein activation by soluble CD4 and monoclonal antibodies. J. Virol., 72:6332-8, 1998. PubMed ID: 9658072.
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Sundling2012
Christopher Sundling, Yuxing Li, Nick Huynh, Christian Poulsen, Richard Wilson, Sijy O'Dell, Yu Feng, John R. Mascola, Richard T. Wyatt, and Gunilla B. Karlsson Hedestam. High-Resolution Definition of Vaccine-Elicited B Cell Responses Against the HIV Primary Receptor Binding Site. Sci. Transl. Med., 4(142):142ra96, 11 Jul 2012. PubMed ID: 22786681.
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Teeraputon2005
Sirilak Teeraputon, Suda Louisirirojchanakul, and Prasert Auewarakul. N-Linked Glycosylation in C2 Region of HIV-1 Envelope Reduces Sensitivity to Neutralizing Antibodies. Viral Immunol., 18(2):343-353, Summer 2005. PubMed ID: 16035946.
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Thali1991
M. Thali, U. Olshevsky, C. Furman, D. Gabuzda, M. Posner, and J. Sodroski. Characterization of a discontinuous human immunodeficiency virus type 1 gp120 epitope recognized by a broadly reactive neutralizing human monoclonal antibody. J. Virol., 65(11):6188-6193, 1991. An early detailed characterization of the mutations that inhibit the neutralization capacity of the MAb F105, that binds to a discontinuous epitope and inhibits CD4 binding to gp120. PubMed ID: 1717717.
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Thali1992a
M. Thali, C. Furman, D. D. Ho, J. Robinson, S. Tilley, A. Pinter, and J. Sodroski. Discontinuous, Conserved Neutralization Epitopes Overlapping the CD4-Binding Region of Human Immunodeficiency Virus Type 1 gp120 Envelope Glycoprotein. J. Virol., 66:5635-5641, 1992. Maps the relationship between amino acid substitutions that reduce CD4-gp120 interaction, and amino acid substitutions that reduce the binding of discontinuous epitope MAbs that inhibit CD4 binding. PubMed ID: 1380099.
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Thali1994
M. Thali, M. Charles, C. Furman, L. Cavacini, M. Posner, J. Robinson, and J. Sodroski. Resistance to Neutralization by Broadly Reactive Antibodies to the Human Immunodeficiency Virus Type 1 gp120 Glycoprotein Conferred by a gp41 Amino Acid Change. J. Virol., 68:674-680, 1994. A T->A amino acid substitution at position 582 of gp41 conferred resistance to neutralization to 30\% of HIV positive sera (Wilson et al. J Virol 64:3240-48 (1990)). Monoclonal antibodies that bound to the CD4 binding site were unable to neutralize this virus, but the mutation did not reduce the neutralizing capacity of a V2 region MAb G3-4, V3 region MAbs, or gp41 neutralizing MAb 2F5. PubMed ID: 7507184.
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Turbica1995
I. Turbica, M. Posner, C. Bruck, and F. Barin. Simple Enzyme Immunoassay for Titration of Antibodies to the CD4-Binding Site of Human Immunodeficiency Virus Type 1 gp120. J. Clin. Microbiol., 33:3319-3323, 1995. PubMed ID: 8586727.
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Visciano2008
Maria Luisa Visciano, Michael Tuen, Miroslaw K. Gorny, and Catarina E. Hioe. In Vivo Alteration of Humoral Responses to HIV-1 Envelope Glycoprotein gp120 by Antibodies to the CD4-Binding Site of gp120. Virology, 372(2):409-420, 15 Mar 2008. PubMed ID: 18054978.
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Wang2007a
Bao-Zhong Wang, Weimin Liu, Sang-Moo Kang, Munir Alam, Chunzi Huang, Ling Ye, Yuliang Sun, Yingying Li, Denise L. Kothe, Peter Pushko, Terje Dokland, Barton F. Haynes, Gale Smith, Beatrice H. Hahn, and Richard W. Compans. Incorporation of High Levels of Chimeric Human Immunodeficiency Virus Envelope Glycoproteins into Virus-Like Particles. J. Virol., 81(20):10869-10878, Oct 2007. PubMed ID: 17670815.
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Watkins1993
B. A. Watkins, M. S. Reitz, Jr., C. A. Wilson, K. Aldrich, A. E. Davis, and M. Robert-Guroff. Immune escape by human immunodeficiency virus type 1 from neutralizing antibodies: evidence for multiple pathways. J. Virol., 67:7493-7500, 1993. A neutralization resistance point mutation (HXB2 A281V) was studied using a variety of MAbs, and it was shown that this substitution affects a different epitope than a previously characterized neutralization escape mutant (A582T) (Reitz 1988, Wilson 1990). PubMed ID: 7693973.
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Wilkinson2005
Royce A. Wilkinson, Chayne Piscitelli, Martin Teintze, Lisa A. Cavacini, Marshall R. Posner, and C. Martin Lawrence. Structure of the Fab Fragment of F105, a Broadly Reactive Anti-Human Immunodeficiency Virus (HIV) Antibody That Recognizes the CD4 Binding Site of HIV Type 1 gp120. J. Virol., 79(20):13060-13069, Oct 2005. PubMed ID: 16189008.
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Wilkinson2007
Royce A. Wilkinson, Jody R. Evans, Jon M. Jacobs, Dustin Slunaker, Seth H. Pincus, Abraham Pinter, Charles A. Parkos, James B. Burritt, and Martin Teintze. Peptides Selected from a Phage Display Library with an HIV-Neutralizing Antibody Elicit Antibodies to HIV gp120 in Rabbits, But Not to The Same Epitope. AIDS Res. Hum. Retroviruses, 23(11):1416-1427, Nov 2007. PubMed ID: 18184085.
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Williams2017a
Wilton B. Williams, Jinsong Zhang, Chuancang Jiang, Nathan I. Nicely, Daniela Fera, Kan Luo, M. Anthony Moody, Hua-Xin Liao, S. Munir Alam, Thomas B. Kepler, Akshaya Ramesh, Kevin Wiehe, James A. Holland, Todd Bradley, Nathan Vandergrift, Kevin O. Saunders, Robert Parks, Andrew Foulger, Shi-Mao Xia, Mattia Bonsignori, David C. Montefiori, Mark Louder, Amanda Eaton, Sampa Santra, Richard Scearce, Laura Sutherland, Amanda Newman, Hilary Bouton-Verville, Cindy Bowman, Howard Bomze, Feng Gao, Dawn J. Marshall, John F. Whitesides, Xiaoyan Nie, Garnett Kelsoe, Steven G. Reed, Christopher B. Fox, Kim Clary, Marguerite Koutsoukos, David Franco, John R. Mascola, Stephen C. Harrison, Barton F. Haynes, and Laurent Verkoczy. Initiation of HIV Neutralizing B Cell Lineages with Sequential Envelope Immunizations. Nat. Commun., 8(1):1732, 23 Nov 2017. PubMed ID: 29170366.
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Willis2022
Jordan R. Willis, Zachary T. Berndsen, Krystal M. Ma, Jon M. Steichen, Torben Schiffner, Elise Landais, Alessia Liguori, Oleksandr Kalyuzhniy, Joel D. Allen, Sabyasachi Baboo, Oluwarotimi Omorodion, Jolene K. Diedrich, Xiaozhen Hu, Erik Georgeson, Nicole Phelps, Saman Eskandarzadeh, Bettina Groschel, Michael Kubitz, Yumiko Adachi, Tina-Marie Mullin, Nushin B. Alavi, Samantha Falcone, Sunny Himansu, Andrea Carfi, Ian A. Wilson, John R. Yates III, James C. Paulson, Max Crispin, Andrew B. Ward, and William R. Schief. Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors. Immunity, 55(11):2149-2167e9 doi, Nov 2022. PubMed ID: 36179689
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Wisnewski1996
A. Wisnewski, L. Cavacini, and M. Posner. Human antibody variable region gene usage in HIV-1 infection. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol., 11:31-38, 1996. PubMed ID: 8528730.
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Wolfe1996
E. J. Wolfe, L. A. Cavacini, M. H. Samore, M. R. Posner, C. Kozial, C. Spino, C. B. Trapnell, N. Ketter, S. Hammer, and J. G. Gambertoglio. Pharmacokinetics of F105, a Human Monoclonal Antibody, in Persons Infected with Human Immunodeficiency Virus Type 1. Clin. Pharmacol. Ther., 59:662-667, 1996. PubMed ID: 8681491.
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Wu2008
Xueling Wu, Anna Sambor, Martha C. Nason, Zhi-Yong Yang, Lan Wu, Susan Zolla-Pazner, Gary J. Nabel, and John R. Mascola. Soluble CD4 Broadens Neutralization of V3-Directed Monoclonal Antibodies and Guinea Pig Vaccine Sera against HIV-1 Subtype B and C Reference Viruses. Virology, 380(2):285-295, 25 Oct 2008. PubMed ID: 18804254.
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Wu2009
Xueling Wu, Tongqing Zhou, Sijy O'Dell, Richard T. Wyatt, Peter D. Kwong, and John R. Mascola. Mechanism of Human Immunodeficiency Virus Type 1 Resistance to Monoclonal Antibody b12 That Effectively Targets the Site of CD4 Attachment. J. Virol., 83(21):10892-10907, Nov 2009. PubMed ID: 19692465.
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Wu2009a
Lan Wu, Tongqing Zhou, Zhi-yong Yang, Krisha Svehla, Sijy O'Dell, Mark K. Louder, Ling Xu, John R. Mascola, Dennis R. Burton, James A. Hoxie, Robert W. Doms, Peter D. Kwong, and Gary J. Nabel. Enhanced Exposure of the CD4-Binding Site to Neutralizing Antibodies by Structural Design of a Membrane-Anchored Human Immunodeficiency Virus Type 1 gp120 Domain. J. Virol., 83(10):5077-5086, May 2009. PubMed ID: 19264769.
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Wu2010
Xueling Wu, Zhi-Yong Yang, Yuxing Li, Carl-Magnus Hogerkorp, William R. Schief, Michael S. Seaman, Tongqing Zhou, Stephen D. Schmidt, Lan Wu, Ling Xu, Nancy S. Longo, Krisha McKee, Sijy O'Dell, Mark K. Louder, Diane L. Wycuff, Yu Feng, Martha Nason, Nicole Doria-Rose, Mark Connors, Peter D. Kwong, Mario Roederer, Richard T. Wyatt, Gary J. Nabel, and John R. Mascola. Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1. Science, 329(5993):856-861, 13 Aug 2010. PubMed ID: 20616233.
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Wu2011
Xueling Wu, Tongqing Zhou, Jiang Zhu, Baoshan Zhang, Ivelin Georgiev, Charlene Wang, Xuejun Chen, Nancy S. Longo, Mark Louder, Krisha McKee, Sijy O'Dell, Stephen Perfetto, Stephen D. Schmidt, Wei Shi, Lan Wu, Yongping Yang, Zhi-Yong Yang, Zhongjia Yang, Zhenhai Zhang, Mattia Bonsignori, John A. Crump, Saidi H. Kapiga, Noel E. Sam, Barton F. Haynes, Melissa Simek, Dennis R. Burton, Wayne C. Koff, Nicole A. Doria-Rose, Mark Connors, NISC Comparative Sequencing Program, James C. Mullikin, Gary J. Nabel, Mario Roederer, Lawrence Shapiro, Peter D. Kwong, and John R. Mascola. Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing. Science, 333(6049):1593-1602, 16 Sep 2011. PubMed ID: 21835983.
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Wyatt1992
R. Wyatt, M. Thali, S. Tilley, A. Pinter, M. Posner, D. Ho, J. Robinson, and J. Sodroski. Relationship of the Human Immunodeficiency Virus Type 1 gp120 Third Variable Loop to Elements of the CD4 Binding Site. J. Virol., 66:6997-7004, 1992. This paper examines mutations which alter MAb binding and neutralization. Anti-V3 MAb 9284 has enhanced binding due to a mutation in the C4 region that is also important for CD4 binding, and anti-CD4 binding MAbs F105, 1.5e and 1125H show increased precipitation of a gp120 from which the V3 loop was deleted, relative to wild type, in RIPA buffer containing non-ionic detergents. PubMed ID: 1279195.
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Wyatt1993
R. Wyatt, N. Sullivan, M. Thali, H. Repke, D. Ho, J. Robinson, M. Posner, and J. Sodroski. Functional and Immunologic Characterization of Human Immunodeficiency Virus Type 1 Envelope Glycoproteins Containing Deletions of the Major Variable Regions. J. Virol., 67:4557-4565, 1993. Affinity of neutralizing MAbs directed against the CD4 binding site was increased dramatically by deletion mutants across the V1/V2 and V3 structures, suggesting that these domains mask these conserved discontinuous epitopes. PubMed ID: 8331723.
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Wyatt1997
R. Wyatt, E. Desjardin, U. Olshevsky, C. Nixon, J. Binley, V. Olshevsky, and J. Sodroski. Analysis of the Interaction of the Human Immunodeficiency Virus Type 1 gp120 Envelope Glycoprotein with the gp41 Transmembrane Glycoprotein. J. Virol., 71:9722-9731, 1997. This study characterized the binding of gp120 and gp41 by comparing Ab reactivity to soluble gp120 and to a soluble complex of gp120 and gp41 called sgp140. The occlusion of gp120 epitopes in the sgp140 complex provides a guide to the gp120 domains that interact with gp41, localizing them in C1 and C5 of gp120. Mutations that disrupt the binding of the occluded antibodies do not influence NAb binding or CD4 binding, thus if the gp41 binding domain is deleted, the immunologically desirable features of gp120 for vaccine design are still intact. PubMed ID: 9371638.
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Wyatt1998
R. Wyatt, P. D. Kwong, E. Desjardins, R. W. Sweet, J. Robinson, W. A. Hendrickson, and J. G. Sodroski. The Antigenic Structure of the HIV gp120 Envelope Glycoprotein. Nature, 393:705-711, 1998. Comment in Nature 1998 Jun 18;393(6686):630-1. The spatial organization of the neutralizing epitopes of gp120 is described, based on epitope maps interpreted in the context of the X-ray crystal structure of a ternary complex that includes a gp120 core, CD4 and a neutralizing antibody. PubMed ID: 9641684.
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Xiang2002
Shi-Hua. Xiang, Peter D. Kwong, Rishi Gupta, Carlo D. Rizzuto, David J. Casper, Richard Wyatt, Liping Wang, Wayne A. Hendrickson, Michael L. Doyle, and Joseph Sodroski. Mutagenic Stabilization and/or Disruption of a CD4-Bound State Reveals Distinct Conformations of the Human Immunodeficiency Virus Type 1 gp120 Envelope Glycoprotein. J. Virol., 76(19):9888-9899, Oct 2002. PubMed ID: 12208966.
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Xiang2003
Shi-Hua Xiang, Liping Wang, Mariam Abreu, Chih-Chin Huang, Peter D. Kwong, Eric Rosenberg, James E. Robinson, and Joseph Sodroski. Epitope Mapping and Characterization of a Novel CD4-Induced Human Monoclonal Antibody Capable of Neutralizing Primary HIV-1 Strains. Virology, 315(1):124-134, 10 Oct 2003. PubMed ID: 14592765.
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Xu2002
Weidong Xu, Regina Hofmann-Lehmann, Harold M. McClure, and Ruth M. Ruprecht. Passive Immunization with Human Neutralizing Monoclonal Antibodies: Correlates of Protective Immunity against HIV. Vaccine, 20(15):1956-1960, 6 May 2002. PubMed ID: 11983253.
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Yang2000
Xinzhen Yang, Michael Farzan, Richard Wyatt, and Joseph Sodroski. Characterization of Stable, Soluble Trimers Containing Complete Ectodomains of Human Immunodeficiency Virus Type 1 Envelope Glycoproteins. J. Virol., 74(12):5716-5725, Jun 2000. PubMed ID: 10823881.
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Yang2002
Xinzhen Yang, Juliette Lee, Erin M. Mahony, Peter D. Kwong, Richard Wyatt, and Joseph Sodroski. Highly Stable Trimers Formed by Human Immunodeficiency Virus Type 1 Envelope Glycoproteins Fused with the Trimeric Motif of T4 Bacteriophage Fibritin. J. Virol., 76(9):4634-4642, 1 May 2002. PubMed ID: 11932429.
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Yang2005b
Xinzhen Yang, Svetla Kurteva, Sandra Lee, and Joseph Sodroski. Stoichiometry of Antibody Neutralization of Human Immunodeficiency Virus Type 1. J. Virol., 79(6):3500-3508, Mar 2005. PubMed ID: 15731244.
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York2001
J. York, K. E. Follis, M. Trahey, P. N. Nyambi, S. Zolla-Pazner, and J. H. Nunberg. Antibody binding and neutralization of primary and T-cell line-adapted isolates of human immunodeficiency virus type 1. J. Virol., 75(6):2741--52, Mar 2001. URL: http://jvi.asm.org/cgi/content/full/75/6/2741. PubMed ID: 11222697.
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Yu2018
Wen-Han Yu, Peng Zhao, Monia Draghi, Claudia Arevalo, Christina B. Karsten, Todd J. Suscovich, Bronwyn Gunn, Hendrik Streeck, Abraham L. Brass, Michael Tiemeyer, Michael Seaman, John R. Mascola, Lance Wells, Douglas A. Lauffenburger, and Galit Alter. Exploiting Glycan Topography for Computational Design of Env Glycoprotein Antigenicity. PLoS Comput. Biol., 14(4):e1006093, Apr 2018. PubMed ID: 29677181.
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Yuan2005
Wen Yuan, Stewart Craig, Xinzhen Yang, and Joseph Sodroski. Inter-Subunit Disulfide Bonds in Soluble HIV-1 Envelope Glycoprotein Trimers. Virology, 332(1):369-383, 5 Feb 2005. PubMed ID: 15661168.
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Yuan2006
Wen Yuan, Jessica Bazick, and Joseph Sodroski. Characterization of the Multiple Conformational States of Free Monomeric and Trimeric Human Immunodeficiency Virus Envelope Glycoproteins after Fixation by Cross-Linker. J. Virol., 80(14):6725-6737, Jul 2006. PubMed ID: 16809278.
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Zhang2002
Peng Fei Zhang, Peter Bouma, Eun Ju Park, Joseph B. Margolick, James E. Robinson, Susan Zolla-Pazner, Michael N. Flora, and Gerald V. Quinnan, Jr. A Variable Region 3 (V3) Mutation Determines a Global Neutralization Phenotype and CD4-Independent Infectivity of a Human Immunodeficiency Virus Type 1 Envelope Associated with a Broadly Cross-Reactive, Primary Virus-Neutralizing Antibody Response. J. Virol., 76(2):644-655, Jan 2002. PubMed ID: 11752155.
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Zhou2007
Tongqing Zhou, Ling Xu, Barna Dey, Ann J. Hessell, Donald Van Ryk, Shi-Hua Xiang, Xinzhen Yang, Mei-Yun Zhang, Michael B. Zwick, James Arthos, Dennis R. Burton, Dimiter S. Dimitrov, Joseph Sodroski, Richard Wyatt, Gary J. Nabel, and Peter D. Kwong. Structural Definition of a Conserved Neutralization Epitope on HIV-1 gp120. Nature, 445(7129):732-737, 15 Feb 2007. PubMed ID: 17301785.
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Zhou2010
Tongqing Zhou, Ivelin Georgiev, Xueling Wu, Zhi-Yong Yang, Kaifan Dai, Andrés Finzi, Young Do Kwon, Johannes F. Scheid, Wei Shi, Ling Xu, Yongping Yang, Jiang Zhu, Michel C. Nussenzweig, Joseph Sodroski, Lawrence Shapiro, Gary J. Nabel, John R. Mascola, and Peter D. Kwong. Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01. Science, 329(5993):811-817, 13 Aug 2010. PubMed ID: 20616231.
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Zwick2003a
Michael B. Zwick, Robert Kelleher, Richard Jensen, Aran F. Labrijn, Meng Wang, Gerald V. Quinnan, Jr., Paul W. H. I. Parren, and Dennis R. Burton. A Novel Human Antibody against Human Immunodeficiency Virus Type 1 gp120 Is V1, V2, and V3 Loop Dependent and Helps Delimit the Epitope of the Broadly Neutralizing Antibody Immunoglobulin G1 b12. J. Virol., 77(12):6965-6978, Jun 2003. PubMed ID: 12768015.
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Sliepen2019
Kwinten Sliepen, Byung Woo Han, Ilja Bontjer, Petra Mooij, Fernando Garces, Anna-Janina Behrens, Kimmo Rantalainen, Sonu Kumar, Anita Sarkar, Philip J. M. Brouwer, Yuanzi Hua, Monica Tolazzi, Edith Schermer, Jonathan L. Torres, Gabriel Ozorowski, Patricia van der Woude, Alba Torrents de la Pena, Marielle J. van Breemen, Juan Miguel Camacho-Sanchez, Judith A. Burger, Max Medina-Ramirez, Nuria Gonzalez, Jose Alcami, Celia LaBranche, Gabriella Scarlatti, Marit J. van Gils, Max Crispin, David C. Montefiori, Andrew B. Ward, Gerrit Koopman, John P. Moore, Robin J. Shattock, Willy M. Bogers, Ian A. Wilson, and Rogier W. Sanders. Structure and immunogenicity of a stabilized HIV-1 envelope trimer based on a group-M consensus sequence. Nat Commun, 10(1):2355 doi, May 2019. PubMed ID: 31142746
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Displaying record number 641
Download this epitope
record as JSON.
MAb ID |
b6 (IgG1b6) |
HXB2 Location |
Env |
Env Epitope Map
|
Author Location |
gp120 |
Research Contact |
Dennis Burton, Scripps, San Diego, CA, USA |
Epitope |
|
Ab Type |
gp120 CD4bs |
Neutralizing |
no View neutralization details |
Contacts and Features |
View contacts and features |
Species
(Isotype)
|
human |
Patient |
Donor b |
Immunogen |
HIV-1 infection |
Keywords |
adjuvant comparison, antibody binding site, antibody generation, antibody interactions, antibody sequence, assay or method development, binding affinity, dynamics, effector function, enhancing activity, escape, glycosylation, immunoprophylaxis, kinetics, mimics, neutralization, polyclonal antibodies, review, SIV, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity, viral fitness and/or reversion |
Notes
Showing 78 of
78 notes.
-
b6: The polyclonal response of human subjects VC20013 and VC10014 demonstrated increasing neutralization breadth against a panel of HIV-1 isolates over time. Full-length functional env genes were cloned longitudinally from these subjects from months after infection through 2.6 to 5.8 years of infection. Motifs associated with the development of breadth in published, cross-sectional studies were found in the viral sequences of both subjects. To test the immunogenicity of envelope vaccines derived from time points obtained during and after broadening of neutralization activity within these subjects, rabbits were coimmunized 4 times with selected multiple gp160 DNAs and gp140-trimeric envelope proteins. In an assay of rabbit polyclonal responses, the most rapid and persistent neutralization of multiclade tier 1 viruses was elicited by envelopes that were circulating in plasma at time points prior to the development of 50% neutralization breadth in both human subjects. The breadth elicited in rabbits was not improved by exposure to later envelope variants. Env immunogen sequences were tested for binding to a panel of well studied mAbs of various binding types (VRC01, HJ16, b12, b6, PG9, PGT121, 2G12, 2F5, F240); all gp140s bound to weak or non-neutralizing antibodies b6 and F240. MAb b6 also bound BG505 SOSIP, while F240 did not, suggesting that cluster I gp41 epitopes, which become exposed during gp120 shedding, are more easily accessed on these trimers than on BG505-SOSIP. These data have implications for vaccine development in describing a target time point to identify optimal env immunogens.
Malherbe2014
(vaccine antigen design, vaccine-induced immune responses, binding affinity, polyclonal antibodies)
-
b6: This study used directed evolution to overcome the instability and heterogeneity of a primary Env isolate (ADA) in order to design better immunogens. HIV-1 virions were subjected to iterative cycles of destabilization and replication to select for Envs with enhanced stability. Several mutations in Env were associated with increased trimer stability, primarily in the heptad repeat regions of gp41 and V1 of gp120. Mutations from the most stable Envs were combined into a variant Env, termed "comb-mut", with superior homogeneity and stability. Comb-mut had greater binding affinity for PGT128, PG9, PG16, 2G12, VRC01, b12, and CD4-IgG2, but decreased binding to 4E10, 2F5, b6, 19b, 17b, 7B2, and D50. Comb-mut was more sensitive to neutralization by PG9. One specific mutation (K574) was shown to decrease the neutralization IC50 of mAbs b12, 2F5, 4E10, b6, 2G12, 8K8 and inhibitors sCD4, T-20, and PF-68742. Several of the Env substitutions were shown to stabilize Env spikes from HIV-1 clades A, B, and C. Spike stabilizing mutations may be useful in the development of Env immunogens that stably retain native, trimeric structure.
Leaman2013
(mimics, neutralization, vaccine antigen design, binding affinity)
-
b6: Using subtype A BG505 Env structural information, improved variants of subtype B JRFL and subtype C 16055 Env native flexibly linked (NFL) trimers were generated. The trimer-derived (TD) residues that increased well-ordered, homogeneous, stable, and soluble trimers did not require positive or negative selection as previously needed [Guenaga2015, PLoS Pathos. 11(1):e1004570]. ELISA binding to the two CD4bs-targeting nnAbs, b6 and F105 was inefficient as desired, for the NFL TD as well as NFL TD CC (disulfide link stabilized) trimers, indicating that these trimers were probably in the desired, closed conformation.
Guenaga2015a
(antibody interactions, assay or method development, vaccine antigen design, structure)
-
b6: To understand early bnAb responses, 51 HIV-1 clade C infected infants were assayed for neutralization of a 12-virus multi-clade panel. Plasma bnAbs targeting V2-apex on Env were predominant in infant elite and broad neutralizers. In infant elite neutralizers, multi-variant infection was associated with plasma bnAbs targeting diverse autologous viruses. A panel of mAbs (PG9, PG16, PGT145, PGDM1400, VRC26.25, 10-1074, BG18, AIIMS-P01, PGT121, PGT128, PGT135, VRC01, N6, 3BNC117, PGT151, 35O22, 10E8, 4E10, F105, 17b, A32, 48d, b6, 447-52d) was assayed for their ability to neutralize Env clones from infant elite neutralizers; circulating viral variants in infant elite neutralizers were most susceptible to V2-apex bnAbs.
Mishra2020a
(neutralization, polyclonal antibodies)
-
b6: In vertically-infected infant AIIMS731, a rare HIV-1 mutation in hypervariable loop 2 (L184F) was studied. In patient sequences, this mutation was present in the majority of clones. A panel of 6 V2 bnAbs (PG9, PG16, PGT145, PGDM1400, CAP256.25, and CH01) was assayed for neutralization of 6 patient viral clones. The AIIMS731 viral variants segregated into 4 neutralization-sensitive and 2 resistant clones; sensitive clones carried 184F, while resistant clones carried the rare 184L mutation. A large panel of bnAbs targeting non-V2 epitopes was used to assess the neutralization of the 6 patient viral variants. The bnAb panel consisted of V3/N332 glycan supersite bnAbs (10-1074, BG18, AIIMS-P01, PGT121, PGT128, and PGT135), CD4bs bnAbs (VRC01, VRC03, VRC07-523LS, N6, 3BNC117, and NIH45-46 G54W), a silent face-targeting bnAb (PG05), fusion peptide and gp120-gp41 interface bnAbs (PGT151, 35O22, and N123-VRC34.01), and MPER bnAbs (10E8, 4E10, and 2F5). All of these bnAbs had similar neutralization efficiencies for all 6 clones, suggesting that the L184F mutation was specific for viral escape from neutralization by V2 apex bnAbs. A panel of non-neutralizing mAbs (V3 loop-targeting non-nAbs 447-52D and 19b, and CD4-induced non-nAbs 17b, A32, 48d, and b6), were also assessed; 2 of the variants (the same 2 susceptible to the V2 bnAbs) showed moderate neutralization by 447-52D, 19b, 17b, and 48d. The structure of ligand-free BG505 SOSIP trimer revealed that the side chain of L184 was outward facing and did not make significant intraprotomeric interactions, but upon mutating L184 to F184, a disruption of the accessible surface between the bulky side chain of F184 on one protomer and R165 on the neighboring protomer was seen. Thus, the L184F mutation resulted in increased susceptibility to neutralization by antibodies known to target the relatively more open conformation of Env on tier 1 viruses, suggesting that the rare L184F mutation allowed Env to sample more open states resembling the CD4-bound conformation where the CCR5 binding site is exposed.
Mishra2020
(neutralization, polyclonal antibodies)
-
b6: Rabbits were immunized with a DNA vaccine encoding JR-CSF gp120. Five sera with potent autologous neutralizing activity were selected and compared with a human neutralizing plasma (Z23) and monoclonal antibodies targeting various regions of gp120 (VRC01, b12, b6, F425, 2F5, 2G12, and X5). The rabbit sera contained different neutralizing activities dependent on C3 and V5, C3 and V4, or V4 regions of the glycan-rich outer domain of gp120. All sera showed enhanced neutralizing activity toward an Env variant that lacked a glycosylation site in V4. The JR-CSF gp120 epitopes recognized by the sera were distinct from those of the mAbs. The activity of one serum required specific glycans that are also important for 2G12 neutralization, and this serum blocked the binding of 2G12 to gp120. The findings show that different fine specificities can achieve potent neutralization of HIV-1, yet this strong activity does not result in improved breadth.
Narayan2013
(neutralization, polyclonal antibodies)
-
b6: An R5 virus isolated from chronic patient NAB01 (Patient Record# 4723) was adapted in culture to growth in the presence of target cells expressing reduced levels of CD4. Entry kinetics of the virus were altered, and these alterations resulted in extended exposure of CD4-induced neutralization-sensitive epitopes to CD4. Adapted and control viruses were assayed for their neutralization by a panel of neutralizing antibodies targeting several different regions of Env (PGT121, PGT128, 1-79, 447-52d, b6, b12, VRC01, 17b, 4E10, 2F5, Z13e1). Adapted viruses showed greater sensitivity to antibodies targeting the CD4 binding site and the V3 loop. This evolution of Env resulted in increased CD4 affinity but decreased viral fitness, a phenomenon seen also in the immune-privileged CNS, particularly in macrophages.
Beauparlant2017
(neutralization, viral fitness and/or reversion, dynamics, kinetics)
-
b6: The authors used nuclear magnetic resonance (NMR) to define the structure of the HIV-1 MPER when linked to the transmembrane domain (MPER-TMD) in the context of a lipid bilayer. In particular, they looked at the accessibility of the MPER-TMD to 2F5, 4E10, 10E8 and DH570. The MPER appears to be accessible up to ∼10% of the time to the 2F5, 4E10, and 10E8 Fabs but ∼40% of time to the DH570 Fab. To assess possible functional roles for the MPER in membrane fusion, they generated 17 Env mutants using the sequence of a clade A isolate, 92UG037.8, mutating each of the three structural elements: hydrophobic core, turn, and kink. Mutants W670A (hydrophobic core), F673A (turn), and W680A (kink), while still sensitive to VRC01, became much more resistant to the trimer-specific bNAbs and also gained sensitivity to b6, 3791, and 17b. All mutants with changes at W666 in the hydrophobic core and K683 at the kink lost infectivity almost completely. For the rest of the mutants, infectivity ranged from 4.3 to 50.8% of that of the wild type, showing that key residues important for stabilizing the MPER structure are also critical for Env-induced membrane fusion activity, especially in the context of viral infection.
Fu2018
(antibody binding site, antibody interactions, neutralization, variant cross-reactivity, binding affinity, structure)
-
b6: The first cryo-EM structure of a cross-linked vaccine antigen was solved. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a bNAb PGV04 Fab fragment revealed how cross-linking affects key properties of the trimer. SOSIP and GLA-SOSIP trimers were compared for antigenicity by ELISA, using a large panel of mAbs previously determined to react with BG505 Env. Non-NAbs like b6 globally lost reactivity (7-fold median loss of binding), likely because of covalent stabilization of the cross-linked ‘closed’ form of the GLA-SOSIP trimer that binds non-NAbs weakly or not at all. V3-specific non-NAbs showed 2.1–3.3-fold reduced binding. Three autologous rabbit monoclonal NAbs to the N241/N289 ‘glycan-hole’ surface, showed a median ˜1.5-fold reduction in binding. V3 non-NAb 4025 showed residual binding to the GLA-SOSIP trimer. By contrast, bNAbs broadly retained reactivity significantly better than non-NAbs, with exception of PGT145 (3.3-5.3 fold loss of binding in ELISA and SPR).
Schiffner2018
(vaccine antigen design, binding affinity, structure)
-
b6: Nanodiscs (discoidal lipid bilayer particles of 10-17 nm surrounded by membrane scaffold protein) were used to incorporate Env complexes for the purpose of vaccine platform generation. The Env-NDs (Env-NDs) were characterized for antigenicity and stability by non-NAbs and NAbs. Most NAb epitopes in gp41 MPER and in the gp120:gp41 interface were well exposed while non-NAb cell surface epitopes were generally masked. Anti-CD4bs non-NAb b6, binds at a fraction of the binding of 2G12 to Env-ND, and this binding is insensitive to glutaraldehyde treatment .
Witt2017
(vaccine antigen design, binding affinity)
-
b6: In the RV305 HIV-1 vaccine trial, two boosts of either ALVAC-HIV, AIDSVAX B/E gp120 or ALVAC-HIV + AIDSVAX B/E gp120 were given to HIV-1-uninfected RV144 vaccine-recipients. While no bNAb plasma activity was induced in this trial as well, an increased frequency of memory B cells that produce Env-specific anti-CD4bs antibodies with long HCDR3s was detected. In a binding assay, B6 binding was reduced by some mutants of subtype B Env protein YU2.
Easterhoff2017
(binding affinity)
-
b6: Three strategies were applied to perturb the structure of Env in order to make the protein more susceptible to neutralization: exposure to cold, Env-activating ligands, and a chaotropic agent. A panel of mAbs (E51, 48d, 17b, 3BNC176, 19b, 447-52D, 39F, b12, b6, PG16, PGT145, PGT126, 35O22, F240, 10E8, 7b2, 2G12) was used to test the neutralization resistance of a panel of subtype B and C pseudoviruses with and without these agents. Both cold and CD4 mimicking agents (CD4Ms) increased the sensitivity of some viruses. The chaotropic agent urea had little effect by itself, but could enhance the effects of cold or CD4Ms. Thus Env destabilizing agents can make Env more susceptible to neutralization and may hold promise as priming vaccine antigens.
Johnson2017
(vaccine antigen design)
-
b6: This study performed cyclical permutation of the V1 loop of JRFL in order to develop better gp120 trimers to elicit neutralizing antibodies. Some mutated trimers showed improved binding to several mAbs, including VRC01, VRC03, VRC-PG04, PGT128, PGT145, PGDM1400, b6, and F105. Guinea pigs immunized with prospective trimers showed improved neutralization of a panel of HIV-1 pseudoviruses.
Kesavardhana2017
(vaccine antigen design, vaccine-induced immune responses)
-
b6: This study investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit NAbs. Rabbits were immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). N197 glycan- and residue 230- removal conferred sensitivity to Trimer VLP sera and DNA trimer sera respectively, showing for the first time that strain-specific holes in the "glycan fence" can allow the development of tier 2 NAbs to native spikes. All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. N197 glycan mutants were tested against b6 showing a loss of tier 2 phenotype. The results are in Table S5.
Crooks2015
(glycosylation, neutralization)
-
b6: This study assessed the ADCC activity of antibodies of varied binding types, including CD4bs (b6, b12, VRC01, PGV04, 3BNC117), V2 (PG9, PG16), V3 (PGT126, PGT121, 10-1074), oligomannose (2G12), MPER (2F5, 4E10, 10E8), CD4i (17b, X5), C1/C5 (A32, C11), cluster I (240D, F240), and cluster II (98-6, 126-7). ADCC activity was correlated with binding to Env on the surfaces of virus-infected cells. ADCC was correlated with neutralization, but not always for lab-adapted viruses such as HIV-1 NLA-3. MAb b6 had strong ADCC activity against cells infected with 1 of 3 strains tested.
vonBredow2016
(effector function)
-
b6: Two stable homogenous gp140 Env trimer spikes, Clade A 92UG037.8 Env and Clade C C97ZA012 Env, were identified. 293T cells stably transfected with either presented fully functional surface timers, 50% of which were uncleaved. A panel of neutralizing and non-neutralizing Abs were tested for binding to the trimers. Non-neutralizing CD4bs Ab, b6 did not bind cell surface or neutralize 92UG037.8 HIV-1 isolate, but it did bind the gp160ΔCT (missing C-terminal) moderately.
Chen2015
(neutralization, binding affinity)
-
b6: PGT145 was used to positively isolate a subtype B Env trimer immunogen, B41 SOSIP.664, that exists in two conformations, closed and partially open. bNAbs tested against the trimer were able to neutralize the B41 pseudovirus with a wide range of potencies. Among non-NAbs to CD4bs (b6, F91, F105); to CD4i (17b); to gp41ECTO (F240); and to V3 (447-52D, 39F, CO11, 19b and 14e), none neutralized B41 (IC50 >50µg/ml).
Pugach2015
-
b6: Two clade C recombinant Env glycoprotein trimers, DU422 and ZM197M, with native-like structural and antigenic properties involving epitopes against all known classes of bNAbs, were produced and characterized. These Clade C trimers (10-15% of which are in a partially open form) were more like B41 Clade B trimers which have 50-75% trimers in the partially open configuration than like B505 Clade B trimers, almost 100% in the closed, prefusion state. The Clade C trimers have very low affinity for the CD4bs non-NAb b6, and b6 was unable to neutralize the equivalent pseudotyped viruses for either trimer.
Julien2015
(assay or method development, structure)
-
b6: A new trimeric immunogen, BG505 SOSIP.664 gp140, was developed that bound and activated most known neutralizing antibodies but generally did not bind antibodies lacking neuralizing activity. This highly stable immunogen mimics the Env spike of subtype A transmitted/founder (T/F) HIV-1 strain, BG505. Anti-CD4bs non-NAb b6 did not neutralize BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, but did recognize and bind the immunogen itself.
Sanders2013
(assay or method development, neutralization, binding affinity)
-
b6: The study detailed binding kinetics of the interaction between BG505 SOSIP.664 trimer or its variants (gp120 monomer; first study of disulfide-stabilized variant gp120-gp41ECTO protomer) and several mAbs, both neutralizing (VRC01, PGV04, PG9, PG16, PGT121, PGT122, PGT123, PGT145, PGT151, 2G12) and non-neutralizing (b6, b12, 14e, 19b, F240). Non-neutralizing, anti-CD4bs Ab, b6, does not neutralize BG505.T332N pseudovirus; binds neglibly to the trimer, but well to the protomer and monomer immunogens.
Yasmeen2014
(antibody binding site, assay or method development)
-
b6: The study's goal was to produce modified SOSIP trimers that would reduce the exposure - and, by inference, the immunogenicity - of non-NAb epitopes such as V3. The binding of several modified SOSIP trimers was compared among 12 neutralizing (PG9, PG16, PGT145, PGT121, PGT126, 2G12, PGT135, VRC01, CH103, CD4, IgG2, PGT151, 35O22) and 3 non-neutralizing antibodies (14e, 19b, b6). The V3 non-NAbs 447-52D, 39F, 14e, and 19b bound less well to all A316W variant trimers compared to wild-type trimers. Mice and rabbits immunized with modified, stabilized SOSIP trimers developed fewer V3 Ab responses than those immunized with native trimers.
deTaeye2015
(antibody binding site)
-
b6: The effect of low pH and HIV-1 Abs which increased the transcytosis of the virus by 20 fold, has been reported. This enhanced transcytosis was due to the Fc neonatal receptor (FcRn), which facilitates HIV-1's own transmission by usurping Ab responses directed against itself. Viruses transcytosed by poorly neutralizing b6 at pH 6.0 were more infectious than those by non-FcRn binding pathway.
Gupta2013
-
b6: A panel of NAbs and non-neutralizing Abs (NoNAbs) displaying the highest Fc γR-mediated inhibitory activity and significant ADCC were selected and formulated in a microbicidal gel and tested for their antiviral activity against SHIVSF162P3 vaginal challenge in non-human primates. Combination of 2G12, 2F5 and 4E10 fully prevented vaginal transmission. Two NoNAbs 246-D and 4B3 had no impact on viral acquisition, but reduced plasma viral load.
Moog2014
(effector function, SIV)
-
b6: The original Fab fragment was derived from a combinatorial phage library from bone marrow of an HIV-1 positive individual who had been asymptomatic for six years. It was subsequently sequenced by Barbas1993.
Burton1991,Barbas1993
(antibody generation, antibody sequence)
-
b6: Isolation of VRC06 and VRC06b MAbs from a slow progressor donor 45 is reported. This is the same donor from whom bnMAbs VRC01, VRC03 and NIH 45-46 were isolated and the new MAbs are clonal variants of VRC03. b6 was used as a non- neutralizing MAb to compare neutralizing specificity of VRC06.
Li2012
-
B6: Antigenic properties of 2 biochemically stable and homogeneous gp140 trimers (A clade 92UG037 and C clade CZA97012) were compared with the corresponding gp120 monomers derived from the same percursor sequences. The trimers had nearly all the antigenic properties expected for native viral spikes and were markedly different from monomeric gp120. b6, a non-neutralizing MAb, bound to A clade gp120, not not to gp120, indicating that b6 epitope is occluded by the trimer configuration.
Kovacs2012
(antibody binding site, neutralization, binding affinity)
-
b6: Intrinsic reactivity of HIV-1, a new property regulating the level of both entry and sensitivity to Abs has been reported. This activity dictates the level of responsiveness of Env protein to co-receptor, CD4 engagement and Abs. HIV-1 has developed steric constraints on the Abs binding to CD4BS. Role of b6 has been discussed as a CD4BS binding Ab. The sensitivity of HIV-1 to F105 was enhanced by the altered gp41, J1Hx(66, 197).
Haim2011
(antibody interactions)
-
b6: This study reports the isolation of a panel of Env vaccine elicited CD4bs-directed macaque mAbs and genetic and functional features that distinguish these Abs from CD4bs MAbs produced during chronic HIV-1 infection. b6 was used as a control Abs in virus neutralization assay.
Sundling2012
(vaccine-induced immune responses)
-
b6: In order to increase recognition of CD4 by Env and to elicit stronger neutralizing antibodies against it, two Env probes were produced and tested - monomeric Env was stabilized by pocket filling mutations in the CD4bs (PF2) and trimeric Env was formed by appending trimerization motifs to soluble gp120/gp14. PF2-containing proteins were better recognized by bNMAb against CD4bs and more rapidly elicited neutralizing antibodies against the CD4bs. Trimeric Env, however, elicited a higher neutralization potency that mapped to the V3 region of gp120.
Feng2012
(neutralization)
-
b6: The sera of 113 HIV-1 seroconverters from three cohorts were analyzed for binding to a set of well-characterized gp120 core and resurfaced stabilized core (RSC3) protein probes, and their cognate CD4bs knockout mutants. b6 bound very strongly to the gp120 core and to the gp120 core D368R but did not bind to RSC3, RSC3/G367R, RSC3 Δ3711, and RSC3 Δ3711/P363N.
Lynch2012
(binding affinity)
-
b6: The interaction of the lectin griffithsin (GRFT) with HIV-1 gp120 and its effects on exposure of the CD4-binding site (CD4bs) was studied. GRFT enhanced the binding of HIV-1 to b12 and b6 or the CD4 receptor mimetic CD4-IgG2. The average enhancement of b12 or b6 binding was higher for subtype B viruses than for subtype C.
Alexandre2011
(antibody binding site, glycosylation)
-
b6: The strategy of incorporating extra glycans onto gp120 was explored, with the goal to occlude the epitopes of non-neutralizing MAbs while maintaining exposure of the b12 site. The focus was on the head-to-head comparison of the ability of 2 adjuvants, monophosphoryl lipid A (MPL) and Quil A, to promote CD4-specific Ab responses in mice immunized with the engineered mutant Q105N compared to gp120wt. Neutralizing and non-neutralizing antibodies targeting three areas on gp120 – the CD4bs (F105, b6, b12, b13, VRC01, VRC03 and CD4- IgG2), the glycosylated ‘silent face’ (2G12) and the V3 loop (B4e8) – were assessed for binding. The antibodies b6, b12, b13, VRC01 and 2G12 bound best to mutant Q105N, albeit with lower affinities than to gp120wt. Retention of b6 and b13 binding was not expected, but can be explained by their very similar mode of interaction with the CD4bs compared to b12. Abs F105 and VRC03 did not bind Q105N at all. The V3-specific antibody B4e8 did not bind to Q105N.
Ahmed2012
(adjuvant comparison, antibody binding site, glycosylation, neutralization, escape)
-
b6: Human MAbs b12 and b6 against CD4bs on HIV-1 gp120 and F240 against an immundominant epitope on gp41 were assessed for prevention of vaginal transmission of simian SHIV-162P4 to macaques. Applied vaginally at a high dose, MAb b6 provided sterilizing immunity in 0/5 animals.
Burton2011
(immunoprophylaxis, neutralization, binding affinity)
-
b6: 37 Indian clade C HIV-1 Env clones obtained from five patients with recent infection, at different time points, were studied for sensitivities to their autologous plasma antibodies and mAbs. 3 out of 9 Env clones in patient IVC5 were neutralized by b6.
Ringe2010
(neutralization)
-
b6: Molecular modeling was used to construct a 3D model of an anti-gp120 RNA aptamer, B40t77, in complex with gp120. Externally exposed residues of gp120 that participated in stabilizing interaction with the aptamer were mutated. Binding of b6 to gp120 was inhibited by B40t77, which is suggested to be due to distant conformational changes of gp120 induced by the aptamer.
Joubert2010
(binding affinity, structure)
-
b6: Unlike the MPER MAbs tested, b6 did not show any Env-independent virus capture. MAb competition assays revealed that b6 competed poorly with b12 for capture of virus containing mainly native Env trimers. Denaturation of the trimers resulted in b6 inhibition of b12 capture, and b12 was poor at blocking virion capture by b6, indicating higher affinity of b6 for uncleaved gp160 compared to b12. MAbs m14, m18 and 15e also cross-competed with b6 for virion capture. There was an overall reduction in the efficiency of capture of molecular clones (MC) relative to pseudotyped virions (PSV) by b6, indicating that most of the surplus Env associated with PSV was in the form of unprocessed gp160. Nontrimeric Envs from JR-CSF MC virus were also captured by b6 more efficiently than trimeric Envs from JR-FL.
Leaman2010
(binding affinity)
-
b6: Impact of in vivo Env-CD4 interactions was studied during vaccinations of Rhesus macaques with two Env trimer variants rendered CD4 binding defective (368D/R and 423/425/431 trimers) and wild-type (WT) trimers. Ab binding profiles of the three trimer variants were assessed by binding analyses to different MAbs. CD4bs-directed MAb b6 bound similarly to WT and 423/425/431 trimers but its binding affinity was slightly reduced but not abrogated for 368D/R trimers.
Douagi2010
(binding affinity)
-
b6: The effect of presence and absence of V1 loop was assessed using two approaches: remove V1 loop from the soluble trimeric gp140 construct (ΔV1SF162gp140) and second, substitute the V1 loop on SF162gp140 construct with four different V1 loops from 89.6, YU2, JRFL, and HxB2 (heterologous HIV-1 viruses). Deletion or substitution of V1 loop resulted in some resistance to neutralization by b6 but did not affect the binding affinity to b6. D368R modification to SF162gp120 reduced but did not inhibit its binding affinity to b6 and lowered the neutralization activity by b6.
Ching2010
(neutralization, binding affinity)
-
b6: A set of Env variants with deletions in V1/V2 was constructed. Replication competent Env variants with V1/V2 deletions were obtained using virus evolution of V1/V2 deleted variants. Sensitivity of the evolved ΔV1V2 viruses was evaluated to study accessibility of their neutralization epitopes. b6 bound and neutralized ΔV1V2 variants more potently than the full-length trimer, indicating better exposure of b6 epitope when the V1V2 domain is removed.
Bontjer2010
(neutralization, binding affinity)
-
b6: Both parent and GnTI (complex glycans of the neutralizing face are replaced by fully trimmed oligomannose stumps) viruses were resistant to neutralization by b6, while the N301Q mutant virus was markedly more susceptible to neutralization by b6. This suggests that removal of a key glycan had a greater effect on exposing the b6 epitope, than replacing complex glycans with smaller ones did.
Binley2010
(glycosylation, neutralization)
-
b6: An outer domain (ODec) based immunogen including the whole outer domain and most of the CD4 binding residues was designed and expressed in E-coli bacterial cells. The ODec lacked V1V2 and V3, incorporated 11 designed mutations at the interface of the inner and outer domains of gp120, and was unglycosylated. b6 bound to monomeric gp120 but did not bind to ODec. Sera from rabbits immunized with ODec neutralized 4/5 clade B and 1/2 clade C viruses.
Bhattacharyya2010
(binding affinity)
-
b6: To examine the antigenicity of a defined Ab epitope on the functional envelope spike, a panel of chimeric viruses engrafted at different positions with the hemagglutinin (HA) epitope tag was constructed. b6 neutralized 5/6 chimeric viruses poorly, indicating that the quaternary structure of the spikes was maintained. One virus with the HA-tag inserted in the V2 loop was more sensitive to neutralization by b6 than the wild type, indicating that the HA tag had resulted in localized alternation of gp120.
Pantophlet2009
(neutralization)
-
b6: A set of Env variants with deletions in V1/V2 were constructed. Replication competent Env variants with V1/V2 deletions were obtained using virus evolution of V1/V2 deleted variants. All variants were found sensitive to neutralization by b6 unlike the wild type, which was resistant to neutralization by b6. This indicates that deletion of V1/V2 increases b6 epitope accessibility.
Bontjer2009
(antibody binding site, neutralization)
-
b6: Resurfaced stabilized core 3 (RSC3) protein was designed to preserve the antigenic structure of the gp120 CD4bs neutralizing surface but eliminate other antigenic regions of HIV-1. RSC3 did not show binding to b6.
Wu2010
(binding affinity)
-
b6: A serum adsorption method was developed based on Ab competition. Serum adsorptions to Env were performed in the presence of saturating concentrations of the non-neutralizing competitor MAb b6. The method was validated using b12. All of the b12 neutralizing activity could be adsorbed with gp140-coated beads, but none was adsorbed in the presence of saturating concentrations of b6. Donor sera from elite neutralizers were tested using this method. In one patient, broad serum neutralizing activity was completely inhibited by b6, indicating that CD4bs or CRbs Abs dominate serum neutralization activity in this patient. In 4 donors, b6 inhibited 50-70% of serum neutralization, and in 12 donors, b6 did not block any neutralization activity in sera. Broadly neutralizing sera from elite neutralizers exhibited significant sensitivities to mutations I165A, N332A, and N160K. b6 binding was not affected by the three mutations.
Walker2010
(assay or method development, neutralization, binding affinity)
-
b6: Two formats of Ab libraries displayed on the surface of yeast were combined to construct the first scFab yeast display Ab library. b6 was used to validate the new display system. b6 in the scFab format had a 12-fold higher affinity to ag than b6 expressed in the scFv format. b6 scFab also exhibited similar binding and neutralization profiles as b6 scFv.
Walker2009b
(assay or method development, neutralization, binding affinity)
-
b6: OD (GSL)(δβ20-21)(hCD4-TM) glycoprotein variant was constructed by eliminating V1 and V2 regions, truncating V3, and deleting cleavage, fusion, and interhelical domains from Env derivatives from R3A TA1 virus. In addition, the variant was membrane-anchored, the β20-β21 hairpin was truncated, and the central 20 amino acids of the V3 loop were replaced with a basic hexapeptide. Although this variant showed increased binding to b12 and 2G12, it did not bind to b6.
Wu2009a
(binding affinity)
-
b6: A panel of clade B and C viruses from early infections was used to analyze b6 neutralization resistance. Removal of a glycan at position 301 at the base of the V3 loop rendered PVO.4 strain sensitive to neutralization by b6. In addition, point mutations T569A and I675V in the gp41 region increased viral neutralization sensitivity to b6, indicating their effect on viral spike accessibility.
Wu2009
(glycosylation, neutralization)
-
b6: Binding of b6 to Endo H and mock treated gp120 was determined. b6 did not compete with the broadly neutralizing Ab PG9 for binding to gp120.
Walker2009a
(binding affinity)
-
b6: Subtype A gp140 SOSIP trimers were recognized by b6.
Kang2009
-
b6: Viruses with Envs that mediate high levels of entry into macrophages had similar sensitivity to neutralization by b6 as viruses with low levels of entry into macrophages. Elimination of N-linked glycan at position 386 did not change neutralization sensitivity to b6.
Dunfee2009
(glycosylation, neutralization)
-
b6: Gene encoding gp140 was fused with three trimerization motifs, T4F, GCN and ATC. gp140, gp140(-)(with mutations in the furin-cleavage site), and all three trimerization stabilized gp140 constructs bound b6 less strongly than gp120 did.
Du2009
(binding affinity)
-
b6: b6 neutralized Tier 1 viruses but not Tier 2 viruses. Crystal structure of F105 in complex with gp120 revealed small differences in recognition of gp120 by F105, where all four strands of the bridging sheet were displaced to uncover a hydrophobic region which served for F105 binding. A monomeric disulfide gp120 variant was not bound by b6, suggesting that b6 relies on access to the hydrophobic surface for binding. Structure analyses revealed that b6, and other CD4BS Abs that access this hydrophobic region, induce conformation changes in gp120 that are poorly compatible with functional viral spike. b6 was not able to bind to cleavage-defective envelope glycoproteins.
Chen2009
(neutralization, kinetics, binding affinity)
-
b6: This report investigated whether mannose removal alters gp120 immunogenicity in mice. Approximately 55 mannose residues were removed from gp120 by mannosidase digestion creating D-gp120 for immunization. b6s was able to bind to D-gp120 comparably as to the untreated gp120, indicating that the mannosidase digestion did not affect the antigenicity of gp120.
Banerjee2009
(binding affinity)
-
b6: Molecules designed to eliminate binding by b6 while preserving epitopes of other neutralizing Abs are discussed.
Lin2007
(review)
-
b6: gp120 proteins with double mutation T257S+S375W, which alters the cavity at the epicenter of the CD4 binding region, had no effect on binding to b6 Ab.
Dey2007a
(binding affinity)
-
b6: Sera from gp120 DNA prime-protein boost immunized rabbits competed for binding to b6 while sera from rabbits immunized with protein-only regimen did not, indicating elicitation of b6-like Abs in animals immunized with DNA prime-protein boost regimen.
Vaine2008
(vaccine antigen design)
-
b6: A series of peptide conjugates were constructed via click reaction of both aryl and alkyl acetylenes with an internally incorporated azidoproline 6 derived from parent peptide RINNIPWSEAMM. Many of these conjugates exhibited increase in both affinity for gp120 and inhibition potencies at both the CD4 and coreceptor binding sites. All high affinity peptides inhibited the interactions of YU2 gp120 with b6 Ab. The aromatic, hydrophobic, and steric features in the residue 6 side-chain were found important for the increased affinity and inhibition of the high-affinity peptides.
Gopi2008
-
b6: The study compared Ab neutralization against the JR-FL primary isolate and trimer binding affinities judged by native PAGE. There was direct quantitative relationship between monovalent Fab-trimer binding and neutralization, implying that neutralization begins as each trimer is occupied by one Ab. In BN-PAGE, neutralizing Fabs and sCD4 were able to shift JR-FL trimers, In contrast, most non-neutralizing Fabs, b6 in particular, bound to monomer, but their epitopes were conformationally occluded on trimers, confirming the exclusive relationship of trimer binding and neutralization.
Crooks2008
(antibody binding site, neutralization, binding affinity)
-
b6: Five amino acids in the gp41 N-terminal region that promote gp140 trimerization (I535, Q543, S553, K567 and R588) were considered. Their influence on the function and antigenic properties of JR-FL Env expressed on the surfaces of pseudoviruses and Env-transfected cells was studied. Various non-neutralizing antibodies bind less strongly to the Env mutant, but neutralizing antibody binding is unaffected. b6 captured significantly fewer mutant pseudovirions than wild type, and b6 failed to inhibit infection by either pseudovirus.
Dey2008
(antibody binding site, binding affinity)
-
b6: Molecular mechanism of neutralization by MPER antibodies, 2F5 and 4E10, was studied using preparations of trimeric HIV-1 Env protein in the prefusion, the prehairpin intermediate and postfusion conformations. MAb b6 was used to analyze antigenic properties of construct 92UG-gp140-Fd, derived from isolate 92UG037.8 and stabilized by a C-terminal foldon tag. 92UG-gp140-Fd failed to bind b6, despite high affinity of b6 for 92UG-gp120 core.
Frey2008
(binding affinity)
-
b6: This Ab was used to determine the degree to which fixation of gp120 in its CD4-bound conformation restricts antigenic recognition. b6 was not able to bind well to the stabilized gp120.
Zhou2007
(binding affinity)
-
IgG1b6: JR-FL and YU2 HIV-1 strains were not neutralized by IgG1b6. IgG1b6 and other non-neutralizing Abs only recognized JR-FL cleavage-defective glycoproteins, while the neutralizing Abs (2G12 and IgG1b12) recognized both cleavage competent and cleavage-defective glycoproteins. It is suggested that an inefficient env glycoprotein precursor cleavage exposes non-neutralizing determinants, while only neutralizing regions remain accessible on efficiently cleaved spikes. For YU2, both cleavage-competent and -defective glycoproteins were recognized by both neutralizing and non-neutralizing Abs. IgG1b6, along with other Abs able to neutralize lab-adapted isolates, displayed enhanced viral entry at higher Ab concentrations, whereas the Abs that cannot neutralize any virus did not display such enhancement.
Pancera2005
(antibody binding site, enhancing activity, neutralization, binding affinity)
-
b6: This review summarizes data on the role of NAb in HIV-1 infection and the mechanisms of Ab protection, data on challenges and strategies to design better immunogens that may induce protective Ab responses, and data on structure and importance of MAb epitopes targeted for immune intervention. The importance of standardized assays and standardized virus panels in neutralization and vaccine studies is also discussed.
Srivastava2005
(antibody binding site, neutralization, vaccine antigen design, review)
-
b6: In addition to gp120-gp41 trimers, HIV-1 particles were shown to bear nonfunctional gp120-gp41 monomers and gp120-depleted gp41 stumps on their surface. b6 did not neutralize wildtype virus but it was shown to bind to gp12-gp41 monomers. Monomer binding did not correlate with neutralization, but it did correlate with virus capture. b6 blocked b12 binding to monomeric Env but not to trimeric Env. It is hypothesized that the nonfunctional monomers on the HIV-1 surface serve to divert the Ab response helping it to avoid neutralization.
Moore2006
(antibody binding site, neutralization)
-
b6: Macaques were immunized with SF162gp140, ΔV2gp140, ΔV2ΔV3gp140 and ΔV3gp140 constructs and their antibody responses were compared to the broadly reactive NAb responses in a macaque infected with SHIV SF162P4, and with pooled sera from humans infected with heterologous HIV-1 isolates (HIVIG). b6-like Abs were generated in the SHIV-infected macaque, and may have been present at very low titers in macaques immunized with ΔV2gp140 and ΔV2ΔV3gp140. No b6 Abs were detected in the sera from F162gp140 immunized animals.
Derby2006
(antibody binding site, antibody generation)
-
b6: G1 and G2 recombinant gp120 proteins, consisting of 2F5 and 4E10, and 4E10 epitopes, respectively, engrafted into the V1/V2 region of gp120, were tested as an immunogen to see if they could elicit MPER antibody responses. Deletion of V1/V2 from gp120 or its replacement with G1 and G2 grafts reduced the affinity for b6, however shortening of the N and C termini of the V3 loop did not greatly affect binding.
Law2007
(vaccine antigen design)
-
b6: SOSIP Env proteins are modified by the introduction of a disulfide bond between gp120 and gp41 (SOS), and an I559P (IP) substitution in gp41, and form trimers. The KNH1144 subtype A virus formed more stable trimers than did the prototype subtype B SOSIP Env, JRFL. The stability of gp140 trimers was increased for JR-FL and Ba-L SOSIP proteins by substituting the five amino acid residues in the N-terminal region of gp41 with corresponding residues from KNH1144 virus. b12, 2G12, 2F5, 4E10 and CD4-IgG2 all bound similarly to the WT and to the stabilized JRFL SOSIP timers, suggesting that the trimer-stabilizing substitutions do not impair the overall antigenic structure of gp140 trimers. 17b binding was induced similarly by CD4 for the WT and stabilized forms. Non-neutralizing MAbs PA-1 (V3) and b6 (CD4BS) bound less efficiently to the stabilized trimer.
Dey2007
(antibody binding site, vaccine antigen design)
-
b6: Antigens were designed to attempt to target immune responses toward the IgG1b12 epitope, while minimizing antibody responses to less desirable epitopes. One construct had a series of substitutions near the CD4 binding site (GDMR), the other had 7 additional glycans (mCHO). The 2 constructs did not elicit b12-like neutralizing antibodies, but both antigens successfully dampened other responses that were intended to be dampened while not obscuring b12 binding. CD4BS MAbs except Fab b12 (b6, b3, F105) did not bind to either GDMR or mCHO.
Selvarajah2005
(vaccine antigen design, vaccine-induced immune responses)
-
b6: By adding N-linked glycosylation sites to gp120, epitope masking of non-neutralizing epitopes can be achieved leaving the IgG1b12 binding site intact. This concept was originally tested with the addition of four glycosylation sites, but binding to b12 was reduced. It was modified here to exclude the C1 N-terminal region, and to include only three additional glycosylation sites. This modified protein retains full b12 binding affinity and it masks other potentially competing epitopes, and does not bind to 21 other MAbs to 7 epitopes on gp120, including b6.
Pantophlet2004
(vaccine antigen design)
-
b6: 93 viruses from different clades were tested for their neutralization cross-reactivity using a panel of HIV antibodies. b6 was included as an example of a CD4BS antibody that is not strongly neutralizing, and it only was able to neutralize a few highly sensitive primary viruses and T-cell adapted viral strains that were B clade. Steric restrictions probably block its binding site in most isolates.
Binley2004
(variant cross-reactivity, subtype comparisons)
-
b6: A gp120 molecule was design to focus the immune response onto the IgG1b12 epitope. Ala substitutions that enhance the binding of IgG1b12 and reduce the binding of non-neutralizing MAbs were combined with additional N-linked glycosylation site sequons inhibiting binding of non-neutralizing MAbs; b12 bound to the mutated gp120. C1 and C5 were also removed, but this compromised b12 binding.
Pantophlet2003b
(vaccine antigen design)
-
b6: scFv 4KG5 reacts with a conformational epitope that is formed by the V1V2 and V3 loops and the bridging sheet (C4) region of gp120 and is influenced by carbohydrates. Of a panel of MAbs tested, only NAb b12 enhanced 4KG5 binding to gp120 JRFL. MAbs to the following regions diminished 4KG5 binding: V2 loop, V3 loop, V3-C4 region, CD4BS. MAbs directed against C1, CD4i, C5 regions didn't impact 4KG5 binding. These results suggest that the orientation or dynamics of the V1/V2 and V3 loops restricts CD4BS access on the envelope spike, and IgG1b12 can uniquely remain unaffected by these loops. This was one of the CD4BS MAbs used.
Zwick2003a
(antibody interactions)
-
b6: Thermodynamics of binding to gp120 was measured using isothermal titration calorimetry for sCD4, 17b, b12, 48d, F105, 2G12 and C11 to intact YU2 and the HXBc2 core. The free energy of binding was similar. Enthalpy and entropy changes were divergent, but compensated. Not only CD4 but MAb ligands induced thermodynamic changes in gp120 that were independent of whether the core or the full gp120 protein was used. Non-neutralizing CD4BS and CD4i MAbs (17b, 48d, 1.5e, b6, F105 and F91) had large entropy contributions to free energy (mean: 26.1 kcal/mol) of binding to the gp120 monomer, but the potent CD4BS neutralizing MAb b6 had a much smaller value of 5.7 kcal/mol. The high values suggest surface burial or protein folding an ordering of amino acids. These results suggest that while the trimeric Env complex has four surfaces, a non-neutralizing face (occluded on the oligomer), a variable face, a neutralizing face and a silent face (protected by carbohydrate masking), gp120 monomers further protect receptor binding sites by conformational or entropic masking, requiring a large energy handicap for Ab binding not faced by other anti-gp120 Abs.
Kwong2002
(antibody binding site)
-
b6: Alanine scanning mutagenesis was used to compare substitutions that affected anti-CD4BS NAb b12 binding to those that affect binding of sCD4 and two non-neutralizing anti-CD4BS Abs b3 and b6 -- while the epitope maps overlapped, there were some differences observed -- binding of CD4 was never enhanced, indicating it had evolved to be optimal -- rec gp120s were engineered to contain combinations of Alanine substitutions that enhanced b12 binding, and while binding of b12 to these gp120 monomers was generally maintained or increased, binding by five non-neutralizing anti-CD4bs MAbs (b3, b6, F105, 15e, and F91) was reduced or completely abolished -- 2G12 binding was largely unperturbed, indicating these proteins were not grossly misfolded.
Pantophlet2003
-
b6: Virion capture assays are not a good predictor of neutralization, and the presentation of epitopes using this assay seems to be different from that of functional Envelope spikes on primary isolates -- F105 and b6 could efficiently block the b12-mediated capture of infectious virions in a virus capture, but did not inhibit b12 neutralization -- while b12 was potent at neutralizing the three primary virions JR-CSF, ADA, and 89.6, the Abs F105, 19b, and Fab b6 were overall very poor neutralizers.
Poignard2003
-
b6: The rank order of Fab binding affinity to monomeric gp120 (Loop 2 > 3B3 > b12 = DO8i > b11 > b3 > b14 > b13 > DO142-10 > DA48 > L17) was markedly different than Fab binding affinity to the mature oligomeric form (3B3 > b12 > DO142-10 > Loop 2 > b11 > L17 > b6 > DO8i > b14 > DA48 > b3 > b13) and binding to oligomeric form and neutralization were correlated for both Fabs and MAbs -- authors suggest that neutralization is determined by the fraction of Ab sites occupied on a virion irrespective of the epitope.
Parren1998
-
b6: Neutralizes TCLA strains, but not primary isolates.
Parren1997
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Dey2007
Antu K. Dey, Kathryn B. David, Per J. Klasse, and John P. Moore. Specific Amino Acids in the N-Terminus of the gp41 Ectodomain Contribute to the Stabilization of a Soluble, Cleaved gp140 Envelope Glycoprotein from Human Immunodeficiency Virus Type 1. Virology, 360(1):199-208, 30 Mar 2007. PubMed ID: 17092531.
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Dey2007a
Barna Dey, Marie Pancera, Krisha Svehla, Yuuei Shu, Shi-Hua Xiang, Jeffrey Vainshtein, Yuxing Li, Joseph Sodroski, Peter D Kwong, John R Mascola, and Richard Wyatt. Characterization of Human Immunodeficiency Virus Type 1 Monomeric and Trimeric gp120 Glycoproteins Stabilized in the CD4-Bound State: Antigenicity, Biophysics, and Immunogenicity. J Virol, 81(11):5579-5593, Jun 2007. PubMed ID: 17360741.
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Dey2008
Antu K. Dey, Kathryn B. David, Neelanjana Ray, Thomas J. Ketas, Per J. Klasse, Robert W. Doms, and John P. Moore. N-Terminal Substitutions in HIV-1 gp41 Reduce the Expression of Non-Trimeric Envelope Glycoproteins on the Virus. Virology, 372(1):187-200, 1 Mar 2008. PubMed ID: 18031785.
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Douagi2010
Iyadh Douagi, Mattias N. E. Forsell, Christopher Sundling, Sijy O'Dell, Yu Feng, Pia Dosenovic, Yuxing Li, Robert Seder, Karin Loré, John R. Mascola, Richard T. Wyatt, and Gunilla B. Karlsson Hedestam. Influence of Novel CD4 Binding-Defective HIV-1 Envelope Glycoprotein Immunogens on Neutralizing Antibody and T-Cell Responses in Nonhuman Primates. J. Virol., 84(4):1683-1695, Feb 2010. PubMed ID: 19955308.
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Du2009
Sean X. Du, Rebecca J. Idiart, Ellaine B. Mariano, Helen Chen, Peifeng Jiang, Li Xu, Kristin M. Ostrow, Terri Wrin, Pham Phung, James M. Binley, Christos J. Petropoulos, John A. Ballantyne, and Robert G. Whalen. Effect of Trimerization Motifs on Quaternary Structure, Antigenicity, and Immunogenicity of a Noncleavable HIV-1 gp140 Envelope Glycoprotein. Virology, 395(1):33-44, 5 Dec 2009. PubMed ID: 19815247.
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Dunfee2009
Rebecca L. Dunfee, Elaine R. Thomas, and Dana Gabuzda. Enhanced Macrophage Tropism of HIV in Brain and Lymphoid Tissues Is Associated with Sensitivity to the Broadly Neutralizing CD4 Binding Site Antibody b12. Retrovirology, 6:69, 2009. PubMed ID: 19619305.
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Easterhoff2017
David Easterhoff, M. Anthony Moody, Daniela Fera, Hao Cheng, Margaret Ackerman, Kevin Wiehe, Kevin O. Saunders, Justin Pollara, Nathan Vandergrift, Rob Parks, Jerome Kim, Nelson L. Michael, Robert J. O'Connell, Jean-Louis Excler, Merlin L. Robb, Sandhya Vasan, Supachai Rerks-Ngarm, Jaranit Kaewkungwal, Punnee Pitisuttithum, Sorachai Nitayaphan, Faruk Sinangil, James Tartaglia, Sanjay Phogat, Thomas B. Kepler, S. Munir Alam, Hua-Xin Liao, Guido Ferrari, Michael S. Seaman, David C. Montefiori, Georgia D. Tomaras, Stephen C. Harrison, and Barton F. Haynes. Boosting of HIV Envelope CD4 Binding Site Antibodies with Long Variable Heavy Third Complementarity Determining Region in the Randomized Double Blind RV305 HIV-1 Vaccine Trial. PLoS Pathog., 13(2):e1006182, Feb 2017. PubMed ID: 28235027.
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Feng2012
Yu Feng, Krisha McKee, Karen Tran, Sijy O'Dell, Stephen D. Schmidt, Adhuna Phogat, Mattias N. Forsell, Gunilla B. Karlsson Hedestam, John R. Mascola, and Richard T. Wyatt. Biochemically Defined HIV-1 Envelope Glycoprotein Variant Immunogens Display Differential Binding and Neutralizing Specificities to the CD4-Binding Site. J. Biol. Chem., 287(8):5673-5686, 17 Feb 2012. PubMed ID: 22167180.
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Frey2008
Gary Frey, Hanqin Peng, Sophia Rits-Volloch, Marco Morelli, Yifan Cheng, and Bing Chen. A Fusion-Intermediate State of HIV-1 gp41 Targeted by Broadly Neutralizing Antibodies. Proc. Natl. Acad. Sci. U.S.A., 105(10):3739-3744, 11 Mar 2008. PubMed ID: 18322015.
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Fu2018
Qingshan Fu, Md Munan Shaik, Yongfei Cai, Fadi Ghantous, Alessandro Piai, Hanqin Peng, Sophia Rits-Volloch, Zhijun Liu, Stephen C. Harrison, Michael S. Seaman, Bing Chen, and James J. Chou. Structure of the Membrane Proximal External Region of HIV-1 Envelope Glycoprotein. Proc. Natl. Acad. Sci. U.S.A., 115(38):E8892-E8899, 18 Sep 2018. PubMed ID: 30185554.
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Gopi2008
Hosahudya Gopi, M. Umashankara, Vanessa Pirrone, Judith LaLonde, Navid Madani, Ferit Tuzer, Sabine Baxter, Isaac Zentner, Simon Cocklin, Navneet Jawanda, Shendra R. Miller, Arne Schön, Jeffrey C. Klein, Ernesto Freire, Fred C. Krebs, Amos B. Smith, Joseph Sodroski, and Irwin Chaiken. Structural Determinants for Affinity Enhancement of a Dual Antagonist Peptide Entry Inhibitor of Human Immunodeficiency Virus Type-1. J. Med. Chem., 51(9):2638-2647, 8 May 2008. PubMed ID: 18402432.
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Guenaga2015a
Javier Guenaga, Viktoriya Dubrovskaya, Natalia de Val, Shailendra K. Sharma, Barbara Carrette, Andrew B. Ward, and Richard T. Wyatt. Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers. J. Virol., 90(6):2806-2817, 30 Dec 2015. PubMed ID: 26719252.
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Gupta2013
Sandeep Gupta, Johannes S. Gach, Juan C. Becerra, Tran B. Phan, Jeffrey Pudney, Zina Moldoveanu, Sarah B. Joseph, Gary Landucci, Medalyn Jude Supnet, Li-Hua Ping, Davide Corti, Brian Moldt, Zdenek Hel, Antonio Lanzavecchia, Ruth M. Ruprecht, Dennis R. Burton, Jiri Mestecky, Deborah J. Anderson, and Donald N. Forthal. The Neonatal Fc Receptor (FcRn) Enhances Human Immunodeficiency Virus Type 1 (HIV-1) Transcytosis across Epithelial Cells. PLoS Pathog., 9(11):e1003776, Nov 2013. PubMed ID: 24278022.
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Haim2011
Hillel Haim, Bettina Strack, Aemro Kassa, Navid Madani, Liping Wang, Joel R. Courter, Amy Princiotto, Kathleen McGee, Beatriz Pacheco, Michael S. Seaman, Amos B. Smith, 3rd., and Joseph Sodroski. Contribution of Intrinsic Reactivity of the HIV-1 Envelope Glycoproteins to CD4-Independent Infection and Global Inhibitor Sensitivity. PLoS Pathog., 7(6):e1002101, Jun 2011. PubMed ID: 21731494.
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Johnson2017
Jacklyn Johnson, Yinjie Zhai, Hamid Salimi, Nicole Espy, Noah Eichelberger, Orlando DeLeon, Yunxia O'Malley, Joel Courter, Amos B. Smith, III, Navid Madani, Joseph Sodroski, and Hillel Haim. Induction of a Tier-1-Like Phenotype in Diverse Tier-2 Isolates by Agents That Guide HIV-1 Env to Perturbation-Sensitive, Nonnative States. J. Virol., 91(15), 1 Aug 2017. PubMed ID: 28490588.
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Joubert2010
Marisa K. Joubert, Nichole Kinsley, Alexio Capovilla, B. Trevor Sewell, Mohamed A. Jaffer, and Makobetsa Khati. A Modeled Structure of an Aptamer-gp120 Complex Provides Insight into the Mechanism of HIV-1 Neutralization. Biochemistry, 49(28):5880-5890, 20 Jul 2010. PubMed ID: 20527993.
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Julien2015
Jean-Philippe Julien, Jeong Hyun Lee, Gabriel Ozorowski, Yuanzi Hua, Alba Torrents de la Peña, Steven W. de Taeye, Travis Nieusma, Albert Cupo, Anila Yasmeen, Michael Golabek, Pavel Pugach, P. J. Klasse, John P. Moore, Rogier W. Sanders, Andrew B. Ward, and Ian A. Wilson. Design and Structure of Two HIV-1 Clade C SOSIP.664 Trimers That Increase the Arsenal of Native-Like Env Immunogens. Proc. Natl. Acad. Sci. U.S.A., 112(38):11947-11952, 22 Sep 2015. PubMed ID: 26372963.
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Kang2009
Yun Kenneth Kang, Sofija Andjelic, James M. Binley, Emma T. Crooks, Michael Franti, Sai Prasad N. Iyer, Gerald P. Donovan, Antu K. Dey, Ping Zhu, Kenneth H. Roux, Robert J. Durso, Thomas F. Parsons, Paul J. Maddon, John P. Moore, and William C. Olson. Structural and Immunogenicity Studies of a Cleaved, Stabilized Envelope Trimer Derived from Subtype A HIV-1. Vaccine, 27(37):5120-5132, 13 Aug 2009. PubMed ID: 19567243.
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Kesavardhana2017
Sannula Kesavardhana, Raksha Das, Michael Citron, Rohini Datta, Linda Ecto, Nonavinakere Seetharam Srilatha, Daniel DiStefano, Ryan Swoyer, Joseph G. Joyce, Somnath Dutta, Celia C. LaBranche, David C. Montefiori, Jessica A. Flynn, and Raghavan Varadarajan. Structure-Based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies. J. Biol. Chem., 292(1):278-291, 6 Jan 2017. PubMed ID: 27879316.
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Kovacs2012
James M. Kovacs, Joseph P. Nkolola, Hanqin Peng, Ann Cheung, James Perry, Caroline A. Miller, Michael S. Seaman, Dan H. Barouch, and Bing Chen. HIV-1 Envelope Trimer Elicits More Potent Neutralizing Antibody Responses than Monomeric gp120. Proc. Natl. Acad. Sci. U.S.A., 109(30):12111-12116, 24 Jul 2012. PubMed ID: 22773820.
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Kwong2002
Peter D. Kwong, Michael L. Doyle, David J. Casper, Claudia Cicala, Stephanie A. Leavitt, Shahzad Majeed, Tavis D. Steenbeke, Miro Venturi, Irwin Chaiken, Michael Fung, Hermann Katinger, Paul W. I. H. Parren, James Robinson, Donald Van Ryk, Liping Wang, Dennis R. Burton, Ernesto Freire, Richard Wyatt, Joseph Sodroski, Wayne A. Hendrickson, and James Arthos. HIV-1 Evades Antibody-Mediated Neutralization through Conformational Masking of Receptor-Binding Sites. Nature, 420(6916):678-682, 12 Dec 2002. Comment in Nature. 2002 Dec 12;420(6916):623-4. PubMed ID: 12478295.
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Law2007
Mansun Law, Rosa M. F. Cardoso, Ian A. Wilson, and Dennis R. Burton. Antigenic and Immunogenic Study of Membrane-Proximal External Region-Grafted gp120 Antigens by a DNA Prime-Protein Boost Immunization Strategy. J. Virol., 81(8):4272-4285, Apr 2007. PubMed ID: 17267498.
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Leaman2010
Daniel P. Leaman, Heather Kinkead, and Michael B. Zwick. In-Solution Virus Capture Assay Helps Deconstruct Heterogeneous Antibody Recognition of Human Immunodeficiency Virus Type 1. J. Virol., 84(7):3382-3395, Apr 2010. PubMed ID: 20089658.
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Leaman2013
Daniel P. Leaman and Michael B. Zwick. Increased Functional Stability and Homogeneity of Viral Envelope Spikes through Directed Evolution. PLoS Pathog., 9(2):e1003184, Feb 2013. PubMed ID: 23468626.
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Li2012
Yuxing Li, Sijy O'Dell, Richard Wilson, Xueling Wu, Stephen D. Schmidt, Carl-Magnus Hogerkorp, Mark K. Louder, Nancy S. Longo, Christian Poulsen, Javier Guenaga, Bimal K. Chakrabarti, Nicole Doria-Rose, Mario Roederer, Mark Connors, John R. Mascola, and Richard T. Wyatt. HIV-1 Neutralizing Antibodies Display Dual Recognition of the Primary and Coreceptor Binding Sites and Preferential Binding to Fully Cleaved Envelope Glycoproteins. J. Virol., 86(20):11231-11241, Oct 2012. PubMed ID: 22875963.
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Lin2007
George Lin and Peter L. Nara. Designing Immunogens to Elicit Broadly Neutralizing Antibodies to the HIV-1 Envelope Glycoprotein. Curr. HIV Res., 5(6):514-541, Nov 2007. PubMed ID: 18045109.
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Lynch2012
Rebecca M. Lynch, Lillian Tran, Mark K. Louder, Stephen D. Schmidt, Myron Cohen, CHAVI 001 Clinical Team Members, Rebecca DerSimonian, Zelda Euler, Elin S. Gray, Salim Abdool Karim, Jennifer Kirchherr, David C. Montefiori, Sengeziwe Sibeko, Kelly Soderberg, Georgia Tomaras, Zhi-Yong Yang, Gary J. Nabel, Hanneke Schuitemaker, Lynn Morris, Barton F. Haynes, and John R. Mascola. The Development of CD4 Binding Site Antibodies during HIV-1 Infection. J. Virol., 86(14):7588-7595, Jul 2012. PubMed ID: 22573869.
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Malherbe2014
Delphine C. Malherbe, Franco Pissani, D. Noah Sather, Biwei Guo, Shilpi Pandey, William F. Sutton, Andrew B. Stuart, Harlan Robins, Byung Park, Shelly J. Krebs, Jason T. Schuman, Spyros Kalams, Ann J. Hessell, and Nancy L. Haigwood. Envelope variants circulating as initial neutralization breadth developed in two HIV-infected subjects stimulate multiclade neutralizing antibodies in rabbits. J Virol, 88(22):12949-67 doi, Nov 2014. PubMed ID: 25210191
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Mishra2020
Nitesh Mishra, Shaifali Sharma, Ayushman Dobhal, Sanjeev Kumar, Himanshi Chawla, Ravinder Singh, Bimal Kumar Das, Sushil Kumar Kabra, Rakesh Lodha, and Kalpana Luthra. A Rare Mutation in an Infant-Derived HIV-1 Envelope Glycoprotein Alters Interprotomer Stability and Susceptibility to Broadly Neutralizing Antibodies Targeting the Trimer Apex. J. Virol., 94(19), 15 Sep 2020. PubMed ID: 32669335.
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Mishra2020a
Nitesh Mishra, Shaifali Sharma, Ayushman Dobhal, Sanjeev Kumar, Himanshi Chawla, Ravinder Singh, Muzamil Ashraf Makhdoomi, Bimal Kumar Das, Rakesh Lodha, Sushil Kumar Kabra, and Kalpana Luthra. Broadly Neutralizing Plasma Antibodies Effective against Autologous Circulating Viruses in Infants with Multivariant HIV-1 Infection. Nat. Commun., 11(1):4409, 2 Sep 2020. PubMed ID: 32879304.
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Moog2014
C. Moog, N. Dereuddre-Bosquet, J.-L. Teillaud, M. E. Biedma, V. Holl, G. Van Ham, L. Heyndrickx, A. Van Dorsselaer, D. Katinger, B. Vcelar, S. Zolla-Pazner, I. Mangeot, C. Kelly, R. J. Shattock, and R. Le Grand. Protective Effect of Vaginal Application of Neutralizing and Nonneutralizing Inhibitory Antibodies Against Vaginal SHIV Challenge in Macaques. Mucosal Immunol., 7(1):46-56, Jan 2014. PubMed ID: 23591718.
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Moore2006
Penny L. Moore, Emma T. Crooks, Lauren Porter, Ping Zhu, Charmagne S. Cayanan, Henry Grise, Paul Corcoran, Michael B. Zwick, Michael Franti, Lynn Morris, Kenneth H. Roux, Dennis R. Burton, and James M. Binley. Nature of Nonfunctional Envelope Proteins on the Surface of Human Immunodeficiency Virus Type 1. J. Virol., 80(5):2515-2528, Mar 2006. PubMed ID: 16474158.
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Narayan2013
Kristin M. Narayan, Nitish Agrawal, Sean X. Du, Janelle E. Muranaka, Katherine Bauer, Daniel P. Leaman, Pham Phung, Kay Limoli, Helen Chen, Rebecca I. Boenig, Terri Wrin, Michael B. Zwick, and Robert G. Whalen. Prime-Boost Immunization of Rabbits with HIV-1 gp120 Elicits Potent Neutralization Activity against a Primary Viral Isolate. PLoS One, 8(1):e52732, 9 Jan 2013. PubMed ID: 23326351.
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Pancera2005
Marie Pancera and Richard Wyatt. Selective Recognition of Oligomeric HIV-1 Primary Isolate Envelope Glycoproteins by Potently Neutralizing Ligands Requires Efficient Precursor Cleavage. Virology, 332(1):145-156, 5 Feb 2005. PubMed ID: 15661147.
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Pantophlet2003
Ralph Pantophlet, Erica Ollmann Saphire, Pascal Poignard, Paul W. H. I. Parren, Ian A. Wilson, and Dennis R. Burton. Fine Mapping of the Interaction of Neutralizing and Nonneutralizing Monoclonal Antibodies with the CD4 Binding Site of Human Immunodeficiency Virus Type 1 gp120. J. Virol., 77(1):642-658, Jan 2003. PubMed ID: 12477867.
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Pantophlet2003b
Ralph Pantophlet, Ian A. Wilson, and Dennis R. Burton. Hyperglycosylated Mutants of Human Immunodeficiency Virus (HIV) Type 1 Monomeric gp120 as Novel Antigens for HIV Vaccine Design. J. Virol., 77(10):5889-8901, May 2003. PubMed ID: 12719582.
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Pantophlet2004
R. Pantophlet, I. A. Wilson, and D. R. Burton. Improved Design of an Antigen with Enhanced Specificity for the Broadly HIV-Neutralizing Antibody b12. Protein Eng. Des. Sel., 17(10):749-758, Oct 2004. PubMed ID: 15542540.
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Pantophlet2009
Ralph Pantophlet, Meng Wang, Rowena O. Aguilar-Sino, and Dennis R. Burton. The Human Immunodeficiency Virus Type 1 Envelope Spike of Primary Viruses Can Suppress Antibody Access to Variable Regions. J. Virol., 83(4):1649-1659, Feb 2009. PubMed ID: 19036813.
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Parren1997
P. W. Parren, M. C. Gauduin, R. A. Koup, P. Poignard, Q. J. Sattentau, P. Fisicaro, and D. R. Burton. Erratum to Relevance of the Antibody Response against Human Immunodeficiency Virus Type 1 Envelope to Vaccine Design. Immunol. Lett., 58:125-132, 1997. corrected and republished article originally printed in Immunol. Lett. 1997 Jun;57(1-3):105-112. PubMed ID: 9271324.
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Parren1998
P. W. Parren, I. Mondor, D. Naniche, H. J. Ditzel, P. J. Klasse, D. R. Burton, and Q. J. Sattentau. Neutralization of human immunodeficiency virus type 1 by antibody to gp120 is determined primarily by occupancy of sites on the virion irrespective of epitope specificity. J. Virol., 72:3512-9, 1998. The authors propose that the occupancy of binding sites on HIV-1 virions is the major factor in determining neutralization, irrespective of epitope specificity. Neutralization was assayed T-cell-line-adapted HIV-1 isolates. Binding of Fabs to monomeric rgp120 was not correlated with binding to functional oligomeric gp120 or neutralization, while binding to functional oligomeric gp120 was highly correlated with neutralization. The ratios of oligomer binding/neutralization were similar for antibodies to different neutralization epitopes, with a few exceptions. PubMed ID: 9557629.
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Poignard2003
Pascal Poignard, Maxime Moulard, Edwin Golez, Veronique Vivona, Michael Franti, Sara Venturini, Meng Wang, Paul W. H. I. Parren, and Dennis R. Burton. Heterogeneity of Envelope Molecules Expressed on Primary Human Immunodeficiency Virus Type 1 Particles as Probed by the Binding of Neutralizing and Nonneutralizing Antibodies. J. Virol., 77(1):353-365, Jan 2003. PubMed ID: 12477840.
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Pugach2015
Pavel Pugach, Gabriel Ozorowski, Albert Cupo, Rajesh Ringe, Anila Yasmeen, Natalia de Val, Ronald Derking, Helen J. Kim, Jacob Korzun, Michael Golabek, Kevin de Los Reyes, Thomas J. Ketas, Jean-Philippe Julien, Dennis R. Burton, Ian A. Wilson, Rogier W. Sanders, P. J. Klasse, Andrew B. Ward, and John P. Moore. A Native-Like SOSIP.664 Trimer Based on an HIV-1 Subtype B env Gene. J. Virol., 89(6):3380-3395, Mar 2015. PubMed ID: 25589637.
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Ringe2010
Rajesh Ringe, Madhuri Thakar, and Jayanta Bhattacharya. Variations in Autologous Neutralization and CD4 Dependence of b12 Resistant HIV-1 Clade C env Clones Obtained at Different Time Points from Antiretroviral Naïve Indian Patients with Recent Infection. Retrovirology, 7:76, 2010. PubMed ID: 20860805.
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Sanders2013
Rogier W. Sanders, Ronald Derking, Albert Cupo, Jean-Philippe Julien, Anila Yasmeen, Natalia de Val, Helen J. Kim, Claudia Blattner, Alba Torrents de la Peña, Jacob Korzun, Michael Golabek, Kevin de los Reyes, Thomas J. Ketas, Marit J. van Gils, C. Richter King, Ian A. Wilson, Andrew B. Ward, P. J. Klasse, and John P. Moore. A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but not Non-Neutralizing Antibodies. PLoS Pathog., 9(9):e1003618, Sep 2013. PubMed ID: 24068931.
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Schiffner2018
Torben Schiffner, Jesper Pallesen, Rebecca A. Russell, Jonathan Dodd, Natalia de Val, Celia C. LaBranche, David Montefiori, Georgia D. Tomaras, Xiaoying Shen, Scarlett L. Harris, Amin E. Moghaddam, Oleksandr Kalyuzhniy, Rogier W. Sanders, Laura E. McCoy, John P. Moore, Andrew B. Ward, and Quentin J. Sattentau. Structural and Immunologic Correlates of Chemically Stabilized HIV-1 Envelope Glycoproteins. PLoS Pathog., 14(5):e1006986, May 2018. PubMed ID: 29746590.
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Selvarajah2005
Suganya Selvarajah, Bridget Puffer, Ralph Pantophlet, Mansun Law, Robert W. Doms, and Dennis R. Burton. Comparing Antigenicity and Immunogenicity of Engineered gp120. J. Virol., 79(19):12148-12163, Oct 2005. PubMed ID: 16160142.
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Srivastava2005
Indresh K. Srivastava, Jeffrey B. Ulmer, and Susan W. Barnett. Role of Neutralizing Antibodies in Protective Immunity Against HIV. Hum. Vaccin., 1(2):45-60, Mar-Apr 2005. PubMed ID: 17038830.
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Sundling2012
Christopher Sundling, Yuxing Li, Nick Huynh, Christian Poulsen, Richard Wilson, Sijy O'Dell, Yu Feng, John R. Mascola, Richard T. Wyatt, and Gunilla B. Karlsson Hedestam. High-Resolution Definition of Vaccine-Elicited B Cell Responses Against the HIV Primary Receptor Binding Site. Sci. Transl. Med., 4(142):142ra96, 11 Jul 2012. PubMed ID: 22786681.
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Vaine2008
Michael Vaine, Shixia Wang, Emma T. Crooks, Pengfei Jiang, David C. Montefiori, James Binley, and Shan Lu. Improved Induction of Antibodies against Key Neutralizing Epitopes by Human Immunodeficiency Virus Type 1 gp120 DNA Prime-Protein Boost Vaccination Compared to gp120 Protein-Only Vaccination. J. Virol., 82(15):7369-7378, Aug 2008. PubMed ID: 18495775.
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vonBredow2016
Benjamin von Bredow, Juan F. Arias, Lisa N. Heyer, Brian Moldt, Khoa Le, James E. Robinson, Susan Zolla-Pazner, Dennis R. Burton, and David T. Evans. Comparison of Antibody-Dependent Cell-Mediated Cytotoxicity and Virus Neutralization by HIV-1 Env-Specific Monoclonal Antibodies. J. Virol., 90(13):6127-6139, 1 Jul 2016. PubMed ID: 27122574.
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Walker2009a
Laura M. Walker, Sanjay K. Phogat, Po-Ying Chan-Hui, Denise Wagner, Pham Phung, Julie L. Goss, Terri Wrin, Melissa D. Simek, Steven Fling, Jennifer L. Mitcham, Jennifer K. Lehrman, Frances H. Priddy, Ole A. Olsen, Steven M. Frey, Phillip W . Hammond, Protocol G Principal Investigators, Stephen Kaminsky, Timothy Zamb, Matthew Moyle, Wayne C. Koff, Pascal Poignard, and Dennis R. Burton. Broad and Potent Neutralizing Antibodies from an African Donor Reveal a new HIV-1 Vaccine Target. Science, 326(5950):285-289, 9 Oct 2009. PubMed ID: 19729618.
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Walker2009b
Laura M. Walker, Diana R. Bowley, and Dennis R. Burton. Efficient Recovery of High-Affinity Antibodies from a Single-Chain Fab Yeast Display Library. J. Mol. Biol., 389(2):365-375, 5 Jun 2009. PubMed ID: 19376130.
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Walker2010
Laura M. Walker, Melissa D. Simek, Frances Priddy, Johannes S. Gach, Denise Wagner, Michael B. Zwick, Sanjay K. Phogat, Pascal Poignard, and Dennis R. Burton. A Limited Number of Antibody Specificities Mediate Broad and Potent Serum Neutralization in Selected HIV-1 Infected Individuals. PLoS Pathog., 6(8), 2010. PubMed ID: 20700449.
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Witt2017
Kristen C. Witt, Luis Castillo-Menendez, Haitao Ding, Nicole Espy, Shijian Zhang, John C. Kappes, and Joseph Sodroski. Antigenic Characterization of the Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Precursor Incorporated into Nanodiscs. PLoS One, 12(2):e0170672, 2017. PubMed ID: 28151945.
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Wu2009
Xueling Wu, Tongqing Zhou, Sijy O'Dell, Richard T. Wyatt, Peter D. Kwong, and John R. Mascola. Mechanism of Human Immunodeficiency Virus Type 1 Resistance to Monoclonal Antibody b12 That Effectively Targets the Site of CD4 Attachment. J. Virol., 83(21):10892-10907, Nov 2009. PubMed ID: 19692465.
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Wu2009a
Lan Wu, Tongqing Zhou, Zhi-yong Yang, Krisha Svehla, Sijy O'Dell, Mark K. Louder, Ling Xu, John R. Mascola, Dennis R. Burton, James A. Hoxie, Robert W. Doms, Peter D. Kwong, and Gary J. Nabel. Enhanced Exposure of the CD4-Binding Site to Neutralizing Antibodies by Structural Design of a Membrane-Anchored Human Immunodeficiency Virus Type 1 gp120 Domain. J. Virol., 83(10):5077-5086, May 2009. PubMed ID: 19264769.
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Wu2010
Xueling Wu, Zhi-Yong Yang, Yuxing Li, Carl-Magnus Hogerkorp, William R. Schief, Michael S. Seaman, Tongqing Zhou, Stephen D. Schmidt, Lan Wu, Ling Xu, Nancy S. Longo, Krisha McKee, Sijy O'Dell, Mark K. Louder, Diane L. Wycuff, Yu Feng, Martha Nason, Nicole Doria-Rose, Mark Connors, Peter D. Kwong, Mario Roederer, Richard T. Wyatt, Gary J. Nabel, and John R. Mascola. Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1. Science, 329(5993):856-861, 13 Aug 2010. PubMed ID: 20616233.
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Yasmeen2014
Anila Yasmeen, Rajesh Ringe, Ronald Derking, Albert Cupo, Jean-Philippe Julien, Dennis R. Burton, Andrew B. Ward, Ian A. Wilson, Rogier W. Sanders, John P. Moore, and Per Johan Klasse. Differential Binding of Neutralizing and Non-Neutralizing Antibodies to Native-Like Soluble HIV-1 Env Trimers, Uncleaved Env Proteins, and Monomeric Subunits. Retrovirology, 11:41, 2014. PubMed ID: 24884783.
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Zhou2007
Tongqing Zhou, Ling Xu, Barna Dey, Ann J. Hessell, Donald Van Ryk, Shi-Hua Xiang, Xinzhen Yang, Mei-Yun Zhang, Michael B. Zwick, James Arthos, Dennis R. Burton, Dimiter S. Dimitrov, Joseph Sodroski, Richard Wyatt, Gary J. Nabel, and Peter D. Kwong. Structural Definition of a Conserved Neutralization Epitope on HIV-1 gp120. Nature, 445(7129):732-737, 15 Feb 2007. PubMed ID: 17301785.
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Zwick2003a
Michael B. Zwick, Robert Kelleher, Richard Jensen, Aran F. Labrijn, Meng Wang, Gerald V. Quinnan, Jr., Paul W. H. I. Parren, and Dennis R. Burton. A Novel Human Antibody against Human Immunodeficiency Virus Type 1 gp120 Is V1, V2, and V3 Loop Dependent and Helps Delimit the Epitope of the Broadly Neutralizing Antibody Immunoglobulin G1 b12. J. Virol., 77(12):6965-6978, Jun 2003. PubMed ID: 12768015.
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Willis2022
Jordan R. Willis, Zachary T. Berndsen, Krystal M. Ma, Jon M. Steichen, Torben Schiffner, Elise Landais, Alessia Liguori, Oleksandr Kalyuzhniy, Joel D. Allen, Sabyasachi Baboo, Oluwarotimi Omorodion, Jolene K. Diedrich, Xiaozhen Hu, Erik Georgeson, Nicole Phelps, Saman Eskandarzadeh, Bettina Groschel, Michael Kubitz, Yumiko Adachi, Tina-Marie Mullin, Nushin B. Alavi, Samantha Falcone, Sunny Himansu, Andrea Carfi, Ian A. Wilson, John R. Yates III, James C. Paulson, Max Crispin, Andrew B. Ward, and William R. Schief. Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors. Immunity, 55(11):2149-2167e9 doi, Nov 2022. PubMed ID: 36179689
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Displaying record number 2124
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record as JSON.
MAb ID |
PG9 |
HXB2 Location |
Env |
Env Epitope Map
|
Author Location |
gp120(126-196) |
Epitope |
(Discontinuous epitope)
|
Subtype |
A |
Ab Type |
gp120 V2 // V2 glycan(V2g) // V2 apex, quaternary structure |
Neutralizing |
P (tier 2) View neutralization details |
Contacts and Features |
View contacts and features |
Species
(Isotype)
|
human(IgG1) |
Patient |
Donor 24 |
Immunogen |
HIV-1 infection |
Keywords |
acute/early infection, anti-idiotype, antibody binding site, antibody gene transfer, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autoantibody or autoimmunity, autologous responses, binding affinity, broad neutralizer, chimeric antibody, co-receptor, complement, computational prediction, contact residues, early treatment, effector function, elite controllers and/or long-term non-progressors, escape, genital and mucosal immunity, germline, glycosylation, HIV reservoir/latency/provirus, immunoprophylaxis, immunotherapy, junction or fusion peptide, memory cells, mimics, mother-to-infant transmission, mutation acquisition, neutralization, polyclonal antibodies, rate of progression, review, SIV, structure, subtype comparisons, therapeutic vaccine, transmission pair, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity, viral fitness and/or reversion |
Notes
Showing 206 of
206 notes.
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PG9: This article reviews how B cell receptor sequence analyses and repertoires can be used in vaccine stratagem. Overall, multiple immunogens and their interactions driving bnAb development to generate Abs with special genetic characteristics of V gene restriction, long CDRH3 (bnAbs like PG9 have twice the length of the average naive or memory B cell receptor CDRH3, at 30 aa) and high load SHM are the current effective strategy being used.
Kreer2020
(antibody generation, neutralization, therapeutic vaccine, review, antibody sequence)
-
PG9: The study describes the generation, crystal structure, and immunogenic properties of a native-like Env SOSIP trimer based on a group M consensus (ConM) sequence. A crystal structure of ConM SOSIP.v7 trimer together with nAbs PGT124 and 35O22 revealed that ConM SOSIP.v7 is structurally similar to other Env trimers. In rabbits, the ConM SOSIP trimer induced serum nAbs that neutralized the autologous Tier 1A virus (ConM from 2004) and a related Tier 1B ConS virus (ConM from 2001). These responses target the trimer apex and were enhanced when the trimers were presented on ferritin nanoparticles. The neutralization of ConM and ConS pseudoviruses was tested against a large panel of nAbs and non-nAbs (2219, 2557, 3074, 3869, 447-52D, 830A, 654-30D, 1008-30D, 1570D, 729-30D, F105, 181D, 246D, 50-69D, sCD4, VRC01, 3BNC117, CH31, PG9, PG16, CH01, PGDM1400, PGT128, PGT121, 10-1074, PGT151, VRC43.01, 2G12, DH511.2_K3, 10E8, 2F5, 4E10); most nAbs were able to neutralize these pseudoviruses. Soluble ConM trimers were able to weakly activate B cells expressing PGT121 and PG16 BCRs but were inactive against those expressing VRC01 and PGT145. In contrast, at the same molar amount of trimers, the ConM SOSIP.v7-ferritin nanoparticles activated all 4 B cells efficiently. Binding of bnAbs 2G12 and PGT145 and non-nAbs F105 and 19b to ConM SOSIP.v7 trimer and SOSIP showed that the ferritin-bound trimer bound more avidly than the soluble trimer. This study shows that native-like HIV-1 Env trimers can be generated from consensus sequences, and such immunogens might be suitable vaccine components to prime and/or boost desirable nAb responses.
Sliepen2019
(neutralization, vaccine antigen design)
-
PG9: Membrane-bound BG505-based ApexGT Env trimer vaccine candidates, which bind to inferred germline variants of bnAbs PCT64 and PG9, were developed through directed evolution and characterized. The antigenicity of the most promising immunogen, ApexGT5, was also assessed in variants designed for mRNA delivery. PCT64 and PG9/PG16 lineages were identified to have the highest and most consistent frequencies of precursors in 14 HIV-unexposed donors among 5 V2-apex-targeting bnAb classes which also included PGT141-145/PGDM1400-1414, CH01-CH04 and CAP256-VRC26 lineages. PG9/PG16 heavy chain (HC) precursors were found in 9/14 donors with a median frequency of 0.23 precursors per million BCRs. Of the assessed soluble trimers, PG9 had the greatest binding affinity for ApexGT3 (KD 0.2 nM). PG9 also had a KD value of 8.59 nM for binding to ApexGT5. Membrane-bound DNA-expressed BG505 SOSIP.MD39 (MD39, background for Apex constructs), ApexGT5, ApexGT5.Congly and ApexGT5.Gmax, as well as membrane-bound mRNA-encoded MD39, ApexGT5 and ApexGT5Congly, all had generally similar antigenic profiles and bound PG9 at moderate levels. A 4.75 Å resolution cryo-EM structure of PG9 Fab and ApexGT3.2MUT (PDB 7T77) confirmed 1:1 stoichiometry, angle of approach and extensive apex glycan interaction. The N130 and H185H glycans, present on ApexGT3.2MUT, do not make direct contacts with the PG9 Fab. The observed binding angle could cause structural clashes with an elongated loop2B, such as is found in wild-type BG505, but was similar between germline PG9 iGL and mature PG9. A trimeric interface was required for binding to PG9 iGL, but not mature PG9. Negative stain EM data suggested that an open conformation of an Env trimer would be required to accommodate 3 PG9 Fabs.
Willis2022
(antibody binding site, glycosylation, vaccine antigen design, binding affinity, antibody sequence, structure, antibody lineage, contact residues)
-
PG9: A panel of 30 contemporary subtype B pseudoviruses (PSVs) was generated. Neutralization sensitivities of these PSVs were compared with subtype B strains from earlier in the pandemic using 31 nAbs (PG9, PG16, PGT145, PGDM1400, CH02, CH03, CH04, 830A, PGT121, PGT126, PGT128, PGT130, 10-1074, 2192, 2219, 3074, 3869, 447-52D, b12, NIH45-46, VRC01, VRC03, 3BNC117, HJ16, sCD4, 10E8, 4E10, 2F5, 7H6, 2G12, 35O22). A significant reduction in Env neutralization sensitivity was observed for 27 out of 31 nAbs for the contemporary, as compared to earlier-decade subtype B PSVs. A decline in neutralization sensitivity was observed across all Env domains; the nAbs that were most potent early in the pandemic suffered the greatest decline in potency over time. A metaanalysis demonstrated this trend across multiple subtypes. As HIV-1 Env diversification continues, changes in Env antigenicity and neutralization sensitivity should continue to be evaluated to inform the development of improved vaccine and antibody products to prevent and treat HIV-1.
Wieczorek2023
(neutralization, viral fitness and/or reversion)
-
PG9: Pseudoviruses were made from 13 env sequences of subtypes A6 and CRF63_02A6, based on genetic variants of HIV-1 circulating in the Siberian Federal District. Neutralization of these viruses was tested for 8 bnAbs. Most of the pseudoviruses were sensitive to neutralization by VRC01, PGT126, and 10E8, moderately sensitive to PG9 and 4E10, and resistant to 2G12, PG16, and 2F5. All obtained variants of pseudoviruses were CCR5-tropic.
Rudometova2022
(co-receptor, neutralization, subtype comparisons)
-
PG9: This study analyzed Env sequences of early HIV-1 clonal variants from 31 individuals from the Amsterdam Cohort Studies with diverse levels of heterologous neutralization at 2-4 years post-seroconversion. A number of Env signatures coincided with neutralization development. These included a statistically shorter variable region 1 and a lower probability of glycosylation. Induction of neutralization was associated with a lower probability of glycosylation at position 332, which is involved in the epitopes of many bnAbs. 2G12 and PGT126 were tested for their ability to block infectivity by patient viruses with predicted glycosylation at N332; the NLS glycosylation motif was associated with resistance to these mAbs more often than the NIS glycosylation motif. Sequence Harmony software identified amino acid changes associated with the development of heterologous neutralization. These residues mapped to various Env subdomains, but in particular to the first and fourth variable region, as well as the underlying α2 helix of the third constant region. These findings imply that the development of heterologous neutralization might depend on specific characteristics of early Env. Env signatures that correlate with the induction of neutralization might be relevant for the design of effective HIV-1 vaccines. Primary virus isolates from 21 of the patients were assayed for neutralization by 11 well-known nAbs (b12, VRC01, 447-52D, 2G12, PGT121, PGT126, PG9, PG16, PGT145, 2F5, 4E10).
vandenKerkhof2013
(glycosylation, neutralization, vaccine antigen design, polyclonal antibodies)
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PG9: The polyclonal response of human subjects VC20013 and VC10014 demonstrated increasing neutralization breadth against a panel of HIV-1 isolates over time. Full-length functional env genes were cloned longitudinally from these subjects from months after infection through 2.6 to 5.8 years of infection. Motifs associated with the development of breadth in published, cross-sectional studies were found in the viral sequences of both subjects. To test the immunogenicity of envelope vaccines derived from time points obtained during and after broadening of neutralization activity within these subjects, rabbits were coimmunized 4 times with selected multiple gp160 DNAs and gp140-trimeric envelope proteins. In an assay of rabbit polyclonal responses, the most rapid and persistent neutralization of multiclade tier 1 viruses was elicited by envelopes that were circulating in plasma at time points prior to the development of 50% neutralization breadth in both human subjects. The breadth elicited in rabbits was not improved by exposure to later envelope variants. Env immunogen sequences were tested for binding to a panel of well studied mAbs of various binding types (VRC01, HJ16, b12, b6, PG9, PGT121, 2G12, 2F5, F240); all gp140s bound to weak or non-neutralizing antibodies b6 and F240. MAb b6 also bound BG505 SOSIP, while F240 did not, suggesting that cluster I gp41 epitopes, which become exposed during gp120 shedding, are more easily accessed on these trimers than on BG505-SOSIP. These data have implications for vaccine development in describing a target time point to identify optimal env immunogens.
Malherbe2014
(vaccine antigen design, vaccine-induced immune responses, binding affinity, polyclonal antibodies)
-
PG9: This study explored the basis of the neutralization resistance of tier 3 virus 253-11 (subtype CRF02_AG). Virus 253-11 was resistant to neutralization by 17b, b12, VRC03, F105, SCD4, CH12, Z13e1, PG16, PGT145, 2G12, PGT121, PGT126, PGT128, PGT130, 39F, F240, and 35O22; the virus was sensitive to 3BNC117, NIH45-46G54W, VRC01, 10E8, 2F5, 4E10, PG9, VRC26.26, 10-1074, and PGT151. Virus 253-11 was strikingly resistant to most tested antibodies that target V3/glycans, despite possessing key potential N-linked glycosylation sites, especially N301 and N332, needed for the recognition of this class of antibodies. The resistance of 253-11 was not associated with an unusually long V1/V2 loop, nor with polymorphisms in the V3 loop and N-linked glycosylation sites. The 253-11 MPER was rarely recognized by sera, but was more often recognized in a chimera consisting of a HIV-2 backbone with the 253-11 MPER, suggesting steric or kinetic hindrance of the MPER. Mutations in the 253-11 MPER previously reported to increase the lifetime of the prefusion Env conformation (Y681H, L669S), decreased the resistance of 253-11 to several mAbs, presumably destabilizing its otherwise stable, closed trimer structure. A crystal structure of a recombinant 253-11 SOSIP trimer revealed that the heptad repeat helices in gp41 are drawn in close proximity to the trimer axis and that gp120 protomers also showed a relatively compact form around the trimer axis.
Moyo2018
(neutralization, structure)
-
PG9: This study assessed the ability of single bNAbs and triple bNAb combinations to mediate polyfunctional antiviral activity against a panel of cross-clade simian-human immunodeficiency viruses (SHIVs), which are commonly used as tools for validation of therapeutic strategies in nonhuman primate models. Most bnAbs assayed were capable of mediating both neutralizing and nonneutralizing effector functions (ADCC and ADCP) against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs was highly strain dependent. Several triple bNAb combinations were identified comprising of CD4 binding site-, V2-glycan-, and gp120-gp41 interface-targeting bNAbs that are capable of mediating synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. In assays using the transmitted/founder SHIV.C.CH505, there was a correlation between the neutralization potencies and nonneutralizing effector functions of bnAbs: PG9 was positive for neutralization and binding to infected cells, but negative for ADCC.
Berendam2021
(effector function, neutralization, binding affinity, broad neutralizer)
-
PG9: This study used directed evolution to overcome the instability and heterogeneity of a primary Env isolate (ADA) in order to design better immunogens. HIV-1 virions were subjected to iterative cycles of destabilization and replication to select for Envs with enhanced stability. Several mutations in Env were associated with increased trimer stability, primarily in the heptad repeat regions of gp41 and V1 of gp120. Mutations from the most stable Envs were combined into a variant Env, termed "comb-mut", with superior homogeneity and stability. Comb-mut had greater binding affinity for PGT128, PG9, PG16, 2G12, VRC01, b12, and CD4-IgG2, but decreased binding to 4E10, 2F5, b6, 19b, 17b, 7B2, and D50. Comb-mut was more sensitive to neutralization by PG9. One specific mutation (K574) was shown to decrease the neutralization IC50 of mAbs b12, 2F5, 4E10, b6, 2G12, 8K8 and inhibitors sCD4, T-20, and PF-68742. Several of the Env substitutions were shown to stabilize Env spikes from HIV-1 clades A, B, and C. Spike stabilizing mutations may be useful in the development of Env immunogens that stably retain native, trimeric structure.
Leaman2013
(mimics, vaccine antigen design, binding affinity)
-
PG9: Reduction in exposure of non-neutralizing Ab (nnAb) epitopes on native-like Env trimer immunogens results in bnAbs being elicited that have autologous tier 2 neutralization instead of tier 1. The design of trimer modifications to silence nnAb reactivity were directed towards (1) the V3 loop (2) epitopes exposed through CD4-induced conformational changes (CD4i epitopes) and (3) the exposed SOSIP trimer base that is usually buried within virus membrane. (1) In Steichen2016 2 Env variants of BG505 SOSIP.664 with reduced V3 nnAb-generating activity were created, one using mammalian display screens, BG505 MD39, and the other with an engineered disulfide bond, BG505 SOSIP.DS21. MD39's trimer design was improved by using the Rosetta Design platform and inserting 6 buried mutations to form BG505 Olio6, and both this trimer as well as the DS21 were shown to have reduced antigenicity for nnAb generation in a rabbit vaccine model. (2) To reduce CD4i epitope elicitation of nnAbs, saturation mutagenesis of Olio6 was performed, in search of the trimer that binds VRC01-class bnAbs but not CD4. BG505 Olio6.CD4KO containing the G473T mutation was identified. In addition, for the purposes of nucleic acid-based vaccine platform designs, the natural furin cleavage site between gp120 and gp41 was removed to abolish protease cleavage, by swapping the order of gp14 and gp120 in the gp160 gene, giving the trimer BG505 MD39.CP (circular permutation). (3) The exposed trimer base was masked with glycan in 3 under-glycosylated regions in order to direct bnAb responses to the distal regions (CD4bs, V2 apex, N332 superset) of the trimer instead, generating the GRSF (glycan resurfaced) MD39 and GRSF MD39.CP variants. Furthermore, variants with improved thermostability over MD39 were created, MD37 and MD64. All of these stabilizing mutations were transferred to diverse HIV isolates from different subtypes. Finally 3 subtype C (isolate 327c) trimers were assessed for binding to bnAbs, VRC01, PGT121, PGT151, PGT145, PG9 and to nnAbs, F105 and 17b - PG9 does bind all three.
Kulp2017
(antibody binding site, antibody generation, antibody interactions, assay or method development, autologous responses, vaccine antigen design, structure)
-
PG9: Using subtype A BG505 Env structural information, improved variants of subtype B JRFL and subtype C 16055 Env native flexibly linked (NFL) trimers were generated. The trimer-derived (TD) residues that increased well-ordered, homogeneous, stable, and soluble trimers did not require positive or negative selection as previously needed [Guenaga2015, PLoS Pathos. 11(1):e1004570]. In JRFL trimer-derived Env immunogens, binding to PG9 was restored by the E168K mutation.
Guenaga2015a
(antibody interactions, assay or method development, vaccine antigen design, structure)
-
PG9: Most published structures of bnAbs, yet none of non- or poorly-neutralizing mAbs, were structurally compatible with a newly generated crystal structure of a mature ligand-free endoglycosidase H-treated BG505 SOSIP.664 Env trimer. Robust binding of the structurally incompatible V3- and CD4-bs targeting nAbs could be induced with CD4. A “DS” variant of BG505 SOSIP.664, containing a stabilizing disulfide bond between 201C and 433C mutations, was developed and appeared to represent an obligate intermediate in that it bound only a single CD4 and remained in a prefusion closed conformation. BnAb PG9 was structurally compatible with BG505 SOSIP.664 and had a breadth of 78% (IC50 < 50 μg/ml) in a panel of 170 diverse HIV-1 pseudoviruses.
Kwon2015
(neutralization, vaccine antigen design, structure)
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PG9: Primary HIV-1 Envs were expressed as SHIVs, and responses from infected rhesus macaques showed patterns of Env-antibody coevolution similar to those in humans. This included conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions, and deletions leading to virus persistence. One macaque mAb (RHA1.V2.01), neutralized 49% of a 208-strain panel, and structural analysis revealed a V2-apex mode of recognition that resembles human bnAbs PGT145 or PCT64-35S. Signature sites were analyzed for RHA1.V2.01 and 7 V2 bnAbs (PCT64-34M, PGDM1400, PG9, CH01, PGT145, VRC26.08, VRC26.25).
Roark2021
(mutation acquisition, neutralization, vaccine antigen design, escape)
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PG9: This paper comprehensively defined the effect of every viable single aa mutation in the ectodomain and transmembrane domain of BG505.T332N Env on binding by 9 individual bnAbs targeting 5 epitope classes (VRC01, 3BNC117, PGT121, 10-1074, PG9, PGT145, PGT151, VRC34.01, and 10E8), as well as by a mixture of 3BNC117 and 10-1074. Escape mutations mostly occurred in a small subset of structurally-defined contacts within <4 Å and at sites within 5-10 Å of the Ab. Escape from both V2-apex-targeting bnAbs, PG9 and PGT145, occurred through the elimination of the N160 glycan and/or positive charges from the epitope. Mutations in trimer apex contact sites also facilitated escape. Env sites with the largest cumulative mutational impact on PG9 binding were N160, K171, K169, and T162. See LANL Features and Contacts database for more details.
Dingens2019
(antibody binding site, escape, contact residues)
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PG9: This study aimed to define properties shared by transmitted viruses by comparing antigenic and functional properties of envelope glycoproteins of viral variants isolated during primary infection in 27 patients belonging to 8 transmission clusters. The neutralization of the 27 pseudotyped viruses was assayed with 8 human bnAbs targeting various regions of the virus. The infectious properties of the viruses was assessed by measuring their infectivity and sensitivity to entry inhibitors. Transmitted viruses from the same transmission chain shared many properties, including similar neutralization profiles, sensitivity to inhibitors, and infectivity. All transmitted viruses were CCR5-tropic, sensitive to maraviroc, and resistant to soluble forms of CD4, irrespective of cluster. They were also generally sensitive to bnAbs that target V3 (10-1074, PGT121), CD4bs (3BNC117, NIH45-46G54W), and MPER region (10E8), suggesting that the loss of these epitopes may affect a virus’s capacity to be transmitted. The viruses were somewhat less sensitive to bnAbs targeting the V1V2 region (PG9, PGT145) and gp120/gp41 interface (8ANC195). These data suggest that the transmission bottleneck is governed by selective forces.
Beretta2018
(neutralization, acute/early infection)
-
PG9: This study examined whether HIV-1-specific bnAbs are capable of cross-neutralizing simian immunodeficiency viruses (SIVs) from chimpanzees (n=11) or western gorillas (n=1). BnAbs directed against the epitopes at the CD4 binding site (VRC01, VRC03, VRC-PG04, VRC-CH03, VRC-CH31, F105, b13, NIH45-46G54W, 45-46m2, 45-46m7), V3 (10-1074, PGT121, PGT128, PGT135, and 2G12), and gp41-gp120 interface (8ANC195, 35O22, PGT151, PGT152, PGT158) failed to neutralize SIVcpz and SIVgor strains. V2-directed bNabs (PG9, PG16, PGT145) as well as llama-derived heavy-chain only antibodies recognizing the CD4 binding site or gp41 epitopes (JM4, J3, 3E3, 2E7, 11F1F, Bi-2H10) were either completely inactive or neutralized only a fraction of SIVcpz strains. In contrast, neutralization of SIVcpz and SIVgor strains was achieved with low-nanomolar potency by one antibody targeting the MPER region of gp41 (10E8), as well as functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Igmim2, CD4-218.3-E51, CD4-218.3-E51-mim2), mono- and bispecific anti-human CD4 mAbs (iMab, PG9-iMab, PG16-iMab, LM52, LM52-PGT128), and CCR5 receptor mAbs (PRO140, PRO140-10E8). Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5, and neutralized SIVcpz in chimpanzee CD4+ T cells. These findings provide new insight into the protective capacity of anti-HIV-1 bnAbs and identify candidates for further development to combat SIV infection.
Barbian2015
(neutralization, SIV, binding affinity)
-
PG9: A recombinant native-like Env SOSIP trimer, AMC009, was developed based on viral founder sequences of elite neutralizer H18877. The subtype B AMC009 Env was defined as a Tier 2 virus based on a neutralization assay against well known nAbs (VRC01, 3BNC117, CH31, CH01, PG9, PG16, PGDM1400, 10-1074, PGT128, PGT121, PGT151, VRC34.01, 2G12, 2F5, 4E10, DH511.2.K3_4, 10E8, and the mAb mixture CH01-31).The AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bnAb epitopes. Its overall structure was similar to that of BG505 SOSIP.664, and it resembled one from another elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, AMC009 trimers did not induce autologous neutralizing antibody responses efficiently, while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous tier 2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009, and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the nAb activity from rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers.
Schorcht2020
(neutralization, vaccine-induced immune responses, structure)
-
PG9: HIV-1 and its SIV precursors share a bnAb epitope in Env V2 at the trimer apex. This study tested the immunogenicity of a chimpanzee SIV (SIVcpz) Env trimer. In mice expressing a human V2-apex bnAb heavy-chain precursor, trimer immunization induced V2-directed nAbs. Infection of macaques with chimeric simian-chimpanzee immunodeficiency viruses (SCIVs) elicited high-titer viremia, potent autologous neutralizing antibodies, rapid sequence escape in the canonical V2-apex epitope, and in some cases, low-titer heterologous plasma breadth mapping to the V2-apex. Antibody cloning from 2 macaques (T925 and T927) identified 7 lineages (53 mAbs) with long CDRH3 regions that cross-neutralize some primary HIV-1 strains with low potency. Electron microscopy of members of the two most cross-reactive lineages confirmed V2 targeting with an angle of approach distinct from prototypical V2-apex bNAbs; antibody binding either required or induced an occluded-open trimer. Probing with conformation-sensitive, nonneutralizing antibodies revealed that SCIV-expressed, but not wild-type SIVcpz Envs, as well as a subset of primary HIV-1 Envs, preferentially adopted a more open trimeric state. These results reveal the existence of a cryptic V2 epitope that is exposed in occluded-open SIVcpz and HIV-1 Env trimers and elicits cross-neutralizing responses of limited breadth and potency. This cryptic epitope, which in some Env backgrounds is immunodominant, needs to be considered in immunogen design. As part of the study, binding and neutralization assays used panels of nAbs (PG9, PG16, PGT145, PGDM1400, VRC26.25, CH01, BG1, VRC38.01), non-nAbs (697-D, 1393A, CH58, CAP228-3D, 3074, 447-52D, 17b, A32), and unmutated ancestors (PG9-RUA, PG16-RUA, VRC26-UCA, CH01-RUA).
Bibollet-Ruche2023
(neutralization, vaccine antigen design, vaccine-induced immune responses)
-
PG9: A macaque sequential immunization protocol with increasingly native-like V3-glycan-targeting Env trimers multimerized onto virus-like particles elicited multiple on-target mAbs with heterologous, yet generally weak, neutralization activity and minimal protection in a subsequent intrarectal heterologous challenge with SHIVDH12-V3AD8. The priming immunogen was RC1-4fill (clade A/E, RC1 with 4 additional glycans), a low affinity Env trimer with additional glycans to facilitate V3-glycan targeting and mask BG505 glycan hole, while the boosting immunogens were 11MUTB-4fill (clade A/E), B41-5MUT or B41 wildtype (clade B), AMC011/Du422 (clade B/C), and consensus group M/consensus clade C Env trimers. In a RC1 binding assay, PG9 Fab competed moderately with isolated macaque mAbs (Ab1456 and Ab1461) and itself and modestly with isolated macaque mAb Ab1573.
Escolano2021
(antibody interactions, vaccine antigen design)
-
PG9: HIV-1 bnAbs require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations. Probable mutations occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. The paper introduced the ARMADiLLO program, which estimates how probable a particular mAb mutation is, and thus the key improbable mutations were defined for a panel of 26 bnAbs. The number of improbable mutations ranged from 7 (PGT128) to 23 (VRC01 and 35O22); PG9 had 14 improbable mutations out of 28 total AA mutations, and 0 indels. Single-amino acid reversion mutants were made for key improbable mutations of 3 bnAbs (CH235, VRC01, and BF520.1), and these mutant mAbs were tested for their neutralization ability. The study also noted that bnAbs that had relatively small numbers of improbable single somatic mutations had other unusual characteristics that were due to additional improbable events, such as indels (PGT128) or extraordinary CDR H3 lengths (VRC26.25).
Wiehe2018
(neutralization)
-
PG9: The study assessed the breadths and potencies of 14 bnAbs against 36 viruses reactivated from peripheral blood CD4+ T cells from ARV-treated HIV-infected individuals by using paired neutralization and infected cell binding assays. Infected cell binding correlated with virus neutralization for 10 of 14 antibodies (VRC01, VRC07-523, 3BNC117, N6, PGT121, 10-1074, PGDM1400, PG9, 10E8, and 10E8v4-V5R-100cF). For example, the correlation for 3BNC117 had r=0.82 and P<0.0001. Heterogeneity was observed, however, with a lack of significant correlation for 2G12, CAP256.VRC26.25, 2F5, and 4E10. The study also performed paired infected cell binding and ADCC assays by using two reservoir virus isolates in combination with 9 bNAbs, and the results were consistent with previous studies indicating that infected cell binding is moderately predictive of ADCC activity for bNAbs with matched Fc domains. These data provide guidance on the selection of antibodies for clinical trials.
Ren2018
(effector function, neutralization, binding affinity, HIV reservoir/latency/provirus)
-
PG9: 3 clonally-related autologously-neutralizing mAbs (43A, 43A1, and 43A2), isolated from rabbit 5743 which was co-immunized with BG505- and B41-based SOSIP soluble trimers [Klasse2016, PMID: 27627672], bind to an immunodominant epitope in V1 overlapping the bnAb N332 glycan supersite without interacting with glycans. Of the 43A family members, only 43A, at 2-50 μg/ml concentration, had limited competition with mAb PGT135 with 67-78% residual binding in a BG505 SOSIP.664 binding assay.
Nogal2020
(antibody interactions)
-
PG9: A panel of 33 CRF02_AG pseudoviruses was generated from HIV-1-infected individuals during early stages of infection. Samples represented a 15-year period 1997-2012. These viruses were best neutralized by the CD4bs-directed bnAbs (VRC01, 3BNC117, NIH45-46G54W, and N6) and the MPER-directed bnAb 10E8 in terms of both potency and breadth. There was a higher resistance to bnAbs targeting the V1V2-glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Neutralization by 8ANC195 was also assayed. Combinations of antibodies were predicted by the CombiNaber tool to achieve full coverage across this subtype. There was increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the timespan sampled.
Stefic2019
(neutralization, acute/early infection, subtype comparisons)
-
PG9: The authors review Fc effector functions, which cooperatively with Fab neutralization functions, could be used passively as immunotherapeutic or immunoprophylactic agents of HIV reservoir control or even infection prevention. One effector function, antibody-dependent complement-mediated lysis (ADCML), is seen with IgG1 and IgG3 anti-V1/V2 glycan bnAbs, PG9, PG16, PGT145; but not with 2F5, 4E10, 2G12, VRC01 and 3BNC117 unless they are delivered with anti-regulators of complement activation (RCA) antibodies. Another effector function, antibody-dependent cellular cytotoxicity (ADCC) can slow disease progression by NK-mediated degranulation of infected cells that are coated by bnAbs whose Fc region is recognized by the low affinity NK receptor, FcγRIIIA (or CD16). Strong ADCC was induced by NIH45-46, 3BNC117, 10-1074, PGT121 and 10E8, with intermediate activity for PG16 and VRC01, but no ADCC activation for 12A12, 8ANC195 and 4E10. A final effector function, antibody-dependent phagocytosis (ADP) also eliminates infected cells but through phagocytosis mediated by Fc portions of coating anti-HIV antibodies interacting with other FcγR (or FcαR) on the surface of granulocytes, monocytes or macrophages. This protective mode is less well studied but bnAbs like VRC01 have been engineered to increase phagocytosis by neutrophils. Protein engineering of bispecifics against the surface of infected or reservoir virus cells has potential in the future.
Danesh2020
(antibody interactions, assay or method development, complement, effector function, immunoprophylaxis, neutralization, immunotherapy, early treatment, review, broad neutralizer, HIV reservoir/latency/provirus)
-
PG9: To understand early bnAb responses, 51 HIV-1 clade C infected infants were assayed for neutralization of a 12-virus multi-clade panel. Plasma bnAbs targeting V2-apex on Env were predominant in infant elite and broad neutralizers. In infant elite neutralizers, multi-variant infection was associated with plasma bnAbs targeting diverse autologous viruses. A panel of mAbs (PG9, PG16, PGT145, PGDM1400, VRC26.25, 10-1074, BG18, AIIMS-P01, PGT121, PGT128, PGT135, VRC01, N6, 3BNC117, PGT151, 35O22, 10E8, 4E10, F105, 17b, A32, 48d, b6, 447-52d) was assayed for their ability to neutralize Env clones from infant elite neutralizers; circulating viral variants in infant elite neutralizers were most susceptible to V2-apex bnAbs.
Mishra2020a
(neutralization, polyclonal antibodies)
-
PG9: In vertically-infected infant AIIMS731, a rare HIV-1 mutation in hypervariable loop 2 (L184F) was studied. In patient sequences, this mutation was present in the majority of clones. A panel of 6 V2 bnAbs (PG9, PG16, PGT145, PGDM1400, CAP256.25, and CH01) was assayed for neutralization of 6 patient viral clones. The AIIMS731 viral variants segregated into 4 neutralization-sensitive and 2 resistant clones; sensitive clones carried 184F, while resistant clones carried the rare 184L mutation. A large panel of bnAbs targeting non-V2 epitopes was used to assess the neutralization of the 6 patient viral variants. The bnAb panel consisted of V3/N332 glycan supersite bnAbs (10-1074, BG18, AIIMS-P01, PGT121, PGT128, and PGT135), CD4bs bnAbs (VRC01, VRC03, VRC07-523LS, N6, 3BNC117, and NIH45-46 G54W), a silent face-targeting bnAb (PG05), fusion peptide and gp120-gp41 interface bnAbs (PGT151, 35O22, and N123-VRC34.01), and MPER bnAbs (10E8, 4E10, and 2F5). All of these bnAbs had similar neutralization efficiencies for all 6 clones, suggesting that the L184F mutation was specific for viral escape from neutralization by V2 apex bnAbs. A panel of non-neutralizing mAbs (V3 loop-targeting non-nAbs 447-52D and 19b, and CD4-induced non-nAbs 17b, A32, 48d, and b6), were also assessed; 2 of the variants (the same 2 susceptible to the V2 bnAbs) showed moderate neutralization by 447-52D, 19b, 17b, and 48d. The structure of ligand-free BG505 SOSIP trimer revealed that the side chain of L184 was outward facing and did not make significant intraprotomeric interactions, but upon mutating L184 to F184, a disruption of the accessible surface between the bulky side chain of F184 on one protomer and R165 on the neighboring protomer was seen. Thus, the L184F mutation resulted in increased susceptibility to neutralization by antibodies known to target the relatively more open conformation of Env on tier 1 viruses, suggesting that the rare L184F mutation allowed Env to sample more open states resembling the CD4-bound conformation where the CCR5 binding site is exposed.
Mishra2020
(neutralization, polyclonal antibodies)
-
PG9: This paper isolated and characterized V3-glycan bNAb Ab1485 produced by an elite neutralizing SHIVAD8-EO-infected macaque identified as CE8J. For comparison with Ab1485, the binding of apex mAb PG9 to BG505 was substantially inhibited by itself but not by mAbs 10-1074, 3BNC117, 8ANC195 and VRC34, which all targeted other regions of Env.
Wang2020
(antibody interactions)
-
PG9: A plant-based expression system was used to produce different glycoforms of the bnAbs PG9, PG16, 10–1074, NIH45–46G54W, 10E8, PGT121, PGT128, PGT145, PGT135, and b12. Also produced were mutated forms (N92T) of VRC01 (mVRC01) and NIH45–46G54W (mNIH45–46G54W). The in vivo properties of these mAbs were assessed in macaques to distinguish those most likely to comprise or become a component of an affordable and efficacious immunotherapeutic cocktails. N-glycans within the VL domain impaired the plasma stability of plant-derived bnAbs. While PGT121 and b12 exhibited no immunogenicity in rhesus macaques, VRC01, 10-1074 and NIH45-46G54W elicited high titer anti-idiotypic antibodies. The results indicated that that specific mutations in certain bnAbs caused immunogenicity in macaques. Such immunogenicity in humans would potentially compromise their value for immunotherapy. CHO1-31 was used as a positive control in a neutralization assay.
Rosenberg2015
(anti-idiotype, neutralization, immunotherapy)
-
PG9: HIV-1 env genes were sequenced from 16 mother/infant transmitting pairs. Infant transmitted-founder (T/F) and representative maternal non-transmitted Env variants were identified and used to generate pseudoviruses for paired maternal plasma neutralization analysis. Eighteen out of 21 (85%) infant T/F Env pseudoviruses were neutralization resistant to paired maternal plasma, while all infant T/F viruses were neutralization sensitive to a panel of HIV-1 broadly neutralizing antibodies (2G12, CH01, PG9, PG16, PGT121, PGT126, DH429, b12, VRC01, NIH45-46, CH31, 4E10, 2F5, 10E8, DH512) and variably sensitive to heterologous plasma neutralizing antibodies. Antibody mixture CH01/31 was used as a positive control for neutralization. The infant T/F pseudoviruses were overall more neutralization resistant to paired maternal plasma in comparison to pseudoviruses from maternal non-transmitted variants. These findings suggest that autologous neutralization of circulating viruses by maternal plasma antibodies select for neutralization-resistant viruses that initiate peripartum transmission, raising the speculation that enhancement of this response at the end of pregnancy could reduce infant HIV-1 infection risk.
Kumar2018
(neutralization, acute/early infection, mother-to-infant transmission, transmission pair)
-
PG9: Since cross-reactive antibodies can interfere in immunoassays, HIV-1 mAbs were tested for binding to the SARS-COV-2 spike (S) protein (SARS-COV-2 S cross-reactivity). The following 9 gp120-epitope binding HIV-1 mAbs are cross-reactive with COV-2 S: 2G12, PGT121, PGT126, PGT128, PGT145, PG9, PG16, 10-1074, and 35O22. CD4bs Abs VRC01 and VRC03 are not cross-reactive. Cross-reactivity of the 9 HIV-1 Abs was through glycoepitopes. Glycan-dependent, V3-loop-binding PGT126 and PGT128 as well as 2G12 were the strongest binders of COV-2 S and were found to be immunoreactive but incapable of neutralization or antibody-dependent enhancement (ADE).
Mannar2021
(antibody interactions, effector function, glycosylation, computational prediction, antibody polyreactivity)
-
PG9: Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies was studied by isolation of VRC01-like neutralizers with CD4bs probe; structural definition of gp120 recognition by RSC3-identified antibodies from different donors; functional complementation of heavy and light chains among VRC01-like antibodies; identification of VRC01 antibodies by 454 pyrosequencing; and cross-donor phylogenetic analysis of sequences derived from the same precursor germline gene. b12, among with other RSC3-reactive antibodies, was used for several comparisons and showed dramatic differences in heavy-chain orientation relative to the VRC01. b12 had 48-66% sequence identity of its heavy and light chains to respective chains of VRC-PG04 and VRC-CH31. PG9 and PG16 Abs were compared to for % somatic hyper mutation.
Wu2011
(structure)
-
PG9: Analyses of all PDB HIV1-Env trimer (prefusion, closed) structures fulfilling certain parameters of resolution were performed to classify them on the basis of (a) antibody class which was informed by parental B cells as well as structural recognition, and (b) Env residues defining recognized HIV epitopes. Structural features of the 206 HIV epitope and bNAb paratopes were correlated with functional properties of the breadth and potency of neutralization against a 208-strain panel. Broadly nAbs with >25% breadth of neutralization belonged to 20 classes of antibodies with a large number of protruding loops and high degree of somatic hypermutation (SHM). Analysis of recognized HIV epitopes placed the bNAbs into 6 categories (viz. V1V2, glycan-V3, CD4-binding site, silent face center, fusion peptide and subunit interface). The epitopes contained high numbers of independent sequence segments and glycosylated surface area. PG9-Env formed a distinct group within the V1V2 category, Class PG9, and it has extensive D-gene contribution. Crystal structure data on B-cell culture identified PG9 Fab complexed to V1V2 region of strain ZM109 was found in PDB ID: 3U2S.
Chuang2019
(antibody binding site, antibody interactions, neutralization, binding affinity, antibody sequence, structure, antibody lineage, broad neutralizer)
-
PG9: In an effort to identify new Env immunogens able to elicit bNAbs, this study looked at Envs derived from rare individuals who possess bNAbs and are elite viral suppressors, hypothesizing that in at least some people the antibodies may mediate durable virus control. The Env proteins recovered from these individuals may more closely resemble the Envs that gave rise to bNAbs compared to the highly diverse viruses isolated from normal progressors. This study identified a treatment-naive elite suppressor, EN3 (patient record #4929), whose serum had broad neutralization. The Env sequences of EN3 had much fewer polymorphisms, compared to those of a normal progressor, EN1 (patient record #4928), who also had broad serum neutralization. This result confirmed other reports of slower virus evolution in elite suppressors. EN3 Envelope proteins were unusual in that most possessed two extra cysteines within an elongated V1 region. The impact of the extra cysteines on the binding to bNAbs, virus infectivity, and sensitivity to neutralization suggested that structural motifs in V1 can affect infectivity, and that rare viruses may be prevented from developing escape. As part of this study, the neutralization of pseudotype viruses for EN3 Env clones was assayed for several bNAbs (PG9, PG16, PGT145, PGT121, PGT128, VRC01, 4E10, and 35O22).
Hutchinson2019
(elite controllers and/or long-term non-progressors, neutralization, vaccine antigen design, polyclonal antibodies)
-
PG9: The Chinese HIV Reference Laboratory produced 124 pseudoviruses from patients with subtype B, BC, and CRF01 infections. These viruses were assigned to tiers based on their neutralization by a panel of patient sera. Their neutralization sensitivities were also measured against a panel of well-characterized mAbs (2F5, b12, 2G12, 4E10, 10E8, VRC01, VRC-CH31, CH01, PG9, PG16, PGT121, PGT126).
Nie2020
(assay or method development, neutralization)
-
PG9: Extensive structural and biochemical analyses demonstrated that PGT145 achieves recognition and neutralization by targeting quaternary structure of the cationic trimer apex with long and unusually stabilized anionic β-hairpin HCDR3 loops. Compared to PGT145, PG9 showed increased breadth, neutralization potency, and maximum percentage neutralization (MPN) in the presence of complex/hybrid glycans. In BG505.Env.C2 alanine-scanning neutralization assays, PG9 had similar results as CH01, consistent with both CH01 and PG9 being representatives of hammerhead-class, and very dissimilar results to PGT145-like antibodies.
Lee2017
(antibody binding site, neutralization)
-
PG9: Three vaccine regimens administered in guinea pigs over 200 weeks were compared for ability to elicit NAb polyclonal sera. While tier 1 NAb responses did increase with vaccination, tier 2 NAb heterologous responses did not. The 3 regimens were C97 (monovalent, Clade C gp140), 4C (tetravalent, 4 Clade C mosaic gp140s), ABCM (tetravalent, Clades A, B, C and mosaic gp140s). Polyclonal sera generated from the 4C and ABCM regimens, compared to the C97 regimen, were able to more successfully outcompete PG9 binding to gp140 antigens.
Bricault2018
(antibody generation, vaccine-induced immune responses, polyclonal antibodies)
-
PG9: Novel Env pseudoviruses were derived from 22 patients in China infected with subtype CRF01_AE viruses. Neutralization IC50 was determined for 11 bNAbs: VRC01, NIH45-46G54W, 3BNC117, PG9, PG16, 2G12, PGT121, 10-1074, 2F5, 4E10, and 10E8. The CRF01_AE pseudoviruses exhibited different susceptibility to these bNAbs. Overall, 4E10, 10E8, and 3BNC117 neutralized all 22 env-pseudotyped viruses, followed by NIH45-46G54W and VRC01, which neutralized more than 90% of the viruses. 2F5, PG9, and PG16 showed only moderate breadth, while the other three bNAbs neutralized none of these pseudoviruses. Specifically, 10E8, NIH45-46G54Wand 3BNC117 showed the highest efficiency, combining neutralization potency and breadth. Mutations at position 160, 169, 171 were associated with resistance to PG9 and PG16, while loss of a potential glycan at position 332 conferred insensitivity to V3-glycan-targeting bNAbs. These results may help in choosing bNAbs that can be used preferentially for prophylactic or therapeutic approaches in China.
Wang2018a
(assay or method development, neutralization, subtype comparisons)
-
PG9: Two conserved tyrosine (Y) residues within the V2 loop of gp120, Y173 and Y177, were mutated individually or in combination, to either phenylalanine (F) or alanine (A) in several strains of diverse subtypes. In general, these mutations increased neutralization sensitivity, with a greater impact of Y177 over Y173 single mutations, of double over single mutations, and of A over F substitutions. The Y173A Y177A double mutation in HIV-1 BaL increased sensitivity to most of the weakly neutralizing MAbs tested (2158, 447-D, 268-D, B4e8, D19, 17b, 48d, 412d) and even rendered the virus sensitive to non-neutralizing antibodies against the CD4 binding site (F105, 654-30D, and b13). In the case of V2 mAb 697-30D, residue Y173 is part of its epitope, and thus abrogates its binding and has no effect on neutralization; the Y177A mutant alone did increase neutralization sensitivity to this mAb. When the double mutant was tested against bnAbs, there was a large decrease in neutralization sensitivity compared to WT for many bnAbs that target V1, V2, or V3 (PG9, PG16, VRC26.08, VRC38, PGT121, PGT122, PGT123, PGT126, PGT128, PGT130, PGT135, VRC24, CH103). The double mutation had lesser or no effect on neutralization by one V3 bnAb (2G12) and by most bnAbs targeting the CD4 binding site (VRC01, VRC07, VRC03, VRC-PG04, VRC-CH31, 12A12, 3BNC117, N6), the gp120-gp41 interface (35O22, PGT151), or the MPER (2F5, 4E10, 10E8).
Guzzo2018
(antibody binding site, neutralization)
-
PG9: To reduce local V2 flexibility and improve the binding of V2-dependent bNAbs and germline precursor bNAbs, the authors designed BG505 SOSIP.664 trimer variants whose V1 and V2 domains were stabilized by introducing disulfide bonds either within the V2 loop or between the V1 and V2 loops. The resulting SOSIP trimer variants — E153C/K178C, E153C/K178C/G152E and I184C/E190C — have improved reactivity with V2 bNAbs and their inferred germline precursors and are more sensitive to neutralization by V2 bNAbs. PGT121, PG9, PG16, and CH01 bound better to the E153C/R178C/G152E mutant than to SOSIP.664. The I184C/E190C mutant bound all the V2 bNAbs (PG9, PG16, PGT145, VRC26.09, and CH01) better than SOSIP.664. I184C/E190C was more sensitive to neutralization by V2 bNAbs compared with BG505 (by 5-fold for PG9, 3-fold for PG16, 6-fold for CH01, and 3-fold for PGDM1400).
deTaeye2019
(neutralization, vaccine antigen design, binding affinity)
-
PG9: The authors used genome-editing techniques (CRISPR-Cas9) to modify HIV specific B cell receptors. In particular, they replaced the heavy chain variable region in B cell lines with that from the HIV broadly neutralizing antibody PG9. The chimeric PG9 antibodies they created could neutralize one or more of the PG9-sensitive viruses, and most neutralized multiple viruses from different clades in a global panel, although none of the chimeric antibodies were as broadly neutralizing as the original PG9 HC/LC pair.
Voss2019
(neutralization, antibody sequence, broad neutralizer, chimeric antibody)
-
PG9: This study looks at the role of somatic mutations within antibody variable and framework regions (FWR) in bNAbs and how these mutations alter thermostability and neutralization as the Ab lineage reaches maturation. The emergence and selection of different mutations in the complementarity-determining and framework regions are necessary to maintain a balance between antibody function and stability. The study shows that all major classes of bNAbs (DH270, CH103, CH235, PG9 etc.) have lower thermostability than their corresponding inferred UCA antibodies. Fab interdomain flexibility mutations are selected early in Ab development.
Henderson2019
(neutralization, antibody lineage, broad neutralizer)
-
PG9: Two HIV-1-infected individuals, VC10014 and VC20013, were monitored from early infection until well after they had developed broadly neutralizing activity. The bNAb activity developed about 1 year after infection and mapped to a single epitope in both subjects. Isolates from each subject, taken at five different time points, were tested against monoclonal bNAbs: VRC01, B12, 2G12, PG9, PG16, 4E10, and 2F5. In subject VC10014, the bNAb activity developed around 1 year postinfection and targeted an epitope that overlaps the CD4-BS and is similar to (but distinct from) bNAb HJ16. In the case of VC20013, the bNAb activity targeted a novel epitope in the MPER that is critically dependent on residue 677 (mutation K677N).
Sather2014
(neutralization, broad neutralizer)
-
PG9: This study demonstrated that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens eliciting Ab responses with greater neutralization breadth. Data from four large virus panels were used to comprehensively map viral signatures associated with bNAb sensitivity, hypervariable region characteristics, and clade effects. The bNAb signatures defined for the V2 epitope region were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine which resulted in increased breadth of nAb responses compared with Env 459C alone. PG9 was used as V2 Ab and Clade B was resistant to PG9. Based on structural contacts for PG9, phylogenetically corrected signatures and statistical support for other V2 Abs contacts were analyzed.
Bricault2019
(antibody binding site, neutralization, vaccine antigen design, computational prediction, subtype comparisons, broad neutralizer)
-
PG9: The influence of a V2 State 2/3-stabilizing Env mutation, L193A, on ADCC responses mediated by sera from HIV-1-infected individuals was evaluated. Conformations spontaneously sampled by the Env trimer at the surface of infected cells had a significant impact on ADCC. State 1-preferring ligand PG9 recognized L193A variants of CH58 and CH77 IMCs with less efficiently compared to the WT.
Prevost2018
(effector function)
-
PG9: A simple method to quantify and compare serum neutralization probabilities in described. The method uses logistic regression to model the probability that a serum neutralizes a virus with an ID50 titer above a cutoff. The neutralization potency (NP) identifies where the probabilities of neutralizing and not neutralizing a virus are equal and is not absolute as it depends on the ID50 cutoff. It provides a continuous measure for sera, which builds upon established tier categories now used to rate virus sensitivity. These potency comparisons are similar to comparing geometric mean neutralization titers, but instead are represented in tier-like terms. Increasing the number of bNAbs increases NP and slope, where the higher the slope, the sharper the boundary (lower scatter) between viruses neutralized and not neutralized. PG9 was used in analysis of monoclonal bNAb combinations.
Hraber2018
(assay or method development, neutralization)
-
PG9: This review summarizes current advances in antibody lineage-based design and epitope-based vaccine design. Antibody lineage-based design is described for VRC01, PGT121 and PG9 antibody classes, and epitope-based vaccine design is described for the CD4-binding site, as well as fusion peptide and glycan-V3 cites of vulnerability.
Kwong2018
(antibody binding site, vaccine antigen design, vaccine-induced immune responses, review, antibody lineage, broad neutralizer, junction or fusion peptide)
-
PG9: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. PG9, a prototype super-Ab, was isolated from direct functional screening of B cell clones from an HIV elite neutralizer and was an order of magnitude more potent than first-generation bNAbs. Recently recombinant native-like HIV Env trimers have enabled the identification of exceptionally potent ‘PG9-class’ bNAbs e.g., PG16, PGT141-144, CH01-04, PGDM1400–1412 and CAP256-VRC26.01-12. Antigenic region V2 apex (Table:1)
Walker2018
(antibody binding site, review, broad neutralizer)
-
PG9: The authors selected an optimal panel of diverse HIV-1 envelope glycoproteins to represent the antigenic diversity of HIV globally in order to be used as antigen candidates. The selection was based on genetic and geographic diversity, and experimentally and computationally evaluated humoral responses. The eligibility of the envelopes as vaccine candidates was evaluated against a panel of antibodies for breadth, affinity, binding and durability of vaccine-elicited responses. The antigen panel was capable of detecting the spectrum of V2-specific antibodies that target epitopes from the V2 strand C (V2p), the integrin binding motif in V2 (V2i), and the quaternary epitope at the apex of the trimer (V2q).
Yates2018
(vaccine antigen design, vaccine-induced immune responses, binding affinity)
-
PG9: The effects of 16 glycoengineering (GE) methods on the sensitivities of 293T cell-produced pseudoviruses (PVs) to a large panel of bNAbs were investigated. Some bNAbs were dramatically impacted. PG9 and were up to 30-fold more potent against PVs produced with co-transfected α-2,6 sialyltransferase. PGT151 and PGT121 were more potent against PVs with terminal SA removed. 35O22 and CH01 were more potent against PV produced in GNT1-cells. The effects of GE on bNAbs VRC38.01, VRC13 and PGT145 were inconsistent between Env strains, suggesting context-specific glycan clashes. Overexpressing β-galactosyltransferase during PV production 'thinned' glycan coverage, by replacing complex glycans with hybrid glycans. This impacted PV sensitivity to some bNAbs. Maximum percent neutralization by excess bnAb was also improved by GE. Remarkably, some otherwise resistant PVs were rendered sensitive by GE. Germline-reverted versions of some bnAbs usually differed from their mature counterparts, showing glycan indifference or avoidance, suggesting that glycan binding is not germline-encoded but rather, it is gained during affinity maturation. Overall, these GE tools provided new ways to improve bnAb-trimer recognition that may be useful for informing the design of vaccine immunogens to try to elicit similar bnAbs.
Crooks2018
(vaccine antigen design, antibody lineage)
-
PG9: A panel of bnAbs were studied to assess ongoing adaptation of the HIV-1 species to the humoral immunity of the human population. Resistance to neutralization is increasing over time, but concerns only the external glycoprotein gp120, not the MPER, suggesting a high selective pressure on gp120. Almost all the identified major neutralization epitopes of gp120 are affected by this antigenic drift, suggesting that gp120 as a whole has progressively evolved in less than 3 decades.
Bouvin-Pley2014
(neutralization)
-
PG9: A rare glycan hole at the V2 apex is enriched in HIV isolates neutralized by inferred precursors of prototype V2-apex bNAbs. To investigate whether this feature could focus neutralizing responses onto the apex bnAb region, rabbits were immunized with soluble trimers adapted from these Envs. Potent autologous tier 2 neutralizing responses targeting basic residues in strand C of the V2 region, which forms the core epitope for V2-apex bnAbs, were observed. Neutralizing monoclonal antibodies (mAbs) derived from these animals display features promising for subsequent broadening of the response. Four human anti-V2 bnAbs (PG9, CH01, PGT145, and CAP256.09) were used as a basis of comparison.
Voss2017
(vaccine antigen design)
-
PG9: This study describes the generation of CHO cell lines stably expressing the following vaccine Env Ags: CRF01_AE A244 Env gp120 protein (A244.AE) and 6240 Env gp120 protein (6240.B). The antigenic profiles of the molecules were assessed with a panel of well-characterized mAbs recognizing critical epitopes and glycosylation analysis confirming previously identified sites and revealing unknown sites at non-consensus motifs. A244.AE gp120 showed low level of binding to PG9 in ELISA EC50 and Surface Plasmon Resonance (SPR) assays. 6240.B gp120 exhibited binding to PG9.
Wen2018
(glycosylation, vaccine antigen design)
-
PG9: The prophylactic and therapeutic potential of an engineered single gene–encoded tandem bispecific immunoadhesin (IA) molecule BiIA-SG was studied. Before engineering BiIAs, codon-optimized scFvs of bNAbs PG9, PG16, PGT128, VRC01, and Hu5A8 were synthesized. The VL/VH domain of each scFv was engineered as a corresponding IA by fusion with human IgG1-Fc to generate IA-PG9, IA-PG16, IA-PGT128, IA-VRC01, and IA-Hu5A8. While all IAs exhibited specific anti–HIV-1 activity, only IA-PGT128 displayed similar potency and the same sigmoidal slope of 100% neutralization as previously described for the native PGT128, and IA-PGT128 in combination with IA-Hu5A8 exhibited the best synergistic effect based on computational synergy volumes. IA-PGT128 and IA-Hu5A8 were therefore used for BiIA construction.
Wu2018
-
PG9: Assays of poly- and autoreactivity demonstrated that broadly neutralizing NAbs are significantly more poly- and autoreactive than non-neutralizing NAbs. PG9 is polyreactive, but not autoreactive.
Liu2015a
(autoantibody or autoimmunity, antibody polyreactivity)
-
PG9: Panels of C clade pseudoviruses were computationally downselected from the panel of 200 C clade viruses defined by Rademeyer et al. 2016. A 12-virus panel was defined for the purpose of screening sera from vaccinees. Panels of 50 and 100 viruses were defined as smaller sets for use in testing magnitude and breadth against C clade. Published neutralization data for 16 mAbs was taken from CATNAP for the computational selections: 10-1074, 10-1074V, PGT121, PGT128, VRC26.25, VRC26.08, PGDM1400, PG9, PGT145, VRC07-523, 10E8, VRC13, 3BNC117, VRC07, VRC01, 4E10.
Hraber2017
(assay or method development, neutralization)
-
PG9: A panel of 14 pseudoviruses of subtype CRF01_AE was developed to assess the neutralization of several neutralizing antibodies (b12, PG9, PG16, 4E10, 10E8, 2F5, PGT121, PGT126, 2G12). Neutralization was assessed in both TZM-bl and A3R5 cell-based assays. Most viruses were more susceptible to mAb-neutralization in A3R5 than in the TZM-bl cell-based assay. The increased neutralization sensitivity observed in the A3R5 assay was not linked to the year of virus transmission or to the stages of infection, but chronic viruses from the years 1990-92 were more sensitive to neutralization than the more current viruses, in both assays.
Chenine2018
(assay or method development, neutralization, subtype comparisons)
-
PG9: The immunologic effects of mutations in the Env cytoplasmic tail (CT) that included increased surface expression were explored using a vaccinia prime/protein boost protocol in mice. After vaccinia primes, CT- modified Envs induced up to 7-fold higher gp120-specific IgG, and after gp120 protein boosts, they elicited up to 16-fold greater Tier-1 HIV-1 neutralizing antibody titers.
Hogan2018
(vaccine antigen design)
-
PG9: Env trimers were engineered with selective deglycosylation around the CD4 binding site to see if they could be useful vaccine antigens. The neutralization of glycan-deleted trimers was tested for a set of bnAbs (PG9, PGT122, PGT135, b12, CH103, HJ16, VRC01, VRC13, PGT151, 8ANC195, 35O22), and the antigens elicited potent neutralization based on the CD4 supersite. A crystal structure was made of one of these Env trimers bound to Fabs 35O22 and 3H+109L. Guinea pigs vaccinated with these antigens achieved neutralization of deglycosylated Envs. Glycan-deleted Env trimers may be useful as priming antigens to increase the frequency of CD4 site-directed antibodies.
Zhou2017
(glycosylation, neutralization, vaccine antigen design, vaccine-induced immune responses)
-
PG9: Env from of a highly neutralization-resistant isolate, CH120.6, was shown to be very stable and conformationally-homogeneous. Its gp140 trimer retains many antigenic properties of the intact Env, while its monomeric gp120 exposes more epitopes. Thus trimer organization and stability are important determinants for occluding epitopes and conferring resistance to antibodies. Among a panel of 21 mAbs, CH120.6 was resistant to neutralization by all non-neutralizing and strain-specific mAbs, regardless of the location of their epitopes. It was weakly neutralized by several broadly-neutralizing mAbs (VRC01, NIH45-46, 12A12, PG9, PG16, PGT128, 4E10, and 10E8), and well neutralized by only 2 (PGT145 and 10-1074).
Cai2017
(neutralization)
-
PG9: A panel of mAbs (2G12, VRC01, HJ16, 2F5, 4E10, 35O22, PG9, PGT121, PGT126, 10-1074) was tested to compare their efficacy in cell-free versus cell-cell transmission. Almost all bNAbs (with the exception of anti-CD4 mAb Leu3a) blocked cell-free infection with greater potency than cell-cell infection, and showed greater potency in neutralization of cell-free viruses. The lower effectiveness on neutralization was particularly pronounced for transmitted/founder viruses, and less pronounced for chronic and lab-adapted viruses. The study highlights that the ability of an antibody to inhibit cell-cell transmission may be an important consideration in the development of Abs for prophylaxis.
Li2017
(immunoprophylaxis, neutralization)
-
PG9: The next generation of a computational neutralization fingerprinting (NFP) being used as a way to predict polyclonal Ab responses to HIV infection is presented. A new panel of 20 pseudoviruses, termed f61, was developed to aid in the assessment of experimental neutralization. This panel was used to assess 22 well-characterized bNAbs and mixtures thereof (HJ16, VRC01, 8ANC195, IGg1b12, PGT121, PGT128, PGT135, PG9, PGT151, 35O22, 10E8, 2F5, 4E10, VRC27, VRC-CH31, VRC-PG20, PG04, VRC23, 12A12, 3BNC117, PGT145, CH01). The new algorithms accurately predicted VRC01-like and PG9-like antibody specificities.
Doria-Rose2017
(neutralization, computational prediction)
-
PG9: This review focuses on the potential role of HIV-1-specific NAbs in preventing HIV-1 infection. Several NAbs have provided protection from infection in SHIV challenge studies in primates: b12, VRC01, VRC07-523LS, 3BNC117, PG9, PGT121, PGT126, 10-1074, 2G12, 4E10, 2F5, 10E8.
Pegu2017
(immunoprophylaxis, review)
-
PG9: The ability of neutralizing and nonneutralizing mAbs to block infection in models of mucosal transmission was tested. Neutralization potency did not fully predict activity in mucosal tissue. CD4bs-specific bNAbs, in particular VRC01, blocked HIV-1 infection across all cellular and tissue models. MPER (2F5) and outer domain glycan (2G12) bNAbs were also efficient in preventing infection of mucosal tissues, while bNAbs targeting V1-V2 glycans (PG9 and PG16) were more variable. Non-nAbs alone and in combinations, were poorly protective against mucosal infection. The protection provided by specific bNAbs demonstrates their potential over that of nonneutralizing antibodies for preventing mucosal entry. PG9 and PG16 were selected to represent mAbs of the V1-V2 glycan class.
Cheeseman2017
(genital and mucosal immunity, immunoprophylaxis)
-
PG9: To understand HIV neutralization mediated by the MPER, antibodies and viruses were studied from CAP206, a patient known to produce MPER-targeted neutralizing mAbs. 41 human mAbs were isolated from CAP206 at various timepoints after infection, and 4 macaque mAbs were isolated from animals immunized with CAP206 Env proteins. Two rare, naturally-occuring single-residue changes in Env were identified in transmitted/founder viruses (W680G in CAP206 T/F and Y681D in CH505 T/F) that made the viruses less resistant to neutralization. The results point to the role of the MPER in mediating the closed trimer state, and hence the neutralization resistance of HIV. CH58 was one of several mAbs tested for neutralization of transmitted founder viruses isolated from clade C infected individuals CAP206 and CH505, compared to T/F viruses containing MPER mutations that confer enhanced neutralization sensitivity.
Bradley2016a
(neutralization)
-
PG9: This study performed cyclical permutation of the V1 loop of JRFL in order to develop better gp120 trimers to elicit neutralizing antibodies. Some mutated trimers showed improved binding to several mAbs, including VRC01, VRC03, VRC-PG04, PGT128, PGT145, PGDM1400, b6, and F105. Guinea pigs immunized with prospective trimers showed improved neutralization of a panel of HIV-1 pseudoviruses. Binding of PG9 to JRFL was abolished by mutations N156K or N160K.
Kesavardhana2017
(vaccine antigen design, vaccine-induced immune responses)
-
PG9: This study investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit NAbs. Rabbits were immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). N197 glycan- and residue 230- removal conferred sensitivity to Trimer VLP sera and DNA trimer sera respectively, showing for the first time that strain-specific holes in the "glycan fence" can allow the development of tier 2 NAbs to native spikes. All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. A bioinformatics analysis suggested shared features of one of the trimer VLP sera and monoclonal antibody PG9, consistent with its trimer-dependency. PG9 was 1 of 2 reference PG9-like bNAbs - PG9 and PGT145.
Crooks2015
(glycosylation, neutralization)
-
PG9: Env residue N197 on the BG505-SOSIP trimer was mutated to test the effect of its glycosylation on the binding kinetics of CD4BS and other mAbs. Removal of the glycan had little effect on the overall structure of the molecule. Its removal resulted in increased binding of CD4 and CD4BS antibodies (VRC01, VRC03, V3-3074), but little effect on bNAbs targeting other epitopes (PG9, PG16, PGT145, 17b, A32, 2G12, PGT121, PGT126). Two CD4BS-binding antibodies tested (b12, F105) had insufficient breadth to bind the BG505-SOSIP trimer. Removal of the N197 glycan may allow for the development of better SOSIP immunogens, particularly to elicit CD4BS-specific Abs.
Liang2016
(glycosylation, vaccine antigen design)
-
PG9: Binding of PG9 to properly folded and glycosylated fragments of Env V1/V2 (scaffolds) is described. Scaffolds from 3 different clades of HIV-1 bound to PG9 with high affinity. Mutations I169K, E172V, T161M, N156I, S164G, D167G (includng those outside of the antibody contact region) improved binding.
Morales2016
(antibody binding site, vaccine antigen design)
-
PG9: Chimeric antigen receptors (CAR), i.e., fusion proteins made from single-chain antibodies, may be a useful approach to immunotherapy. A set of mAbs were chosen based on their binding to a variety of sites on Env and availability of antibody sequences. The chimeric receptors were created by fusing the antibody's heavy chain, light chain, and two signaling domains into a single molecule. All 7 antibodies used to make the chimeric receptors (10E8, 3BNC117, PGT126, VRC01, X5, PGT128, PG9) showed specific killing of HIV-1 infected cells and suppression of viral replication against a panel of HIV-1 strains.
Ali2016
(immunotherapy, chimeric antibody)
-
PG9: This review classified and mapped the binding regions of 32 bNAbs isolated 2010-2016.
Wu2016
(review)
-
PG9: This study produced Env SOSIP trimers for clades A (strain BG505), B (strain JR-FL), and G (strain X1193). Based on simulations, the MAb-trimer structures of all MAbs tested needed to accommodate at least one glycan, including both antibodies known to require specific glycans (PG9, PGT121, PGT135, 8ANC195, 35O22) and those that bind the CD4-binding site (b12, CH103, HJ16, VRC01, VRC13). A subset of monoclonal antibodies bound to glycan arrays assayed on glass slides (VRC26.09, PGT121, 2G12, PGT128, VRC13, PGT151, 35O22), while most of the antibodies did not have affinity for oligosaccharide in the context of a glycan array (PG9, PGT145, PGDM1400, PGT135, b12, CH103, HJ16, VRC16, VRC01, VRC-PG04, VRC-CH31, VRC-PG20, 3BNC60, 12A12, VRC18b, VRC23, VRC27, 1B2530, 8ANC131, 8ANC134, 8ANC195).
Stewart-Jones2016
(antibody binding site, glycosylation, structure)
-
PG9: This study assessed the ADCC activity of antibodies of varied binding types, including CD4bs (b6, b12, VRC01, PGV04, 3BNC117), V2 (PG9, PG16), V3 (PGT126, PGT121, 10-1074), oligomannose (2G12), MPER (2F5, 4E10, 10E8), CD4i (17b, X5), C1/C5 (A32, C11), cluster I (240D, F240), and cluster II (98-6, 126-7). ADCC activity was correlated with binding to Env on the surfaces of virus-infected cells. ADCC was correlated with neutralization, but not always for lab-adapted viruses such as HIV-1 NLA-3.
vonBredow2016
(effector function)
-
PG9: This review summarizes representative anti-HIV MAbs of the first generation (2G12, b12, 2F5, 4E10) and second generation (PG9, PG16, PGT145, VRC26.09, PGDM1400, PGT121, PGT124, PGT128, PGT135, 10-1074, VRC01, 3BNC117, CH103, PGT151, 35O22, 8ANC195, 10E8). Structures, epitopes, VDJ usage, CDR usage, and degree of somatic hypermutation are compared among these antibodies. The use of SOSIP trimers as immunogens to elicit B-cell responses is discussed.
Burton2016
(review, structure)
-
PG9: HIV-1 bNAb eptiope networks were predicted using 4 algorithms informed by neutralization assays using 282 Env from multiclade viruses. Patch clusters of possible Ab epitope regions were tested for significant sensitivity by site-directed mutagenesis. Epitope (Ab binding site) networks of critical Env residues for 21 bNAb (b12, PG9, PG16, PGT121, PGT122, PGT123, PGT125, PGT126, PGT127, PGT128, PGT130, PGT131, PGT135, PGT136, PGT137, PGT141, PGT142, PGT143, PGT144, PGT145 and PGV04) were delineated and found to be located mostly in variable loops of gp120, particularly in V1/V2.
Evans2014
(antibody binding site, computational prediction)
-
PG9: Two stable homogenous gp140 Env trimer spikes, Clade A 92UG037.8 Env and Clade C C97ZA012 Env, were identified. 293T cells stably transfected with either presented fully functional surface timers, 50% of which were uncleaved. A panel of neutralizing and non-neutralizing Abs were tested for binding to the trimers. V1/V2 glycan bNAb PG9 bound cell surface tightly whether the trimer contained its C-terminal or not, and was competed out by sCD4. It was able to neutralize the 92UG037.8 HIV-1 isolate.
Chen2015
(neutralization, binding affinity)
-
PG9: Factors that independently affect bNAb induction and evolution were identified as viral load, length of untreated infection, and viral diversity. Black subjects induced bNAbs more than white subjects, but this did not correlate with type of Ab response. Fingerprint analyses of induced bNAbs showed strong subtype dependency, with subtype B inducing significantly higher levels of CD4bs Abs and non-subtype B inducing V2-glycan specific Abs. Of the 239 bNAb antibody inducers found from 4,484 HIV-1 infected subjects,the top 105 inducers' neutralization fingerprint and epitope specificity was determined by comparison to the following antibodies - PG9, PG16, PGDM1400, PGT145 (V2 glycan); PGT121, PGT128, PGT130 (V3 glycan); VRC01, PGV04 (CD4bs) and PGT151 (interface) and 2F5, 4E10, 10E8 (MPER).
Rusert2016
(neutralization, subtype comparisons, broad neutralizer)
-
PG9: PGT145 was used to positively isolate a subtype B Env trimer immunogen, B41 SOSIP.664-D7324, that exists in two conformations, closed and partially open. bNAbs tested against the trimer were able to neutralize the B41 pseudovirus with a wide range of potencies. All tested non-NAbs did not neutralize B41 (IC50 >50µg/ml). V1/V2 glycan bNAb, PG9, neutralized B41 psuedovirus and bound B41 trimer well.
Pugach2015
-
PG9: The first generation of HIV trimer soluble immunogens, BG505 SOSIP.664 were tested in a mouse model for generation of nAb to neutralization-resistant circulating HIV strains. No such NAbs were induced, as mouse Abs targeted the bottom of soluble Env trimers, suggesting that the glycan shield of Env trimers is impenetrable to murine B cell receptors and that epitopes at the trimer base should be obscured in immunogen design in order to avoid non-nAb responses. Association and dissociation of known anti-trimer bNAbs (VRC01, PGT121, PGT128, PGT151, PGT135, PG9, 35O22, 3BC315 and PGT145) were found to be far greater than murine generated non-NAbs.
Hu2015
-
PG9: A comprehensive antigenic map of the cleaved trimer BG505 SOSIP.664 was made by bNAb cross-competition. Epitope clusters at the CD4bs, quaternary V1/V2 glycan, N332-oligomannose patch and new gp120-gp41 interface and their interactions were delineated. Epitope overlap, proximal steric inhibition, allosteric inhibition or reorientation of glycans were seen in Ab cross-competition. Thus bNAb binding to trimers can affect surfaces beyond their epitopes. PG9, PG16 and PG145, all V1/V2 glycan trimer apex bNAbs, were strongly, reciprocally competitive with one another. V3 glycan bNAbs PGT121, PGT122, PGT123 inhibited binding of PG9 strongly, but in a non-reciprocal manner.
Derking2015
(antibody interactions, neutralization, binding affinity, structure)
-
PG9: Two clade C recombinant Env glycoprotein trimers, DU422 and ZM197M, with native-like structural and antigenic properties involving epitopes against all known classes of bNAbs, were produced and characterized. These Clade C trimers (10-15% of which are in a partially open form) were more like B41 Clade B trimers which have 50-75% trimers in the partially open configuration than like B505 Clade B trimers, almost 100% in the closed, prefusion state. The Clade C trimers are weakly reactive with the V1/V2 glycan bNAb, PG9, and while neutralization of the DU422 pseudotyped virus is robust, that of the ZM197M pseudovirus is moderate.
Julien2015
(assay or method development, structure)
-
PG9: HIV-1 escape from the N332-glycan dependent bNAb, PGT135, developed in an elite controller but without change to the PGT135-binding Env epitope itself. Instead an insertion increasing V1 length by up to 21 residues concomitant with an additional 1-3 glycans and 2-4 cysteines shields the epitope from PGT135. The majority of viruses tested developed a 14-fold resistance to PGT135 from month 7 to 11. In comparison, no significant difference in HIV-1 against bNAb PG9 was seen.
vandenKerkhof2016
(elite controllers and/or long-term non-progressors, neutralization, escape)
-
PG9: A new trimeric immunogen, BG505 SOSIP.664 gp140, was developed that bound and activated most known neutralizing antibodies but generally did not bind antibodies lacking neuralizing activity. This highly stable immunogen mimics the Env spike of subtype A transmitted/founder (T/F) HIV-1 strain, BG505. Anti-V1/V2 glycan bNAb PG9, neutralized BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, and was shown to recognize and bind the immunogen too.
Sanders2013
(assay or method development, neutralization, binding affinity)
-
PG9: This review discusses an array of methods to engineer more effective bNAbs for immunotherapy. Antibody PG9 was mentioned as an example of engineering through rational mutations; PG9-N100(F)Y stabilizes the CDR-H3 in the active conformation, thus improving neutralization.
Hua2016
(immunotherapy, review)
-
PG9: Site-specific analysis of N-glycosylation sites of a soluble recombinant trimerBG505 SOSIP.664 is presented. Neutralization profiles for V1V2 Ab, PG9, to multiple epitopes were determined. Removing the N156 or N160 glycans from either of the BG505 test viruses reduced the neutralization activities of PG9.
Behrens2016
(antibody binding site, glycosylation)
-
PG9: A mathematical model was developed to predict the Ab concentration at which antibody escape variants outcompete their ancestors, and this concentration was termed the mutant selection window (MSW). The MSW was determined experimentally for 12 pairings of diverse HIV strains against 7 bnAbs (b12, 2G12, PG9, PG16, PGT121, PGT128, 2F5). The neutralization of of PG9 was assayed against 5 resistant and 5 sensitive strains.
Magnus2016
(neutralization, escape)
-
PG9: A panel of Env-specific mAbs was isolated from 6 HIV1-infected lactating women. Antibodies in colostrum may help prevent mucosal infection of the infant, so this study aimed to define milk IgGs for future vaccination strategies to reduce HIV transmission during lactation. Despite the high rate of VH1-69 usage among colostrum Env specific B cells, it did not correlate with distinct gp120 epitope specificity or function. PG9 was compared to the newly-derived mAbs; it had no cross-reactivity with gut bacteria, and tested negative in two tests of autoreactivity.
Jeffries2016
(antibody polyreactivity)
-
PG9: The study detailed binding kinetics of the interaction between BG505 SOSIP.664 trimer or its variants (gp120 monomer; first study of disulfide-stabilized variant gp120-gp41ECTO protomer) and several mAbs, both neutralizing (VRC01, PGV04, PG9, PG16, PGT121, PGT122, PGT123, PGT145, PGT151, 2G12) and non-neutralizing (b6, b12, 14e, 19b, F240). V1V2 quarternary-dependent epitope-binding bNAb, PG9, bound trimer best, but less well to protomer and BG505 gp120's monomer.
Yasmeen2014
(antibody binding site, assay or method development)
-
PG9: Neutralization breadth in 157 antiretroviral-naive individuals infected for less than 1 year post-infection was studied and compared to a cohort of 170 untreated chronic patients. A range of neutralizing activities was observed with a panel of six recombinant viruses from five different subtypes. Some sera were broadly reactive, predominantly targeting envelope epitopes within the V2 glycan-dependent region. The Env neutralization breadth was positively associated with time post infection. PG9 has been used as a control in detection of glycan-dependent HIV-1 neutralizing sera.
Sanchez-Merino2016
(neutralization, acute/early infection)
-
PG9: A new, current, mostly tier2 panel of 200 C-clade Env-psuedotyped viruses from early (< 100d) infection in southern Africa was used to assess antibody responses to natural infection and to vaccines. Viruses were assayed with bNAbs targeting the V2 glycan (PG9, VRC26.25), the MPER site (4E10), the CD4 binding site (VRC01), and the V3/C3 glycan site (PGT128). For 4E10 (and all other Abs besides PGT128) there was no significant difference in neutralization between pre-seroconversion and post-seroconversion viruses. Viruses collected pre-seroconversion were more resistant to neutralization by serum than those post-seroconversion. As the epidemic matured over 13 years, viruses also became more resistant to mAbs tested.
Rademeyer2016
(assay or method development, neutralization)
-
PG9: The sequential development of three distinct bnAb responses within a single host, CAP257, over 4.5 years of infection has been described. It showed how escape from the first wave of Abs targeting V2 exposed a second site that was the stimulus for a new wave of glycan dependent bnAbs against the CD4 binding site. These data highlighted how Ab evolution in response to viral escape mutations served to broaden the host immune response to two epitopes. A third wave of neutralization targeting an undefined epitope that did not appear to overlap with the four known sites of vulnerability on the HIV-1 envelope has been reported. These data supported the design of templates for sequential immunization strategies.
Wibmer2013
(escape)
-
PG9: This study examined the neutralization of group N, O, and P primary isolates of HIV-1 by diverse antibodies. Cross-group neutralization was observed only with the bNAbs targeting the N160 glycan-V1/V2 site. Four group O isolates, 1 group N isolate, and the group P isolates were neutralized by PG9 and/or PG16 or PGT145 at low concentrations. None of the non-M primary isolates were neutralized by bNAbs targeting other regions, except 10E8, which weakly neutralized 2 group N isolates, and 35O22 which neutralized 1 group O isolate. Bispecific bNAbs (PG9-iMab and PG16-iMab) very efficiently neutralized all non-M isolates with IC50 below 1 ug/mL, except for 2 group O strains. Anti V1/V2 bNAb PG9 was able to neutralize 5/16 tested non-M primary isolates at an IC50< 10µg/ml, 2 of them highly with a value under 1 µg/ml and 3 moderately.
Morgand2015
(neutralization, subtype comparisons)
-
PG9: The neutralization of 14 bnAbs was assayed against a global panel of 12 or 17 Env pseudoviruses. From IC50, IC80, IC90, and IC99 values, the slope of the dose-response curve was calculated. Each class of Ab had a fairly consistent slope. Neutralization breadth was strongly correlated with slope. An IIP (Instantaneous Inhibitory Potential) value was calculated, based on both the slope and IC50, and this value may be predictive of clinical efficacy. PG9, a V2-glycan bnAb belonged to a group with slopes <1.
Webb2015
(neutralization)
-
PG9: This study evaluated the binding of 15 inferred germline (gl) precursors of bNAbs that are directed to different epitope clusters, to 3 soluble native-like SOSIP.664 Env trimers - BG505, B41 and ZM197M. The trimers bound to some gl precursors, particularly those of V1V2-targeted Abs. These trimers may be useful for designing immunogens able to target gl precursors. V1/V2 apex-binding gl-PG9 precursor bound to 2/3 trimers, BG505 and ZM197M.
Sliepen2015
(binding affinity, antibody lineage)
-
PG9: Computational modeling was used to examine antibody recognition of glycans, using a V1V2 bNAb (PG9) and a V3 bnAb (PGT128). Both PG9 and PGT128 have a long CDR H3 loop that can penetrate the glycan shield and form interactions with gp120. The modeling results showed that the tip of the CDR H3 loop is flexible in the free antibodies and is able to move within the bound conformation, which likely increases the penetrability of the glycan shield.
Qi2016
(glycosylation)
-
PG9: To test whether NAbs can inhibit viral transmission through mucosal tissue, 4 bNAbs (PG9, PG16, VRC01, 4E10) were tested in tissue culture models of human colonic and ectocervical tissues. All 4 nAbs reduced HIV transmission, with a relative efficacy of PG16 > PG9 > VRC01 >> 4E10. The nAbs had a good safety profile and were not affected by the presence of semen.
Scott2015
(immunotherapy)
-
PG9: The study's goal was to produce modified SOSIP trimers that would reduce the exposure - and, by inference, the immunogenicity - of non-NAb epitopes such as V3. The binding of several modified SOSIP trimers was compared among 12 neutralizing (PG9, PG16, PGT145, PGT121, PGT126, 2G12, PGT135, VRC01, CH103, CD4, IgG2, PGT151, 35O22) and 3 non-neutralizing antibodies (14e, 19b, b6). The V3 non-NAbs 447-52D, 39F, 14e, and 19b bound less well to all A316W variant trimers compared to wild-type trimers. Mice and rabbits immunized with modified, stabilized SOSIP trimers developed fewer V3 Ab responses than those immunized with native trimers.
deTaeye2015
(antibody binding site)
-
PG9: Deep-sequencing and computational methods were used to identify HCDR3 sequences in HIV-naïve donors that mediated binding and neutralization of HIV by mimicking the bnAb PG9 long HCDR3 region when expressed in the context of the rest of the PG9 antibody sequence. 2 naturally occurring HCDR3 sequences from 2 different donors of 70 studied were predicted to adopt a PG9-like hammerhead conformation and were able to bind and neutralize PG9-susceptible viruses. In addition, computational design was used to mimic the process of maturation by somatic mutation of HCDR3 sequences from the HIV-1–naïve repertoire that were predicted to adopt a PG9-like hammerhead conformation. Two to seven mutations in eight different HCDR3 sequences facilitated neutralization of HIV when grafted on a PG9 Ab background.
Willis2016
(antibody lineage)
-
PG9: HIV-1 strains were isolated from 60 patients infected with CRFs 01_AE, 07_BC, and 08_BC. Eight CRF01 strains that produced high-titer Env pseudoviruses were studied further. All were sensitive to neutralization by VRC01, PG9, PG16, and NIH45-46, but insensitive to 2G12. The PG9 have affinity for epitopes located in the conserved regions of the V2-V3 loop. Binding of PG9 and PG16 with the virus was largely dependent on the same residues, although PG16 was more sensitive to V3 loop substitutions than PG9. Sequence analysis of PG9- and PG16-resistant viruses revealed complex mutation patterns associated with residues that are critical for PG9/PG16 binding. CNAE14 was shown to be resistant to both PG9 and PG16. It is likely that substitutions S158T, S162T, K305T, and I307T jointly contribute to this resistance phenotype.
Chen2016
(neutralization, subtype comparisons)
-
PG9: A large cross-sectional study of sera from 205 ART-naive patients infected with different HIV clades was tested against a panel of 219 cross-clade Env-pseudotyped viruses. Their neutralization was compared to the neutralization of 10 human bNAbs (10E8, 4E10, VRC01, PG9, PGT145, PGT128, 2F5, CH01, b12, 2G12) tested with a panel of 119 Env-pseudotyped viruses. Results from b12 and 2G12 suggested that these bnAbs may not be as broadly neutralizing as previously thought. PG9 neutralized 86% of the 199 viruses tested.
Hraber2014
(neutralization)
-
PG9: The study compared binding and neutralization of 4 V2 apex bnAbs (PG9, CH01, PGT145, and CAP256.VRC26.09). All recognized a core epitope on V1/V2 (the N-linked glycan at N160 and cysteine-linked lysine rich, HXB2:126-196), which includes residue N160 as well as N173. The lysine rich region on strand C of HIV-1 V2 that is key for binding to the nAb contains the sequence (168)KKQK(171). Inferred germline versions of three of the prototype bnAbs were able to neutralize specific Env isolates. Soluble Env derived from one of these isolates was shown to form a well-ordered Env trimer that could serve as an immunogen to initiate a V2-apex bnAb response. Escape from bnAb PG9 was seen in patient Donor_64 by mutations K169T and K171E. 99% amino acid sequence identity exists between PG9 and CAP256.09 in VH-germline gene.
Andrabi2015
(antibody binding site, neutralization, vaccine antigen design, escape, antibody lineage)
-
PG9: Double, triple or quadruple combinations of fifteen bNAbs that target 4 distinct epitope regions: the CD4 binding site (3BNC117, VRC01, VRC07, VRC07-523, VRC13), the V3-glycan supersite (10–1074, 10-1074V, PGT121, PGT128), the V1/V2-glycan site (PG9, PGT145, PGDM1400, CAP256-VRC26.08, CAP256-VRC26.25), and the gp41 MPER epitope (10E8) were studied. Their neutralization potency and breadth were assayed against a panel of 200 acute/early subtype C strains, and compared to a novel, highly accurate predictive mathematical model (no-overlap Bliss Hill model, CombiNaber tool, LANL HIV Immunology database). These data were used to predict the best combinations of bNAbs for immunotherapy.
Wagh2016
(neutralization, immunotherapy)
-
PG9: An atomic-level understanding of V1V2-directed bNAb recognition in a donor was used in the design of V1V2 scaffolds capable of interacting with quaternary-specific V1V2-directed bNAbs. The cocrystal structure of V1V2 with antibody CH03 from a second donor is reported and Env interactions of antibody CAP256-VRC26 from a third donor are modeled. V1V2-directed bNAbs used strand-strand interactions between a protruding Ab loop and a V1V2 strand but differed in their N-glycan recognition. Ontogeny analysis indicated that protruding loops develop early, and glycan interactions mature over time. Combination of the atomic-level information and negative-stain EM of PG9 in complex with a soluble trimeric Env mimic, BG505 SOSIP.664, suggest that the quaternary dependency of PG9 arises from its recognition of glycan N160 from a neighboring protomer24.
Gorman2016
(glycosylation, structure, antibody lineage)
-
PG9: The human Ab gene repertoires of uninfected and HIV-1-infected individuals were studied at genomic DNA (gDNA) and cDNA levels to determine the frequencies of putative germline Ab genes of known HIV-1 bnAbs. All libraries were deep sequenced and analysed using IMGT/HighV-QUEST software (http://imgt.org/HighV-QUEST/index. The human gDNA Ab libraries were more diverse in heavy and light chain V-gene lineage usage than the cDNA libraries. This implied that the human gDNA Ab gene repertoires may have more potential than the cDNA repertoires to develop HIV-1 bnmAbs. Relatively high frequencies of the VH and VKs and VLs that used the same V-genes and had the same CDR3 lengths as known HIV-1 bnmAbs regardless of (D)J-gene usage. Frequencies of the VLs with the identical VJ recombinations to PG9 were relatively high. The putative germline genes were determined for a set of mAbs (b12, VRC01, VRC03, NIH45-46, 3BNC60, PG9, PGT127, and X5).
Zhang2013
(antibody lineage, germline)
-
PG9: Galactosyl ceramide (Galcer), a glycosphingolipid, is a receptor for the HIV-1 Env glycoprotein. This study has mimicked this interaction by using an artificial membrane containing synthetic Galcer and recombinant HIV-1 Env proteins to identify antibodies that would block the HIV-1 Env-Galcer interaction. HIV-1 ALVAC/AIDSVAX vaccinee-derived MAbs specific for the gp120 C1 region blocked Galcer binding of a transmitted/founder HIV-1 Env gp140. The antibody-dependent cellular cytotoxicity-mediating CH38 IgG and its natural IgA isotype were the most potent blocking antibodies. PG9 exhibited moderate Env-Galcer blocking.
Dennison2014
(antibody binding site, antibody interactions, effector function, glycosylation)
-
PG9: A unified convergent strategy for the rapid production of bi-, tri-, and tetra-antennary complex type N-glycans with and without terminal N-acetylneuraminic acid residues connected via the α-2,6 or α-2,3 linkages is reported which may facilitate the design of carbohydrate-based immunogens. A glycan microarray-based profiling of PG9 was used to understand the binding specificity. No detectable binding for PG9, probably due to (1) very weak binding affinity toward protein/peptide free glycans, (2) the requirement of closely spaced Man5GlcNAc2 (N160) and complex type glycan (N156/163) as PG9 epitopes, and (3) the heterogeneous distribution of NHS groups on glass slides resulting in uneven and low-density glycan arrays.
Shivatare2013
(glycosylation, structure)
-
PG9: The effect of PNGS on viral infectivity and antibody neutralization (2F5, 4E10, b12, VRC01, VRC03, PG9, PG16, 3869) was evaluated through systemic mutations of each PNGS on CRF07_BC strain. Mutations at N197 (C2), N301 (V3), N442 (C4), and N625 (gp41) rendered the virus more susceptible to neutralization by MAbs that recognize the CD4 binding site or gp41. Generally, mutations on V4/V5 loops, C2/C3/C4 regions, and gp41 reduced the neutralization sensitivity to PG16. However, mutation of N289 (C2) made the virus more sensitive to both PG9 and PG16. Mutations at N142 (V1), N355 (C3) and N463 (V5) conferred resistance to neutralization by anti-gp41 MAbs. Available structural information of HIV Env and homology modeling was used to provide a structural basis for the observed biological effects of these mutations.
Wang2013
(neutralization, structure)
-
PG9: Incomplete neutralization may decrease the ability of bnAbs to protect against HIV exposure. In order to determine the extent of non-sigmoidal slopes that plateau at <100% neutralization, a panel of 24 bnMAbs targeting different regions on Env was tested in a quantitative pseudovirus neutralization assay on a panel of 278 viral clones. All bNAbs had some viruses that they neutralized with a plateau <100%, but those targeting the V2 apex and MPER did so more often. All bnMAbs assayed had some viruses for which they had incomplete neutralization and non-sigmoidal neutralization curves. bNAbs were grouped into 3 groups based on their neutralization curves: group 1 antibodies neutralized more than 90% of susceptible viruses to >95% (PGT121-123, PGT125-128, PGT136, PGV04); group 2 was less effective, resulting in neutralization of 60-84% of susceptible viruses to >95% (b12, PGT130-131, PGT135, PGT137, PGT141-143, PGT145, 2G12, PG9); group 3 neutralized only 36-60% of susceptible viruses to >95% (PG16, PGT144, 2F5, 4E10).
McCoy2015
(neutralization)
-
PG9: The neutralization abilities of Abs were enhanced by bioconjugation with aplaviroc, a small-molecule inhibitor of virus entry into host cells. Diazonium hexafluorophosphate was used. The conjugated Abs blocked HIV-1 entry through two mechanisms: by binding to the virus itself and by blocking the CCR5 receptor on host cells. Chemical modification did not significantly alter the potency and the pharmacokinetics. The PG9-aplaviroc conjugate was tested against a panel of 117 HIV-1 strains and was found to neutralize 100% of the viruses. PG9-aplaviroc conjugate IC50s were lower than those of PG9 in neutralization studies of 36 of the 117 HIV-1 strains.
Gavrilyuk2013
(neutralization)
-
PG9: This study investigated the immunogenicity of three ΔV1V2 deleted variants of the HIV-1 Env protein. The mutant ΔV1V2.9.VK induced a prominent response directed to epitopes effectively bound and neutralized the ΔV1V2 Env virus. This Env variant efficiently neutralized tier 1 virus SF162.This did not result in broad neutralization of neutralization-resistant virus isolates. BG505 SOSIP.664 trimers bind very efficiently to quaternary structure dependent, broadly neutralizing PG9 against the V1V2 domain.
Bontjer2013
(vaccine antigen design, structure)
-
PG9: This review surveyed the Vectored Immuno Prophylaxis (VIP) strategy, which involves passive immunization by viral vector-mediated delivery of genes encoding bnAbs for in vivo expression. Recently published studies in humanized mice and macaques were discussed as well as the pros and cons of VIP towards clinical applications to control HIV endemics.
Yang2014
(immunoprophylaxis, review, antibody gene transfer)
-
PG9: The ability of bNAbs to inhibit the HIV cell entry was tested for b12, VRC01,VRC03, PG9, PG16, PGT121, 2F5, 10E8, 2G12. Among them, PGT121, VRC01, and VRC03 potently inhibited HIV entry into CD4+ T cells of infected individuals whose viremia was suppressed by ART.
Chun2014
(immunotherapy)
-
PG9: Pairwise combinations of 6 NAbs (4E10, 2F5, 2G12, b12, PG9, PG16) were tested for neutralization of pseudoviruses and transmitted/founder viruses. Each of the NAbs tested targets a different region of gp120 or gp41. Some pairwise combinations enhanced neutralization synergistically, suggesting that combinations of NAbs may enhance clinical effectiveness.
Miglietta2014
(neutralization)
-
PG9: The infectious virion (iVirions) capture index (IVCI) of different Abs have been determined. bnAbs captured higher proportions of iVirions compared to total virus particles (rVirions) indicating the capacity, breadth and selectively of bnAbs to capture iVirions. IVCI was additive with a mixture of Abs, providing proof of concept for vaccine-induced effect of improved capacity. bnAb PG9 showed significantly high IVCI and captured 100% of CRF01_A/E infectious virions AE.92TH023 and AE.CM244, as well as subtype B MN virus.
Liu2014
(binding affinity)
-
PG9: Study evaluated 4 gp140 Env protein vaccine immunogens derived from an elite neutralizer donor VC10042, an HIV+ African American male from Vanderbilt cohort. Env immunogens, VC10042.05, VC10042.05RM, VC10042.08 and VC10042.ela, elicited high titers of cross-reactive Abs recognizing V1/V2 regions. PG9 exhibited very weak binding with trimeric VC10042.ela and moderate binding with monomeric form of all 4 immunogens.
Carbonetti2014
(elite controllers and/or long-term non-progressors, vaccine-induced immune responses)
-
PG9: The study compared various factors affecting the accessibility of epitopes for antibodies targeting the V2 integrin (V2i) region, versus the V3 region. CD4 treament of BaL and JRFL pseudoviruses increased their neutralization sensitivity to V3 MAbs, but not to V2i MAbs. Viruses grown in a glycosidase inhibitor were more sensitive to neutralization by V3, but not V2i, MAbs. Increasing the time of virus-MAb interaction increased virus neutralization by some V2i MAbs and all V3 MAbs. The structural dynamics of V2i and V3 epitopes has important effects in neutralization. Some experiments also included V2p antibodies CH58, CH59, and PG9 for comparison.
Upadhyay2014
(glycosylation, neutralization)
-
PG9: A gp140 trimer mosaic construct (MosM) was produced based on M group sequences. MosM bound to CD4 as well as multiple bNAbs, including VRC01, 3BNC117, PGT121, PGT126, PGT145, PG9 and PG16. The immunogenicity of this construct, both alone and mixed together with a clade C Env protein vaccine, suggest a promising approach for improving NAb responses.
Nkolola2014
(vaccine antigen design)
-
PG9: Cross-group neutralization of HIV-1 isolates from groups M, N, O, and P was tested with diverse patient sera and bNAbs PG9, PG16, 4E10, b12, 2F5, 2G12, VRC01, VRC03, and HJ16. The primary isolates displayed a wide spectrum of sensitivity to neutralization by the human sera, with some cross-group neutralization clearly observed. Among the bNAbs, only PG9 and PG16 showed any cross-group neutralization. The group N prototype strain YBF30 was highly sensitive to neutralization by PG9, and the interaction between their key residues was confirmed by molecular modeling. The conservation of the PG9/PG16 epitope within groups M and N suggests its relevance as a vaccine immunogen.
Braibant2013
(neutralization, variant cross-reactivity)
-
PG9: The V2 region where PG9, an anti-V1V2 bNAb binds exists as a beta-strand.
Haynes2013
(review)
-
PG9: PG9 was one of 10 MAbs used to study chronic vs. consensus vs. transmitted/founder (T/F) gp41 Envs for immunogenicity. Consensus Envs were the most potent eliciters of response but could only neutralize tier 1 and some tier 2 viruses. T/F Envs elicited the greatest breadth of NAb response; and chronic Envs elicited the lowest level and narrowest response. This V1V2 conformational loop binding Nab bound well at <10 nM to 3/5 chronic Envs, 2/6 Consensus Envs and 2/7 T/F Envs.
Liao2013c
(antibody interactions, binding affinity)
-
PG9: Design, synthesis and antigenic evaluation of novel cyclic V1V2 glycopeptides carrying defined N-linked glycans, N160 and N156/N173 has been reported in terms of PG9 and PG16 binding and neutralization. A Man5GlcNAc2 glycan at N160 and a sialyted N-glycan are crtical for antigen binding.
Amin2013
(glycosylation)
-
PG9: Binding properties of a synthesized V1V2 glycopeptide immunogen that selectively targets bnAbs' naive B cells is reported. The unmutated common ancestor (UCA) of PG9 showed nanomolar affinity to V1V2 bearing Man5GlcNAc2 glycan units. Binding of PG9 was undetectable however in the absence of the V2 backbone peptide suggesting a very weak binding affinity to oligomannose glycan alone. Disulfide-linked dimer formation was also required for PG9 binding to V1V2.
Alam2013
-
PG9: PG9 in combination with NAbs NH45-46m2 and NIH46-42m7 was able to control viremia as well as to reduce routes to escape of YU-2 HIV-1.
Diskin2013
-
PG9: This study showed that the inability of Env to elicit the production of broadly neutralizing Abs is due to the inability of diverse Env to engage the germ line B cell receptor forms of known bNAbs. PG9 showed binding to 61% of the recombinant Envs tested including 7 out of 17 clade B Envs, 11 of 16 clade C Envs, 6 of 7 clade A Envs and the gp120 form of A/E A244 Env. The predicted germ line version of PG9 did not exhibit any detectable binding against these Envs. Ca2+ influx through the PG9 BCR was also tested as a function of binding affinity.
McGuire2014
(antibody interactions, antibody lineage)
-
PG9: The neutralization profile of 1F7, a human CD4bs mAb, is reported and compared to other bnNAbs. 1F7 exhibited extreme potency against primary HIV-1, but limited breadth across clades. PG9 neutralized 83% of a cross-clade panel of 157 HIV-1 isolates (Fig. S1) while 1F7 neutralized only 20% of the isolates.
Gach2013
(neutralization)
-
PG9: This study reports the development of a new cell-line (A3R5)-based highly sensitive Ab detection assay. This T-lymphoblastoid cell-line stably expreses CCR5 and recognizes CCR5-tropic circulating strains of HIV-1. A3R5 cells showed greater neutralization potency compared to the current cell-line of choice TZM-bl. PG9 was used as a reference Ab in neutralization assay comparing A3R5 and TZM-bl.
McLinden2013
(assay or method development)
-
PG9: A highly conserved mechanism of exposure of ADCC epitopes on Env is reported, showing that binding of Env and CD4 within the same HIV-1 infected cell effectively exposes these epitopes. The mechanism might explain the evolutionary advantage of downregulation of cell surface CD4v by the Vpu and Nef proteins. PG9 was used in CD4 coexpression and competitive binding assay.
Veillette2014
(effector function)
-
PG9: Clade A Env sequence, BG505, was identified to bind to bNAbs representative of most of the known NAb classes. This sequence is the best natural sequence match (73%) to the MRCA sequence from 19 Env sequences derived from PG9 and PG16 MAbs' donor. A point mutation at position L111A of BG505 enabled more efficient production of a stable gp120 monomer, preserving the major neutralization epitopes. The antisera produced by this adjuvanted formulation of gp120 competed with bnAbs from 3 classes of non-overlapping epitopes. PG9 showed very high neutralization titer against BG505 pseudovirus in a competitive binding assay as shown in Table 1. Env sequence from PG9 donor showed potential N glycosylation (PNG) sites at position 160 and 156, suggesting that a substitution at one of these sites is not the primary cause of neutralization resistance to PG9 (Table 4). This emphasizes that the BG505 L111Agp120 immunogen can elicit a robust Ab response to PG9.
Hoffenberg2013
(antibody interactions, glycosylation, neutralization)
-
PG9: High affinity binding of PG9 with a soluble SOSIP.664 gp140 trimer constructed from the Clade A BG505 sequence was demonstrated. This enabled structural and biophysical characterization of the PG9:Env trimer complex. Electron microscopy (EM) and other assays indicate that only a single PG9-Fab binds to the Env trimer. EM reconstruction also demonstrated that PG9 recognized the trimer asymmetrically at its apex via contact with 2 of the 3 gp120 protomers. In addition to N156 and N160 glycan interactions with a scaffolded V1/V2 domain, PG9 also makes secondary interactions with an N160 glycan from an adjacent gp120 protomer in the Ab-trimer complex. A glycan mutation to PG9 caused a >10fold reduction of Fab affinity for the BG505 SOSIP.664 gp 140 trimer reflecting adverse effects on trimer binding and virus neutralization. PG9 recognized glycosylated Env proteins with much higher affinity compared to non-glycosylated ones.
Julien2013
(antibody interactions, glycosylation, structure)
-
PG9: To focus immune responses to sites of NAb vulnerability while avoiding immune-evasion by the rest of Env, MPER, V1/V2, and V3 glycan sites were transplanted onto algorithm-identified acceptor scaffolds (proteins with a backbone geometry that recapitulates the antigenicity of the transplanted site). The V1/V2-transplant was not successful in eliciting a robust PG9 response.
Zhou2014
(vaccine antigen design)
-
PG9: This is a review of identified bNAbs, including the ontogeny of B cells that give rise to these antibodies. Breadth and magnitude of neutralization, unique features and similar bNAbs are listed. PG9 is a V1/V2-directed Ab, with breadth 70%, IC50 0.31 μg per ml, and its unique feature is its extended CDR H3, which is often tyrosine-sulfated. Similar MAbs include PG16 and CH01-04.
Kwong2013
(review)
-
PG9: 8 bNAbs (PGT151 family) were isolated from an elite neutralizer. The new bNAbs bind a previously unknown glycan-dependent epitope on the prefusion conformation of gp41. These MAbs are specific for the cleaved Env trimer and do not recognize uncleaved Env trimer. PGT151 family Abs showed 1 log higher neutralization potency than PG9.
Falkowska2014
-
PG9: A statistical model selection method was used to identify a global panel of 12 reference Env clones among 219 Env-pseudotyped viruses that represent the spectrum of neutralizing activity seen with sera from 205 chronically HIV-1-infected individuals. This small final panel was also highly sensitive for detection of many of the known bNAbs, including this one. The small panel of 12 Env clones should facilitate assessments of vacine-elicited NAbs.
Decamp2014
(assay or method development)
-
PG9: The conserved central region of gp120 V2 contains sulfated tyrosines (Tys173 and Tys177) that in the CD4-unbound prefusion state mediate intramolecular interaction between V2 and the conserved base of the third variable loop (V3), functionally mimicking sulfated tyrosines in CCR5 and anti-coreceptor-binding-site antibodies such as 412d. Enhancement of tyrosine sulfation decreased binding and neutralization of HIV-1 BaL by monomeric sCD4, 412d, and anti-V3 antibodies and increased recognition by the trimer-preferring antibodies PG9, PG16, CH01, and PGT145. Conversely, inhibition of tyrosine sulfation increased sensitivity to soluble CD4, 412d, and anti-V3 antibodies and diminished recognition by trimer-preferring antibodies. These results identify the sulfotyrosine-mediated V2-V3 interaction as a critical constraint that stabilizes the native HIV-1 envelope trimer and modulates its sensitivity to neutralization.
Cimbro2014
-
PG9:X-ray crystallography, surface plasmon resonance and pseudovirus neutralization were used to characterize a heavy chain only llama antibody, named JM4. The full-length IgG2b version of JM4 neutralizes over 95% of circulating HIV-1 isolates. JM4 targets a hybrid epitope on gp120 that combines elements from both the CD4 binding region and the coreceptor binding surface. JM4 IgG2b was able to potently neutralize the HIV-1 isolates that were resistant to PG9.
Acharya2013
(neutralization)
-
PG9: 12 somatically related nAbs were isolated from donor CAP256. All nAbs of CAP256-VRC26 lineage had long CDRH3 regions necessary to penetrate the glycan shield and engage the V1V2 epitope. Both CAP256-VRC26 Abs and PG9 class nAbs showed similarity in recognizing the trimeric V1V2 cap. Unlike PG9, the CAP256-VRC26 Abs were only partially and variably sensitive to loss of glycans at N160 and N156.
Doria-Rose2014
(glycosylation)
-
PG9: This is a review of a satellite symposium at the AIDS Vaccine 2012 conference, focusing on antibody gene transfer. Phil Johnson presented results comparing an immunoadhesin form of the antibody PG9 with the native IgG architecture in which he found that the native IgG architecture had a neutralization potency tenfold greater than that of the immunoadhesin, suggesting that natural antibody architectures are more preferable for further clinical development.
Balazs2013
(immunoprophylaxis)
-
PG9: A computational method to predict Ab epitopes at the residue level, based on structure and neutralization panels of diverse viral strains has been described. This method was evaluated using 19 Env-Abs, including PG9, against 181 diverse HIV-1 strains with available Ab-Ag complex structures.
Chuang2013
(computational prediction)
-
PG9: This study reports the glycan binding specificities and atomic level details of PG16 epitope and somatic mechanisms of clonal antibody diversification. Three PG16 specific residues Arg94LC, Ser95LC and His95LC (RSH) are found to be critical for sialic acid binding on complex glycan. RSH residues were introduced into PG9 to produce a chimeric antibody with enhanced neutralization. The co-crystal structure of PG9 bound to V1-V2 is discussed and compared to PG16 and PG9-PG16-RSH chimeric Ab based on its ability to recognize a combination of N-linked glycans and envelope polypeptide. PG9, PG16, and PG9-PG16-RSH were negative in assays of autoreactivity.
Pancera2013
(antibody binding site, autoantibody or autoimmunity, glycosylation, structure, chimeric antibody)
-
PG9: Four V2 MAbs CH58, CH59, HG107 and HG120 were isolated from RV144 Thai HIV-1 vaccinees. These MAbs recognized residue 169, neutralized laboratory HIV-1 (tier 1 strains) and mediated ADCC. PG9 was used in the study as a V1-V2 bnAb control to study the binding of the new mAb isolates. While PG9, PG16 and CH01 binding was abrogated by N160K and N156Q mutations and also by native glycosylation, the binding of CH58 and CH59 was not affected. Crystal structures revealed that CH58, CH59, and PG9 recognize overlapping V2 epitopes in dramatically different conformations, ranging from helical to beta strands.
Liao2013b
(effector function, structure)
-
PG9: The complexity of the epitopes recognized by ADCC responses in HIV-1 infected individuals and candidate vaccine recipients is discussed in this review. PG9 is discussed as the V2 region-targeting, anti-gp120 BNAb exhibiting ADCC activity and having a discontinuous epitope. RV144 vaccine induced mAbs CH58 and CH59 also bind to the same region of PG9, but do not display preferential binding to gp120 and don't bind to glycans in position 156 and 160.
Pollara2013
(effector function, review)
-
PG9: "Neutralization fingerprints" for 30 neutralizing antibodies were determined using a panel of 34 diverse HIV-1 strains. 10 antibody clusters were defined: VRC01-like, PG9-like, PGT128-like, 2F5-like, 10E8-like and separate clusters for b12, CD4, 2G12, HJ16, 8ANC195.
Georgiev2013
(neutralization)
-
PG9: ADCC mediated by CD4i mAbs (or anti-CD4i-epitope mAbs) was studied using a panel of 41 novel mAbs. Three epitope clusters were classified, depending on cross-blocking in ELISA by different mAbs: Cluster A - in the gp120 face, cross-blocking by mAbs A32 and/or C11; Cluster B - in the region proximal to CoRBS (co-receptor binding site) involving V1V2 domain, cross-blocking by E51-M9; Cluster C - CoRBS, cross-blocking by 17b and/or 19e. The ADCC half-maximal effective concentrations of the Cluster A and B mAbs were generally 0.5-1 log lower than those of the Cluster C mAbs, and none of the Cluster A or B mAbs could neutralize HIV-1. Cluster A's A32- and C11-blockable mAbs were suggested to recognize conformational epitopes within the inner domain of gp120 that involve the C1 region. Neutralization potency and breadth were also assessed for these mAbs. No correlation was found between ADCC and neutralization Abs' action or functional responses.
Guan2013
(antibody interactions, effector function)
-
PG9: This study describes an ˜11 Angstrom cryo-EM structure of the trimeric HIV-1 Env precursor in its unliganded state. The three gp120 and gp41 subunits form a cage like structure with an interior void surrounding the trimer axis which restricts Ab access. crystal structure of PG9 was referred in the context of gp120 V1/V2 binding domains.
Mao2012
(structure)
-
PG9: Emergence and evolution of the earliest cross-reactive neutralizing antibody responses were studied in B clade-infected individual, Two distinct epitopes on Env were targeted. First specificity appeared at 3 years post infection and targeted the CD4-binding site. Second specificity appeared a year later. It was due to PG9-like antibodies, which were able to neutralize those viruses not susceptible to the anti-CD4-BS antibodies in AC053.
Mikell2012
(neutralization, rate of progression, polyclonal antibodies)
-
PG9: Neutralization profiles of 7 bnAbs were analyzed against 45 Envs (A, C, D clades), obtained soon after infection (median 59 days). The transmitted variants have distinct characteristics compared to variants from chronic patients, such as shorter variable loops and fewer potential N-linked glycosylation sites (PNGS). PG9 neutralized 49% of these viruses.
Goo2012
(neutralization, rate of progression)
-
PG9: A computational tool (Antibody Database) identifying Env residues affecting antibody activity was developed. As input, the tool incorporates antibody neutralization data from large published pseudovirus panels, corresponding viral sequence data and available structural information. The model consists of a set of rules that provide an estimated IC50 based on Env sequence data, and important residues are found by minimizing the difference between logarithms of actual and estimated IC50. The program was validated by analysis of MAb 8ANC195, which had unknown specificity. Predicted critical N-glycosylation for 8ANC195 were confirmed in vitro and in humanized mice. The key associated residues for each MAb are summarized in the Table 1 of the paper and also in the Neutralizing Antibody Contexts & Features tool at Los Alamos Immunology Database.
West2013
(glycosylation, computational prediction)
-
PG9: Identification of broadly neutralizing antibodies, their epitopes on the HIV-1 spike, the molecular basis for their remarkable breadth, and the B cell ontogenies of their generation and maturation are reviewed. Ontogeny and structure-based classification is presented, based on MAb binding site, type (structural mode of recognition), class (related ontogenies in separate donors) and family (clonal lineage). This MAb's classification: gp120 V1V2 site, penetrating CDR H3 binds two glycans and strand, PG9 class, PG9 family.
Kwong2012
(review, structure, broad neutralizer)
-
PG9: This review discusses the new research developments in bnAbs for HIV-1, Influenza, HCV. Models of the HIV-1 Env spike and of Influenza visrus spike with select bnAbs bound are shown.
Burton2012
(review)
-
PG9: This review discusses how analysis of infection and vaccine candidate-induced antibodies and their genes may guide vaccine design. This MAb is listed as V1/V2 conformational epitope bnAb, isolated after 2009 by neutralization screening of cultured, unselected IgG+ memory B cells.
Bonsignori2012b
(vaccine antigen design, vaccine-induced immune responses, review)
-
PG9: Antigenic properties of 2 biochemically stable and homogeneous gp140 trimers (A clade 92UG037 and C clade CZA97012) were compared with the corresponding gp120 monomers derived from the same percursor sequences. The trimers had nearly all the antigenic properties expected for native viral spikes and were markedly different from monomeric gp120. Both trimers, but not monomers, bound to PG9 and PG16.
Kovacs2012
(antibody binding site, neutralization, binding affinity)
-
PG9: Glycan shield of HIV Env protein helps to escape the Ab recognition. Several of the PGT BnAbs interact directly with the HIV glycan coat. Crystal structures of Fabs PGT127 and PGT128 showed that the high neutralizing potency was mediated by cross-linking Env trimers on the viral surface. PGT128 was compared and referred as an order of magnitude more potent than PG9.
Pejchal2011
(glycosylation, structure, broad neutralizer)
-
PG9: PG9 and PG9-like V1V2-directed MAbs, that require an N-linked glycan at Env 160, were analyzed for gain-of-function mutations. 21 PG9-resistant HIV-1 isolates were analyzed by mutagenesis and neutralization assays. E to K mutations at positions 168, 169, 171 led to the most dramatic improvements on sensitivity to these MAbs (PG9, PG16, CH01, CH04, PGT141, PGT145).
Doria-RoseNA2012
(escape)
-
PG9: The study used the swarm of quasispecies representing Env protein variants to identify mutants conferring sensitivity and resistance to BnAbs. Libraries of Env proteins were cloned and in vitro mutagenesis was used to identify the specific AA responsible for altered neutralization/resistance, which appeared to be associated with conformational changes and exposed epitopes in different regions of gp160. The result showed that sequences in gp41, the CD4bs, and V2 domain act as global regulator of neutralization sensitivity. PG9 was used as BnAb to screen Env clones. wtR clone was weakly sensitive to PG9.
ORourke2012
(neutralization)
-
PG9: Glycan Asn332-targeting broadly cross-neutralizing (BCN) antibodies were studied in 2 C-clade infected women. The ASn332 glycan was absent on infecting virus, but the BCN epitope with Asn332 evolved within 6 months though immune escape from earlier antibodies. Plasma from the subject CAP177 neutralized 88% of a large multi-subtype panel of 225 heterologous viruses, whereas CAP 314 neutralized 46% of 41 heterologous viruses but failed to neutralize viruses that lack glycan at 332. PG9 was referred to have second BCN Ab epitopes at AA 156 and 160 in addition to 332.
Moore2012
(neutralization, escape)
-
PG9: Crystal structures of unliganded core gp120 from HIV-1 clade B, C, and E were determined to understand the mechanism of CD4 binding capacity of unliganded HIV-1. The results suggest that the CD4 bound conformation represents "a ground state" for the gp120 core with variable loop. PG9 was used as a control to prove whether the purified and crystallized gp120 is in the CD4 bound conformational state or not.
Kwon2012
(structure)
-
PG9: Vaccination efficacy of RV144 is described. The authors proposed that RV144 induced antibodies against Env V1/V2. The relationship between vaccine status and V1/V2 sequence have been characterized. The estimated cumulative HIV-1 incidence curve in the vaccine and placebo groups showed immunogenicity for K169 and 1181X genotypes and no immunogenicity for the opposite residues. PG9 was discussed as the quaternary-structure-preferring (QSP) antibody and mutations at positions 169 and 181 were associated with significant alteration in neutralization.
Rolland2012
(vaccine-induced immune responses)
-
PG9: The use of computationally derived B cell clonal lineages as templates for HIV-1 immunogen design is discussed. PG9 has been discussed in terms of immunogenic and functional characteristics of representative HIV-1 BnAbs and their reactions to antigens.
Haynes2012
(antibody interactions, memory cells, vaccine antigen design, review, antibody polyreactivity, broad neutralizer)
-
PG9: Polyclonal B cell responses to conserved neutralization epitopes are reported. Cross-reactive plasma samples were identified and evaluated from 308 subjects tested. PG9 was used as a control mAb in the comprehensive set of assays performed. C1-0763 targeted a region similar to PG9 and PG16 recognizing a V1/V2 loop dependent epitope.
Tomaras2011
(neutralization, polyclonal antibodies)
-
PG9: Several antibodies including 10-1074 were isolated from B-cell clone encoding PGT121, from a clade A-infected African donor using YU-2 gp140 trimers as bait. These antibodies were segregated into PGT121-like (PGT121-123 and 9 members) and 10-1074-like (20 members) groups distinguished by sequence, binding affinity, carbohydrate recognition, neutralizing activity, the V3 loop binding and the role of glycans in epitope formation. PG9 was used as a control. Detail information on the binding and neutralization assays are described in the figures S2-S11.
Mouquet2012a
(glycosylation, neutralization, binding affinity)
-
PG9: YU2 gp140 bait was used to characterize 189 new MAbs representing 51 independent IgG memory B cell clones from 3 clade A or B HIV infected patients exhibiting broad neutralizing activity. PG9 was referred to in discussing the efficiency of YU-2 gp140 trimer as a bait for Ab capture.
Mouquet2011
(neutralization)
-
PG9: The rational design of vaccines to elicit broadly neutralizing antibodies to HIV-1 is discussed in relation to understanding of vaccine recognition sites, the structural basis of interaction with HIV-1 env and vaccine developmental pathways. Role of PG9 has been discussed in terms of humoral immune response during HIV1 infection. The vulnerability sites on the viral spike shows quaternary structural constraints, and maps to the second and third variable regions of gp120 (variable loops V2 and V3). PG9 recognizes these regions and neutralizes 70%–80% of current circulating isolates.
Kwong2011
(antibody binding site, neutralization, vaccine antigen design, review)
-
PG9: A panel of glycan deletion mutants was created by point mutation into HIV gp160, showing that glycans are important targets on HIV-1 glycoproteins for broad neutralizing responses in vivo. Enrichment of high mannose N-linked glycan(HM-glycan) of HIV-1 glycoprotein enhanced neutralizing activity of sera from 8/9 patients. PG9 was used as a control to compare the neutralizing activity of patients' sera.
Lavine2012
(neutralization)
-
PG9: Ab-driven escape and Ab role in infection control and prevention are reviewed. Main focus is on NAbs, but Ab acting through effector mechanisms are also discussed. PG9 is discussed in the context of developing broadly cross-neutralizing antibodies.
Overbaugh2012
(escape, review)
-
PG9: Neutralization activity was compared against MAb 10E8 and other broad and potent neutralizers in a 181-isolate Env-pseudovirus panel. PG9 neutralized 78% of viruses at IC50<50 μg/ml and 65% of viruses at IC50<1 μg/ml, compared with 98% and 72% of MAb 10E8, respectively.
Huang2012a
(neutralization)
-
PG9: Antigenic properties of undigested VLPs and endo H-digested WT trimer VLPs were compared. Binding to E168K+ N189A WT VLPs was dramatic compared to the parent WT VLPs, uncleaved VLPs. There was no significant correlation between E168K+N189A WT VLP binding and PG9 neutralization, while trimer VLP ELISA binding and neutralization exhibited a significant correlation. BN-PAGE shifts using digested E168K + N189A WT trimer VLPs exhibited prominence compared to WT VLPs.
Tong2012
(neutralization, binding affinity)
-
PG9: Broadly neutralizing antibodies circulating in plasma were studied by affinity chromatography and isoelectric focusing. The Abs fell in 2 groups. One group consisted of antibodies with restricted neutralization breadth that had neutral isoelectric points. These Abs bound to envelope monomers and trimers versus core antigens from which variable loops and other domains have been deleted. Another minor group consisted of broadly neutralizing antibodies consistently distinguished by more basic isoelectric points and specificity for epitopes shared by monomeric gp120, gp120 core, or CD4-induced structures. The pI values estimated for neutralizing plasma IgGs were compared to those of human anti-gp120 MAbs, including 5 bnMAbs (PG9, PG16, VRC01, b12, and 2G12), 2 narrowly neutralizing MAbs (17b and E51), and 3 nonneutralizing MAbs (A32, C11, and 19e). bnMAbs PG9 and PG16 exhibited more-neutral pIs (around 7.8), matching the more-neutral end of the plasma-derived fraction series, showing broadly neutralizing, but not most potent activity.
Sajadi2012
(polyclonal antibodies)
-
PG9: Sensitivity to neutralization was studied in 107 full-length Env molecular clones from multiple risk groups in various locations in China. Neutralization sensitivity to plasma pools and bNAbs was not correlated. PG9 neutralized 81% (25/31) and PG16 neutralized 71% (22/31) of the viruses tested. Viruses insensitive to PG9 were all equally insensitive to PG16 but not the other way around, suggesting that PG9 can tolerate more viral glycoprotein amino acid substitutions than PG16.
Shang2011
(glycosylation, neutralization, subtype comparisons)
-
PG9: The sensitivity to PG9 and PG16 of pseudotyped viruses was analysed carrying envelope glycoproteins from the viral quasispecies of three HIV-1 clade CRF01_AE-infected patients. It was confirmed that an acidic residue or a basic residue at position 168 in the V2 loop is a key element determining the sensitivity to PG9 and PG16. In addition, evidence is provided of the involvement of a conserved residue at position 215 of the C2 region in the PG9/PG16 epitopes. Sensitivity to PG9 in 10 Env-pseudotyped viruses was analyzed. Five clones from case 0377 presented a broad and continuous range of sensitivity to PG9. A broader range of sensitivity was observed in case 0978, clone 0978-M3 being resistant to PG9 whereas two other clones, 0978-M1 and 0978-M2, were highly sensitive. Similarly, two clones from case 0858 displayed peculiar patterns of neutralization: clone 0858-M1 was sensitive to neutralization by PG9 only whereas clone 0858-M2 was resistant to PG9. These results showed the broad heterogeneity in sensitivity to PG9 of closely genetically related envelope glycoproteins derived from single viral quasispecies. Clone 0978-M3 from case 0978 was resistant to PG9, whereas clones 0978-M1/M2 were highly sensitive to PG9. 0978-M3 E168K resulted in a high sensitivity to PG9. In contrast, 0978-M2 K168E conferred resistance to PG9. 0858-M2 M215I conferred sensitivity to PG9, whereas the mutant 0858-M2 M475I remained highly resistant to PG9. I215M diminished the sensitivity of all clones to PG9, except that of clone 5008CL2 for PG9.
Thenin2012a
(neutralization)
-
PG9: The interaction of CD4bs-binding MAbs (VRC01, VRC-PG04) and V1V2 glycan-dependent MAbs (PG9, PG16) was analyzed. MAb binding and neutralization studies showed that these two Env targets to not cross-compete and that their combination can mediate additive neutralization. The combination of MAbs VRC01 and PG9 provides a predicted coverage of 97% of 208 isolates at IC50 < 50 μg/ml and of 91% at IC50 < 50 μg/ml. In contrast, the combination of PG9 and PG16 (or the combination of VRC01 and VRC-PG04) was only marginally better than either MAb alone.
Doria-Rose2012
(antibody interactions)
-
PG9: The study showed that alteration between a rare lysine K and a common N-linked glycan at position 160 of HIV-1 gp120 is primarily responsible for toggling between 2909 and PG16/PG9 neutralization sensitivity. These neutralization profiles were mutually exclusive (160K for MAb 2909, 160N for PG16/PG9); there was no case of a virus that was sensitive to both 2909 and PG16/PG9 neutralization. Several more positions were studied: both the PG and 2909 MAbs do not require an asparagine at position 156 for neutralization, both the PG and 2909 antibodies tolerate amino acid variation at position 165, and neither the PG nor the 2909 MAb could tolerate a glutamic acid at position 168.
Wu2011a
(antibody binding site, escape)
-
PG9: An Env obtained from a slow progressing patient was resistant to PG9 and PG16 mAbs. Based on assays of neutralization and glycosylation, it is suggested that the overall neutralization sensitivity of an Env is the outcome of characteristic molecular features of the V2 loop. Neutralization by PG9/16 is balanced by the glycans, net positive charge in the β sheet C region of the V2 loop, and possibly the length of the V2 loop.
Ringe2012
(glycosylation, neutralization)
-
PG9: The neutralization activities of IA versus IgG and Fab versions of three broadly neutralizing antibodies: PG9, PG16, and VRC01 was compared to more fully understand the potential trade-offs in vector and construct design. The potential to combine VCR01 and PG9/PG16 activities to produce a single reagent with two gp120 specificities was also explored. In an Env-pseudotyped HIV-1 neutralization assay against a panel of 30 strains, PG9 neutralized 22 strains in IgG form, 18 stains in Fab form, 20 strains in IA form and 10 strains in scFv form. It was found that the PG9, PG16, and VRC01 IAs were severalfold less potent than their IgG forms.
West2012
(neutralization)
-
PG9: The biological properties of 17 Env-pseudotyped viruses derived from variants of mother–infant pairs infected by HIV-1 strains of the CRF01_AE clade were compared, in order to explore their association with the restrictive transmission of the virus. Maternal clones issued from MIPs (mother-infant pairs) 0377, 0978 and 1021 displayed a broad and continuous range of sensitivity to both PG9 and PG16 whereas all infant clones were highly sensitive to both mAbs PG9 and PG16. When the four MIPs were considered in aggregate, infant clones were significantly more sensitive to PG9 and PG16 compared to maternal clones.
Thenin2012
(neutralization, mother-to-infant transmission)
-
PG9: gp120 was cyclically permuted and new N- and C-termini were created within the V1, V3, and V4 loop regions to reduce the length of the linker joining gp120 and M9. Addition of trimerization domains at the V1 loop of cyclic permutants of gp120 resulted in the formation of predominantly trimeric species, which bound CD4 and neutralizing antibodies b12, PG9, and PG16 with higher affinity.
Saha2012
(binding affinity)
-
PG9: The role of envelope expression context and producer cell type was characterized for nine novel replication-competent chimeric HIV-1 isolates from the dominant circulating HIV-1 subtypes in Africa, where most new HIV-1 infections are occurring. Pseudoviruses generated in 293T cells were the most sensitive to antibody neutralization. There was no difference in the neutralization sensitivity of PBMC versus 293T-derived viruses using the MAb PG9.
Provine2012
(neutralization)
-
PG9: Phenotypic activities of a single transmitted/founder (T/F) virus from 24 acute individuals were compared to that of 17 viruses from chronics. There was a trend towards enhanced sensitivity to neutralization by PG9 of T/F Envs compared to chronic Envs.
Wilen2011
(neutralization)
-
PG9: HIV-1 adaptation to neutralization by MAbs VRC01, PG9, PG16 was studied using HIV-1 variants from historic (1985-1989) and contemporary (2003-2006) seroconverters. PG9 neutralized 52% of contemporary viruses at IC50 < 1 μ g/ml. The median IC50s of PG9 for viruses from historical and contemporary seroconverters were not significantly different. There was no clear correlation between the sensitivity to PG9 and presence or absence of certain amino acids, but more mutations were observed in viruses from contemporary seroconverters than from historical ones, and the absence of a potential N-linked glycosylation site at position 160 of V2 coincided with resistance to PG9.
Euler2011
(glycosylation, neutralization, escape)
-
PG9: Using U87 target cells, PGV04 neutralized 88% of 162 viruses, with IC50<50 μm/mg, with U87 target cells compared to 75% neutralized by PG9. The potency of neutralization was comparable. On the 97-virus panel, using TZM-bl target cells, the breadth of neutralization was similar, but PGV04 had increased potency. The neutralization potency of PG9, PG16, VRC01 and PGV04 was approximately 10-fold greater than that of MAbs b12, 2G12, 2F5 and 4E10. Alanine substitutions D279A, I420A and I423A abrogated PGV04 neutralization, but varied in their effects on VRC01, CD4-IgG and b12.
Falkowska2012
(neutralization, broad neutralizer)
-
PG9: Neutralizing antibody repertoires of 4 HIV-infected donors with remarkably broad and potent neutralizing responses were probed. 17 new monoclonal antibodies that neutralize broadly across clades were rescued. All MAbs exhibited broad cross-clade neutralizing activity, but several showed exceptional potency. Although PG9 neutralized 77% of 162 isolates at IC50<50 μg/ml, it was almost 10-fold less potent than several new antibodies PGT 121-123 and 125-128, for which the median antibody concentration required to inhibit HIV activity by 50% or 90% (IC50 and IC90 values) was almost 10-fold lower than that of PG9, VRC01 and PGV04.
Walker2011
(neutralization, broad neutralizer)
-
PG9: Atomic-level structure of V1/V2 in complex with PG9 is reported. Instead of being confounded by the N-linked glycan that shields most of gp120 from immune recognition, PG9 uses N-linked glycan for binding through a mechanism shared by a number of antibodies capable of effective HIV neutralization. The structure shows that the antibody recognizes glycopeptide conjugates and avoids diversity in V1/V2 by making sequence-independent interactions, such as hydrogen bonds. The structure of PG9 is consistent with published mutational data: some residues such as Phe 176 are critical because they form part of the hydrophobic core on the concave face of the V1/V2 sheet. Others form direct contacts: for example, the tyrosine sulphate at residue 100H of PG9 interacts with residue 168 when it is an Arg (strain ZM109) or Lys (strain CAP45), but would be repelled by a Glu (as in strain JR-FL); JR-FL is resistant to neutralization by PG9, but becomes sensitive if Glu 168 is changed to Lys10. V1/V2–PG9 interaction observed in the scaffolded V1/V2–PG9 crystal structures encompasses much of the PG9/PG16 epitope, and the structural integrity of this epitope is sensitive to appropriate assembly of the viral spike. With both CAP45 and ZM109 strains of gp120, the V1/V2 site recognized by PG9 consists primarily of two glycans and a strand. Minor interaction with strand B and with the B–C connecting loop complete the epitope, with the entire PG9-recognized surface of V1/V2 contained within the B–C hairpin.
McLellan2011
(antibody binding site, structure)
-
PG9: CDR H3 domains derived from 4 anti-HIV mAbs, PG16, PG9, b12, E51, and anti-influenza MAb AVF were genetically linked to glycosil-phosphatidylinositol (GPI) attachment signal of decay-accelerating factor (DAF) to determine whether the exceptionally long and unique structure of the CDR H3 subdomain of PG16 is sufficient for epitope recognition and neutralization. Similar degrees of cell surface expression of CDR H3(PG9)/hinge/His tag/DAFs (GPI-CDR H3(PG9)) was observed compared with those of the other GPI-CDR H3 constructs (PG16, AVF, and E51). GPI-CDR H3(PG9) exhibited the same degree of inhibition against 5 representative HIV-1 pseudotypes as that of GPI-CDR H3(PG16 and E51).
Liu2011
(neutralization, variant cross-reactivity, structure)
-
PG9: One Env clone (4–2.J45) obtained from a recently infected Indian patient (NARI-IVC4) had exceptional neutralization sensitivity compared to other Envs obtained at the same time point from the same patient. 4–2.J45 Env expressing M424 showed relative resistance to PG9 over 4–2.J45 expressing I424, wherein comparable sensitivities were found of other Envs to PG9 except YU2, which showed approximately 8 fold increase in neutralization sensitivity to PG9. The indistinctness in PG9/PG16 sensitivities of 4–2.J45 and YU2 Envs expressing M424 was possibly due to some compensatory and conformational changes elsewhere within Env.
Ringe2011
(neutralization)
-
PG9: Several soluble gp140 Env proteins recognized by PG9 and PG16 were identified, and the effect of Env trimerization, the requirement for specific amino acids at position 160 within the V2 loop, and the importance of proper gp120-gp41 cleavage for MAb binding to soluble gp140s were investigated along with whether and how the kinetics of PG9 and PG16 binding to soluble gp140 correlates with the neutralizing potencies of these MAbs. It is reported that the presence of the extracellular part of gp41 on certain gp140 constructs improves the recognition of the PG9 epitope on the gp120 subunit and the trimerization of soluble gp140 may lead to the partial occlusion of the PG9 epitope. PG9 most efficiently recognized modified SF162 Env, SF162K160N of the small number of soluble gp140 Envs tested. The absence of SF162 neutralization by PG9 is the presence of a lysine at position 160 instead of an asparagine. PG16 recognized a smaller number of gp140s tested here than PG9. It is suggested that any structural differences between the virion-associated Env form and the soluble gp140 form have a greater impact on the PG16 epitope than on the PG9 epitope.
Davenport2011
(antibody binding site, neutralization, binding affinity, structure)
-
PG9: The characteristics of HIV-1-specific NAbs were evaluated in 100 breast-fed infants of HIV-1-positive mothers who were HIV-1 negative at birth and they were monitored until age 2. A panel of eight viruses that included variants representative of those in the study region as well as more diverse strains was used to determine the breadth of the infant NAbs. PG9 had low neutralization potency for 2 (QD435.100 M.ENV.A4 and THRO4156.18) out of 8 pseudoviruses in the panel but high for the rest of them. For maternal variants, PG9 had low neutralization potency for 3 (MF535.B1, MJ613.A2 and MK184.E4) out of 12 variants and high for the rest of them.
Lynch2011
(neutralization, variant cross-reactivity, mother-to-infant transmission)
-
PG9: CAP256, an HIV-1 subtype C-infected (and subsequently superinfected) participant enrolled in the CAPRISA Acute Infection cohort was studied. A subset of mutants were tested for neutralization by PG9/PG16 along with neutralization of ConC by CAP256 plasma nAb. The epitope recognized by CAP256 is distinct from but overlaps that of PG9/PG16.Like CAP256 plasma, both PG9 and PG16 were heavily dependent on K169 and somewhat dependent on K171. A V2 mutation (N160A) had a profound affect on PG9 and PG16 but a more moderate affect on CAP256. The adjacent D167N residue also impacted CAP256 neutralization but not PG9/PG16, and a K168A mutation reduced CAP256 neutralization but in fact enhanced the neutralization of ConC by PG9/16. Both PG9/16 and CAP256, in the context of the ConC backbone, were slightly affected by mutations in the V3 loop (I305, I309, and F317) with mild effect on neutralization sensitivity. The I307A mutation affected both PG9/PG16 slightly but had no discernible effect on CAP256 neutralization. Some similarities between CAP256 and PG9/16 neutralization along with significant differences suggest that the epitopes recognized by these Abs overlapped but were not identical.
Moore2011
(neutralization)
-
PG9: The impact of specific changes at distal sites on antibody binding and neutralization was examined on Q461 variants. The changes at position 675 in conjunction with Thr to Ala at position 569 resulted in a dramatic increase in the neutralization sensitivity to some gp41 and gp120 MAbs and plasma but had less effect on the more potent MAb VRC01. There was an increase in VRC01 neutralization sensitivity to viruses with both mutations with intermediate effect for the individual mutants. There was some detectable PG9 neutralization of the variant bearing the T569A mutation alone but PG9 neutralization was not achieved with a change at position 675 only.
Lovelace2011
(antibody binding site, neutralization, variant cross-reactivity)
-
PG9: This review discusses current understanding of Env neutralization by antibodies in relation to epitope exposure and how this insight might benefit vaccine design strategies. This MAb is in the list of current MAbs with notable cross-neutralizing activity.
Pantophlet2010
(neutralization, variant cross-reactivity, review)
-
PG9: This review outlines the general structure of the gp160 viral envelope, the dynamics of viral entry, the evolution of humoral response, the mechanisms of viral escape and the characterization of broadly neutralizing Abs. It is noted that this MAb shows a significant breadth of neutralization across all clades and extraordinary potency.
Gonzalez2010
(neutralization, variant cross-reactivity, escape, review)
-
PG9: This review discusses recent rational structure-based approaches in HIV vaccine design that helped in understanding the link between Env antigenicity and immunogenicity. PG9 was isolated from a clade A infected donor using a high-throughput functional screening approach. This MAb was mentioned in the context of immunogens based on the epitopes recognized by bNAbs.
Walker2010a
(neutralization, review)
-
PG9: This review discusses the types of B-cell responses desired by HIV-1 vaccines and various methods used for eliciting HIV-1 inhibitory antibodies that include induction and characterization of vaccine-induces B-cell responses. PG9 was mentioned among new MAbs generated by isolating single Env-specific B cells by either single cell sorting by flow cytometry or from memory B-cell cultures coupled with high-throughput neutralization screening assays of B-cell supernatants. PG9 recognizes conserved regions of the variable loops in gp120 and is potent and broadly reactive against approximately 73-79% of HIV-1 strains.
Tomaras2010
(review)
-
PG9: This review discusses strategies for design of neutralizing antibody-based vaccines against HIV-1 and recent major advances in the field regarding isolation of potent broadly neutralizing Abs.
Sattentau2010
(review)
-
PG9: This review focuses on recent vaccine design efforts and investigation of broadly neutralizing Abs and their epitopes to aid in the improvement of immunogen design. NAb epitopes, NAbs response to HIV-1, isolation of novel mAbs, and vaccine-elicited NAb responses in human clinical trials are discussed in this review.
Mascola2010
(review)
-
PG9: Unlike the MPER MAbs tested, PG9 did not show any Env-independent virus capture in the conventional or in the modified version of the virus capture assay.
Leaman2010
-
PG9: Some of the key challenges for the development of an Ab-based HIV vaccine are discussed, such as challenges in identification of epitopes recognized by broadly neutralizing epitopes, the impact of biological mechanisms in addition to Ab neutralization, and the poor persistence of anti-Env Ab responses in the absence of continuous antigenic stimulation.
Lewis2010
(review)
-
PG9: The role of HIV-1 envelope spike density on the virion and the effect it has on MAb avidity, and neutralization potencies of MAbs presented as different isotypes, are reviewed. Engineering approaches and design of immunogens able to elicit intra-spike cross-linking Abs are discussed.
Klein2010
(review)
-
PG9: Novel techniques for generation of broadly neutralizing Abs and how these Ab can aid in development of an effective vaccine are discussed.
Joyce2010
(review)
-
PG9: The review describes several different methods that have been used to isolate and characterize HIV MAbs within the human Ab repertoire. Relative advantages and limitations of methods such as EBV transformation, human hybridoma, non-immortalized B cell culture, combinatorial libraries from B cells and clonal sorting are discussed.
Hammond2010
(review)
-
PG9: This review summarizes novel techniques recently developed for isolation of broadly neutralizing monoclonal Abs from HIV-infected donors. Future challenges and importance of these techniques for development of HIV vaccines is also discussed.
Burton2010
(review)
-
PG9: PG9 epitope structure is reviewed. This review also summarizes data on the evolution of HIV neutralizing Abs, principles of Env immunogen design to elicit broadly neutralizing Abs, and future critical areas of research for development of an Ab-based HIV vaccine.
Hoxie2010
(vaccine antigen design, review)
-
PG9: Novel methods for generation of broadly neutralizing Abs, such as PG9 and PG16 are reviewed. This review also summarizes PG9 and PG16 MAbs, and their similarity to 2909 MAb.
Kwong2009
(review)
-
PG9: Removal of N-linked glycosylation sites was shown to generally lead to a reduction in neutralization sensitivity to PG9, however, the position of the N-linked glycosylation site removed and the magnitude of the effect was isolate dependent. Loss of glycosylation sites in the V1, V2 and V3 loops had greatest effect on reduced neutralization sensitivity. Removal of the N160 glycan was the only substitution that universally eliminated sensitivity to neutralization by PG9. Binding of PG9 to Env transfected cells and to gp120 was not competed by monosaccharides indicating that PG9 sensitivity to glycosylation was due to the effect of glycans on gp120 conformation and PG9 epitope accessibility.
Doores2010
(antibody binding site, glycosylation, neutralization, binding affinity)
-
PG9: The CDR H3 region was shown critical for neutralization activity of the Ab. Affinity maturation of PG9 correlated with Ab neutralization breadth, as light chain V-gene reversion produced chimeric Abs with less neutralization. N-linked glycosylation of PG9 was not required for neutralization. Fab and IgG formats of PG9 had comparable neutralization potencies. The likely site of PG9 reaction with Env was determined to consist of CDR L1 and L2 and the CDR H3 elements.
Pancera2010
(glycosylation, neutralization)
-
PG9: Broadly neutralizing sera from elite neutralizers exhibited significant sensitivities to mutations I165A, N332A, and N160K. PG9 neutralization activity was tested for pseudoviruses with the mutations relative to the WT. PG9 was shown to require N160K glycosylation for potent neutralizing activity. Pseudoviruses produced in cells treated with kifunensine were found resistant to PG9 neutralization. Donor sera that exhibited sensitivity to N160K showed diminished neutralizing activity against kifunensine-treated pseudoviruses, indicating that PG16 and PG9 MAbs mediate most of the sera neutralizing activity. PG16 and PG9 - like Ab were found in 21% of the donors.
Walker2010
(glycosylation, neutralization)
-
PG9: Crystal structure of PG9 light chain was determined and a homology model of Fab PG9 was constructed for comparison to PG16 MAb. PG9 was shown to have a long CDR H3 that forms a unique stable subdomain. A 7-residue specificity loop within CDR H3 was shown to confer fine specificity of PG16 and PG9 MAbs, and to contain important contacts to gp120 as replacement of the 7 residues abolished PG9 neutralization. CDR H3 tyrosine for PG9 was doubly sulfated, and tyrosine sulfation was shown to play a role in both binding and neutralization. Glycosylation of PG9 light chain did not have a significant effect on neutralization.
Pejchal2010
(glycosylation, neutralization, binding affinity, structure)
-
PG9: This MAb was derived from clade A infected patient. PG9 failed to bind to recombinant gp120 or gp41 but exhibited high neutralization breadth and potency, neutralizing 127 out of 162 cross-clade viruses with a potency exceeding that of b12, 2G12, and 2F5. PG9 also potently neutralized IAVI-C18 virus, that is neutralization resistant to all four bNAbs. PG9 competed for gp120 binding with Abs against V2, V3 and CD4i. N-glycosylation sites N156 and N160 in the V2 region were critical in forming PG9 epitope. PG9 preferred binding to trimeric Env due to subunit presentation in this form. This Ab had a long CDRH3 loop.
Walker2009a
(antibody generation, glycosylation, neutralization, variant cross-reactivity, binding affinity)
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M. Bouvin-Pley, M. Morgand, L. Meyer, C. Goujard, A. Moreau, H. Mouquet, M. Nussenzweig, C. Pace, D. Ho, P. J. Bjorkman, D. Baty, P. Chames, M. Pancera, P. D. Kwong, P. Poignard, F. Barin, and M. Braibant. Drift of the HIV-1 Envelope Glycoprotein gp120 Toward Increased Neutralization Resistance over the Course of the Epidemic: A Comprehensive Study Using the Most Potent and Broadly Neutralizing Monoclonal Antibodies. J. Virol., 88(23):13910-13917, Dec 2014. PubMed ID: 25231299.
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Bradley2016a
Todd Bradley, Ashley Trama, Nancy Tumba, Elin Gray, Xiaozhi Lu, Navid Madani, Fatemeh Jahanbakhsh, Amanda Eaton, Shi-Mao Xia, Robert Parks, Krissey E. Lloyd, Laura L. Sutherland, Richard M. Scearce, Cindy M. Bowman, Susan Barnett, Salim S. Abdool-Karim, Scott D. Boyd, Bruno Melillo, Amos B. Smith, 3rd., Joseph Sodroski, Thomas B. Kepler, S. Munir Alam, Feng Gao, Mattia Bonsignori, Hua-Xin Liao, M Anthony Moody, David Montefiori, Sampa Santra, Lynn Morris, and Barton F. Haynes. Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity. EBioMedicine, 12:196-207, Oct 2016. PubMed ID: 27612593.
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Braibant2013
Martine Braibant, Eun-Yeung Gong, Jean-Christophe Plantier, Thierry Moreau, Elodie Alessandri, François Simon, and Francis Barin. Cross-Group Neutralization of HIV-1 and Evidence for Conservation of the PG9/PG16 Epitopes within Divergent Groups. AIDS, 27(8):1239-1244, 15 May 2013. PubMed ID: 23343910.
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Bricault2018
Christine A. Bricault, James M. Kovacs, Alexander Badamchi-Zadeh, Krisha McKee, Jennifer L. Shields, Bronwyn M. Gunn, George H. Neubauer, Fadi Ghantous, Julia Jennings, Lindsey Gillis, James Perry, Joseph P. Nkolola, Galit Alter, Bing Chen, Kathryn E. Stephenson, Nicole Doria-Rose, John R. Mascola, Michael S. Seaman, and Dan H. Barouch. Neutralizing Antibody Responses following Long-Term Vaccination with HIV-1 Env gp140 in Guinea Pigs. J. Virol., 92(13), 1 Jul 2018. PubMed ID: 29643249.
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Bricault2019
Christine A. Bricault, Karina Yusim, Michael S. Seaman, Hyejin Yoon, James Theiler, Elena E. Giorgi, Kshitij Wagh, Maxwell Theiler, Peter Hraber, Jennifer P. Macke, Edward F. Kreider, Gerald H. Learn, Beatrice H. Hahn, Johannes F. Scheid, James M. Kovacs, Jennifer L. Shields, Christy L. Lavine, Fadi Ghantous, Michael Rist, Madeleine G. Bayne, George H. Neubauer, Katherine McMahan, Hanqin Peng, Coraline Chéneau, Jennifer J. Jones, Jie Zeng, Christina Ochsenbauer, Joseph P. Nkolola, Kathryn E. Stephenson, Bing Chen, S. Gnanakaran, Mattia Bonsignori, LaTonya D. Williams, Barton F. Haynes, Nicole Doria-Rose, John R. Mascola, David C. Montefiori, Dan H. Barouch, and Bette Korber. HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design. Cell Host Microbe, 25(1):59-72.e8, 9 Jan 2019. PubMed ID: 30629920.
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Burton2010
Dennis R. Burton and Robin A. Weiss. A Boost for HIV Vaccine Design. Science, 329(5993):770-773, 13 Aug 2010. PubMed ID: 20705840.
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Burton2012
Dennis R. Burton, Pascal Poignard, Robyn L. Stanfield, and Ian A. Wilson. Broadly Neutralizing Antibodies Present New Prospects to Counter Highly Antigenically Diverse Viruses. Science, 337(6091):183-186, 13 Jul 2012. PubMed ID: 22798606.
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Burton2016
Dennis R. Burton and Lars Hangartner. Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design. Annu. Rev. Immunol., 34:635-659, 20 May 2016. PubMed ID: 27168247.
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Cai2017
Yongfei Cai, Selen Karaca-Griffin, Jia Chen, Sai Tian, Nicholas Fredette, Christine E. Linton, Sophia Rits-Volloch, Jianming Lu, Kshitij Wagh, James Theiler, Bette Korber, Michael S. Seaman, Stephen C. Harrison, Andrea Carfi, and Bing Chen. Antigenicity-Defined Conformations of an Extremely Neutralization-Resistant HIV-1 Envelope Spike. Proc. Natl. Acad. Sci. U.S.A., 114(17):4477-4482, 25 Apr 2017. PubMed ID: 28396421.
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Carbonetti2014
Sara Carbonetti, Brian G. Oliver, Jolene Glenn, Leonidas Stamatatos, and D. Noah Sather. Soluble HIV-1 Envelope Immunogens Derived from an Elite Neutralizer Elicit Cross-Reactive V1V2 Antibodies and Low Potency Neutralizing Antibodies. PLoS One, 9(1):e86905, 2014. PubMed ID: 24466285.
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Cheeseman2017
Hannah M. Cheeseman, Natalia J. Olejniczak, Paul M. Rogers, Abbey B. Evans, Deborah F. L. King, Paul Ziprin, Hua-Xin Liao, Barton F. Haynes, and Robin J. Shattock. Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies. J. Virol., 91(1), 1 Jan 2017. PubMed ID: 27795431.
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Chen2015
Jia Chen, James M. Kovacs, Hanqin Peng, Sophia Rits-Volloch, Jianming Lu, Donghyun Park, Elise Zablowsky, Michael S. Seaman, and Bing Chen. Effect of the Cytoplasmic Domain on Antigenic Characteristics of HIV-1 Envelope Glycoprotein. Science, 349(6244):191-195, 10 Jul 2015. PubMed ID: 26113642.
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Chen2016
Danying Chen, Xiaozhou He, Jingrong Ye, Pengxiang Zhao, Yi Zeng, and Xia Feng. Genetic and Phenotypic Analysis of CRF01\_AE HIV-1 env Clones from Patients Residing in Beijing, China. AIDS Res. Hum. Retroviruses, 32(10-11):1113-1124, Nov 2016. PubMed ID: 27066910.
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Chenine2018
Agnes-Laurence Chenine, Melanie Merbah, Lindsay Wieczorek, Sebastian Molnar, Brendan Mann, Jenica Lee, Anne-Marie O'Sullivan, Meera Bose, Eric Sanders-Buell, Gustavo H. Kijak, Carolina Herrera, Robert McLinden, Robert J. O'Connell, Nelson L. Michael, Merlin L. Robb, Jerome H. Kim, Victoria R. Polonis, and Sodsai Tovanabutra. Neutralization Sensitivity of a Novel HIV-1 CRF01\_AE Panel of Infectious Molecular Clones. J. Acquir. Immune Defic. Syndr., 78(3):348-355, 1 Jul 2018. PubMed ID: 29528942.
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Chuang2013
Gwo-Yu Chuang, Priyamvada Acharya, Stephen D. Schmidt, Yongping Yang, Mark K. Louder, Tongqing Zhou, Young Do Kwon, Marie Pancera, Robert T. Bailer, Nicole A. Doria-Rose, Michel C. Nussenzweig, John R. Mascola, Peter D. Kwong, and Ivelin S. Georgiev. Residue-Level Prediction of HIV-1 Antibody Epitopes Based on Neutralization of Diverse Viral Strains. J. Virol., 87(18):10047-10058, Sep 2013. PubMed ID: 23843642.
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Chuang2019
Gwo-Yu Chuang, Jing Zhou, Priyamvada Acharya, Reda Rawi, Chen-Hsiang Shen, Zizhang Sheng, Baoshan Zhang, Tongqing Zhou, Robert T. Bailer, Venkata P. Dandey, Nicole A. Doria-Rose, Mark K. Louder, Krisha McKee, John R. Mascola, Lawrence Shapiro, and Peter D. Kwong. Structural Survey of Broadly Neutralizing Antibodies Targeting the HIV-1 Env Trimer Delineates Epitope Categories and Characteristics of Recognition. Structure, 27(1):196-206.e6, 2 Jan 2019. PubMed ID: 30471922.
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Chun2014
Tae-Wook Chun, Danielle Murray, Jesse S. Justement, Jana Blazkova, Claire W. Hallahan, Olivia Fankuchen, Kathleen Gittens, Erika Benko, Colin Kovacs, Susan Moir, and Anthony S. Fauci. Broadly Neutralizing Antibodies Suppress HIV in the Persistent Viral Reservoir. Proc. Natl. Acad. Sci. U.S.A., 111(36):13151-13156, 9 Sep 2014. PubMed ID: 25157148.
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Cimbro2014
Raffaello Cimbro, Thomas R. Gallant, Michael A. Dolan, Christina Guzzo, Peng Zhang, Yin Lin, Huiyi Miao, Donald Van Ryk, James Arthos, Inna Gorshkova, Patrick H. Brown, Darrell E. Hurt, and Paolo Lusso. Tyrosine Sulfation in the Second Variable Loop (V2) of HIV-1 gp120 Stabilizes V2-V3 Interaction and Modulates Neutralization Sensitivity. Proc. Natl. Acad. Sci. U.S.A., 111(8):3152-3157, 25 Feb 2014. PubMed ID: 24569807.
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Crooks2015
Ema T. Crooks, Tommy Tong, Bimal Chakrabarti, Kristin Narayan, Ivelin S. Georgiev, Sergey Menis, Xiaoxing Huang, Daniel Kulp, Keiko Osawa, Janelle Muranaka, Guillaume Stewart-Jones, Joanne Destefano, Sijy O'Dell, Celia LaBranche, James E. Robinson, David C. Montefiori, Krisha McKee, Sean X. Du, Nicole Doria-Rose, Peter D. Kwong, John R. Mascola, Ping Zhu, William R. Schief, Richard T. Wyatt, Robert G. Whalen, and James M. Binley. Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site. PLoS Pathog, 11(5):e1004932, May 2015. PubMed ID: 26023780.
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Crooks2018
Ema T. Crooks, Samantha L. Grimley, Michelle Cully, Keiko Osawa, Gillian Dekkers, Kevin Saunders, Sebastian Ramisch, Sergey Menis, William R. Schief, Nicole Doria-Rose, Barton Haynes, Ben Murrell, Evan Mitchel Cale, Amarendra Pegu, John R. Mascola, Gestur Vidarsson, and James M. Binley. Glycoengineering HIV-1 Env Creates `Supercharged' and `Hybrid' Glycans to Increase Neutralizing Antibody Potency, Breadth and Saturation. PLoS Pathog., 14(5):e1007024, May 2018. PubMed ID: 29718999.
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Danesh2020
Ali Danesh, Yanqin Ren, and R. Brad Jones. Roles of Fragment Crystallizable-Mediated Effector Functions in Broadly Neutralizing Antibody Activity against HIV. Curr. Opin. HIV AIDS, 15(5):316-323, Sep 2020. PubMed ID: 32732552.
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Davenport2011
Thaddeus M. Davenport, Della Friend, Katharine Ellingson, Hengyu Xu, Zachary Caldwell, George Sellhorn, Zane Kraft, Roland K. Strong, and Leonidas Stamatatos. Binding Interactions between Soluble HIV Envelope Glycoproteins and Quaternary-Structure-Specific Monoclonal Antibodies PG9 and PG16. J. Virol., 85(14):7095-7107, Jul 2011. PubMed ID: 21543501.
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Decamp2014
Allan deCamp, Peter Hraber, Robert T. Bailer, Michael S. Seaman, Christina Ochsenbauer, John Kappes, Raphael Gottardo, Paul Edlefsen, Steve Self, Haili Tang, Kelli Greene, Hongmei Gao, Xiaoju Daniell, Marcella Sarzotti-Kelsoe, Miroslaw K. Gorny, Susan Zolla-Pazner, Celia C. LaBranche, John R. Mascola, Bette T. Korber, and David C. Montefiori. Global Panel of HIV-1 Env Reference Strains for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies. J. Virol., 88(5):2489-2507, Mar 2014. PubMed ID: 24352443.
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Dennison2014
S. Moses Dennison, Kara M. Anasti, Frederick H. Jaeger, Shelley M. Stewart, Justin Pollara, Pinghuang Liu, Erika L. Kunz, Ruijun Zhang, Nathan Vandergrift, Sallie Permar, Guido Ferrari, Georgia D. Tomaras, Mattia Bonsignori, Nelson L. Michael, Jerome H Kim, Jaranit Kaewkungwal, Sorachai Nitayaphan, Punnee Pitisuttithum, Supachai Rerks-Ngarm, Hua-Xin Liao, Barton F. Haynes, and S. Munir Alam. Vaccine-Induced HIV-1 Envelope gp120 Constant Region 1-Specific Antibodies Expose a CD4-Inducible Epitope and Block the Interaction of HIV-1 gp140 with Galactosylceramide. J. Virol., 88(16):9406-9417, Aug 2014. PubMed ID: 24920809.
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Derking2015
Ronald Derking, Gabriel Ozorowski, Kwinten Sliepen, Anila Yasmeen, Albert Cupo, Jonathan L. Torres, Jean-Philippe Julien, Jeong Hyun Lee, Thijs van Montfort, Steven W. de Taeye, Mark Connors, Dennis R. Burton, Ian A. Wilson, Per-Johan Klasse, Andrew B. Ward, John P. Moore, and Rogier W. Sanders. Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer. PLoS Pathog, 11(3):e1004767, Mar 2015. PubMed ID: 25807248.
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deTaeye2015
Steven W. de Taeye, Gabriel Ozorowski, Alba Torrents de la Peña, Miklos Guttman, Jean-Philippe Julien, Tom L. G. M. van den Kerkhof, Judith A. Burger, Laura K. Pritchard, Pavel Pugach, Anila Yasmeen, Jordan Crampton, Joyce Hu, Ilja Bontjer, Jonathan L. Torres, Heather Arendt, Joanne DeStefano, Wayne C. Koff, Hanneke Schuitemaker, Dirk Eggink, Ben Berkhout, Hansi Dean, Celia LaBranche, Shane Crotty, Max Crispin, David C. Montefiori, P. J. Klasse, Kelly K. Lee, John P. Moore, Ian A. Wilson, Andrew B. Ward, and Rogier W. Sanders. Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-Neutralizing Epitopes. Cell, 163(7):1702-1715, 17 Dec 2015. PubMed ID: 26687358.
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deTaeye2019
Steven W. de Taeye, Eden P. Go, Kwinten Sliepen, Alba Torrents de la Peña, Kimberly Badal, Max Medina-Ramírez, Wen-Hsin Lee, Heather Desaire, Ian A. Wilson, John P. Moore, Andrew B. Ward, and Rogier W. Sanders. Stabilization of the V2 Loop Improves the Presentation of V2 Loop-Associated Broadly Neutralizing Antibody Epitopes on HIV-1 Envelope Trimers. J. Biol. Chem., 294(14):5616-5631, 5 Apr 2019. PubMed ID: 30728245.
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Dingens2019
Adam S. Dingens, Dana Arenz, Haidyn Weight, Julie Overbaugh, and Jesse D. Bloom. An Antigenic Atlas of HIV-1 Escape from Broadly Neutralizing Antibodies Distinguishes Functional and Structural Epitopes. Immunity, 50(2):520-532.e3, 19 Feb 2019. PubMed ID: 30709739.
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Diskin2013
Ron Diskin, Florian Klein, Joshua A. Horwitz, Ariel Halper-Stromberg, D. Noah Sather, Paola M. Marcovecchio, Terri Lee, Anthony P. West, Jr., Han Gao, Michael S. Seaman, Leonidas Stamatatos, Michel C. Nussenzweig, and Pamela J. Bjorkman. Restricting HIV-1 Pathways for Escape Using Rationally Designed Anti-HIV-1 Antibodies. J. Exp. Med., 210(6):1235-1249, 3 Jun 2013. PubMed ID: 23712429.
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Doores2010
Katie J. Doores and Dennis R. Burton. Variable Loop Glycan Dependency of the Broad and Potent HIV-1-Neutralizing Antibodies PG9 and PG16. J. Virol., 84(20):10510-10521, Oct 2010. PubMed ID: 20686044.
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Doria-Rose2012
Nicole A. Doria-Rose, Mark K. Louder, Zhongjia Yang, Sijy O'Dell, Martha Nason, Stephen D. Schmidt, Krisha McKee, Michael S. Seaman, Robert T. Bailer, and John R. Mascola. HIV-1 Neutralization Coverage Is Improved by Combining Monoclonal Antibodies That Target Independent Epitopes. J. Virol., 86(6):3393-3397, Mar 2012. PubMed ID: 22258252.
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Doria-Rose2014
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Doria-Rose2017
Nicole A. Doria-Rose, Han R. Altae-Tran, Ryan S. Roark, Stephen D. Schmidt, Matthew S. Sutton, Mark K. Louder, Gwo-Yu Chuang, Robert T. Bailer, Valerie Cortez, Rui Kong, Krisha McKee, Sijy O'Dell, Felicia Wang, Salim S. Abdool Karim, James M. Binley, Mark Connors, Barton F. Haynes, Malcolm A. Martin, David C. Montefiori, Lynn Morris, Julie Overbaugh, Peter D. Kwong, John R. Mascola, and Ivelin S. Georgiev. Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting. PLoS Pathog., 13(1):e1006148, Jan 2017. PubMed ID: 28052137.
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Nicole A. Doria-Rose, Ivelin Georgiev, Sijy O'Dell, Gwo-Yu Chuang, Ryan P. Staupe, Jason S. McLellan, Jason Gorman, Marie Pancera, Mattia Bonsignori, Barton F. Haynes, Dennis R. Burton, Wayne C. Koff, Peter D. Kwong, and John R. Mascola. A Short Segment of the HIV-1 gp120 V1/V2 Region Is a Major Determinant of Resistance to V1/V2 Neutralizing Antibodies. J. Virol., Aug 2012. PubMed ID: 22623764.
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Escolano2021
Amelia Escolano, Harry .B Gristick, Rajeev Gautam, Andrew T. DeLaitsch, Morgan E. Abernathy, Zhi Yang, Haoqing Wang, Magnus A. G. Hoffmann, Yoshiaki Nishimura, Zijun Wang, Nicholas Koranda, Leesa M. Kakutani, Han Gao, Priyanthi N. P. Gnanapragasam, Henna Raina, Ana Gazumyan, Melissa Cipolla, Thiago Y. Oliveira, Victor Ramos, Darrell J. Irvine, Murillo Silva, Anthony P. West, Jr., Jennifer R. Keeffe, Christopher O. Barnes, Michael S. Seaman, Michel C. Nussenzweig, Malcolm A. Martin, and Pamela J. Bjorkman. Sequential Immunization of Macaques Elicits Heterologous Neutralizing Antibodies Targeting the V3-Glycan Patch of HIV-1 Env. Sci. Transl. Med., 13(621):eabk1533, 24 Nov 2021. PubMed ID: 34818054.
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Euler2011
Zelda Euler, Evelien M. Bunnik, Judith A. Burger, Brigitte D. M. Boeser-Nunnink, Marlous L. Grijsen, Jan M. Prins, and Hanneke Schuitemaker. Activity of Broadly Neutralizing Antibodies, Including PG9, PG16, and VRC01, against Recently Transmitted Subtype B HIV-1 Variants from Early and Late in the Epidemic. J. Virol., 85(14):7236-7245, Jul 2011. PubMed ID: 21561918.
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Evans2014
Mark C. Evans, Pham Phung, Agnes C. Paquet, Anvi Parikh, Christos J. Petropoulos, Terri Wrin, and Mojgan Haddad. Predicting HIV-1 Broadly Neutralizing Antibody Epitope Networks Using Neutralization Titers and a Novel Computational Method. BMC Bioinformatics, 15:77, 19 Mar 2014. PubMed ID: 24646213.
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Falkowska2012
Emilia Falkowska, Alejandra Ramos, Yu Feng, Tongqing Zhou, Stephanie Moquin, Laura M. Walker, Xueling Wu, Michael S. Seaman, Terri Wrin, Peter D. Kwong, Richard T. Wyatt, John R. Mascola, Pascal Poignard, and Dennis R. Burton. PGV04, an HIV-1 gp120 CD4 Binding Site Antibody, Is Broad and Potent in Neutralization but Does Not Induce Conformational Changes Characteristic of CD4. J. Virol., 86(8):4394-4403, Apr 2012. PubMed ID: 22345481.
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Falkowska2014
Emilia Falkowska, Khoa M. Le, Alejandra Ramos, Katie J. Doores, Jeong Hyun Lee, Claudia Blattner, Alejandro Ramirez, Ronald Derking, Marit J. van Gils, Chi-Hui Liang, Ryan Mcbride, Benjamin von Bredow, Sachin S. Shivatare, Chung-Yi Wu, Po-Ying Chan-Hui, Yan Liu, Ten Feizi, Michael B. Zwick, Wayne C. Koff, Michael S. Seaman, Kristine Swiderek, John P. Moore, David Evans, James C. Paulson, Chi-Huey Wong, Andrew B. Ward, Ian A. Wilson, Rogier W. Sanders, Pascal Poignard, and Dennis R. Burton. Broadly Neutralizing HIV Antibodies Define a Glycan-Dependent Epitope on the Prefusion Conformation of gp41 on Cleaved Envelope Trimers. Immunity, 40(5):657-668, 15 May 2014. PubMed ID: 24768347.
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Gach2013
Johannes S. Gach, Heribert Quendler, Tommy Tong, Kristin M. Narayan, Sean X. Du, Robert G. Whalen, James M. Binley, Donald N. Forthal, Pascal Poignard, and Michael B. Zwick. A Human Antibody to the CD4 Binding Site of gp120 Capable of Highly Potent but Sporadic Cross Clade Neutralization of Primary HIV-1. PLoS One, 8(8):e72054, 2013. PubMed ID: 23991039.
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Gavrilyuk2013
Julia Gavrilyuk, Hitoshi Ban, Hisatoshi Uehara, Shannon J. Sirk, Karen Saye-Francisco, Angelica Cuevas, Elise Zablowsky, Avinash Oza, Michael S. Seaman, Dennis R. Burton, and Carlos F. Barbas, 3rd. Antibody Conjugation Approach Enhances Breadth and Potency of Neutralization of Anti-HIV-1 Antibodies and CD4-IgG. J. Virol., 87(9):4985-4993, May 2013. PubMed ID: 23427154.
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Georgiev2013
Ivelin S. Georgiev, Nicole A. Doria-Rose, Tongqing Zhou, Young Do Kwon, Ryan P. Staupe, Stephanie Moquin, Gwo-Yu Chuang, Mark K. Louder, Stephen D. Schmidt, Han R. Altae-Tran, Robert T. Bailer, Krisha McKee, Martha Nason, Sijy O'Dell, Gilad Ofek, Marie Pancera, Sanjay Srivatsan, Lawrence Shapiro, Mark Connors, Stephen A. Migueles, Lynn Morris, Yoshiaki Nishimura, Malcolm A. Martin, John R. Mascola, and Peter D. Kwong. Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization. Science, 340(6133):751-756, 10 May 2013. PubMed ID: 23661761.
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Gonzalez2010
Nuria Gonzalez, Amparo Alvarez, and Jose Alcami. Broadly Neutralizing Antibodies and their Significance for HIV-1 Vaccines. Curr. HIV Res., 8(8):602-612, Dec 2010. PubMed ID: 21054253.
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Goo2012
Leslie Goo, Zahra Jalalian-Lechak, Barbra A. Richardson, and Julie Overbaugh. A Combination of Broadly Neutralizing HIV-1 Monoclonal Antibodies Targeting Distinct Epitopes Effectively Neutralizes Variants Found in Early Infection. J. Virol., 86(19):10857-10861, Oct 2012. PubMed ID: 22837204.
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Gorman2016
Jason Gorman, Cinque Soto, Max M. Yang, Thaddeus M. Davenport, Miklos Guttman, Robert T. Bailer, Michael Chambers, Gwo-Yu Chuang, Brandon J. DeKosky, Nicole A. Doria-Rose, Aliaksandr Druz, Michael J. Ernandes, Ivelin S. Georgiev, Marissa C. Jarosinski, M. Gordon Joyce, Thomas M. Lemmin, Sherman Leung, Mark K. Louder, Jonathan R. McDaniel, Sandeep Narpala, Marie Pancera, Jonathan Stuckey, Xueling Wu, Yongping Yang, Baoshan Zhang, Tongqing Zhou, NISC Comparative Sequencing Program, James C. Mullikin, Ulrich Baxa, George Georgiou, Adrian B. McDermott, Mattia Bonsignori, Barton F. Haynes, Penny L. Moore, Lynn Morris, Kelly K. Lee, Lawrence Shapiro, John R. Mascola, and Peter D. Kwong. Structures of HIV-1 Env V1V2 with Broadly Neutralizing Antibodies Reveal Commonalities That Enable Vaccine Design. Nat. Struct. Mol. Biol., 23(1):81-90, Jan 2016. PubMed ID: 26689967.
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Guan2013
Yongjun Guan, Marzena Pazgier, Mohammad M. Sajadi, Roberta Kamin-Lewis, Salma Al-Darmarki, Robin Flinko, Elena Lovo, Xueji Wu, James E. Robinson, Michael S. Seaman, Timothy R. Fouts, Robert C. Gallo, Anthony L. DeVico, and George K. Lewis. Diverse Specificity and Effector Function Among Human Antibodies to HIV-1 Envelope Glycoprotein Epitopes Exposed by CD4 Binding. Proc. Natl. Acad. Sci. U.S.A., 110(1):E69-E78, 2 Jan 2013. PubMed ID: 23237851.
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Guenaga2015a
Javier Guenaga, Viktoriya Dubrovskaya, Natalia de Val, Shailendra K. Sharma, Barbara Carrette, Andrew B. Ward, and Richard T. Wyatt. Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers. J. Virol., 90(6):2806-2817, 30 Dec 2015. PubMed ID: 26719252.
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Guzzo2018
Christina Guzzo, Peng Zhang, Qingbo Liu, Alice L. Kwon, Ferzan Uddin, Alexandra I. Wells, Hana Schmeisser, Raffaello Cimbro, Jinghe Huang, Nicole Doria-Rose, Stephen D. Schmidt, Michael A. Dolan, Mark Connors, John R. Mascola, and Paolo Lusso. Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation. mBio, 9(6), 11 Dec 2018. PubMed ID: 30538178.
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Hammond2010
Philip W. Hammond. Accessing the Human Repertoire for Broadly Neutralizing HIV Antibodies. MAbs, 2(2):157-164, Mar-Apr 2010. PubMed ID: 20168075.
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Haynes2012
Barton F. Haynes, Garnett Kelsoe, Stephen C. Harrison, and Thomas B. Kepler. B-Cell-Lineage Immunogen Design in Vaccine Development with HIV-1 as a Case Study. Nat. Biotechnol., 30(5):423-433, May 2012. PubMed ID: 22565972.
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Haynes2013
Barton F. Haynes and M. Juliana McElrath. Progress in HIV-1 Vaccine Development. Curr. Opin. HIV AIDS, 8(4):326-332, Jul 2013. PubMed ID: 23743722.
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Henderson2019
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Hoffenberg2013
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Peter Hraber, Bette Korber, Kshitij Wagh, David Montefiori, and Mario Roederer. A Single, Continuous Metric To Define Tiered Serum Neutralization Potency against Hiv. eLife, 7, 19 Jan 2018. PubMed ID: 29350181.
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Casey K. Hua and Margaret E. Ackerman. Engineering Broadly Neutralizing Antibodies for HIV Prevention and Therapy. Adv. Drug Deliv. Rev., 103:157-173, 1 Aug 2016. PubMed ID: 26827912.
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Jennie M. Hutchinson, Kathryn A. Mesa, David L. Alexander, Bin Yu, Sara M. O'Rourke, Kay L. Limoli, Terri Wrin, Steven G. Deeks, and Phillip W. Berman. Unusual Cysteine Content in V1 Region of gp120 from an Elite Suppressor That Produces Broadly Neutralizing Antibodies. Front. Immunol., 10:1021, 2019. PubMed ID: 31156622.
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Joyce2010
Joseph G. Joyce and Jan ter Meulen. Pushing the Envelope on HIV-1 Neutralization. Nat. Biotechnol., 28(9):929-931, Sep 2010. PubMed ID: 20829830.
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Jean-Philippe Julien, Jeong Hyun Lee, Gabriel Ozorowski, Yuanzi Hua, Alba Torrents de la Peña, Steven W. de Taeye, Travis Nieusma, Albert Cupo, Anila Yasmeen, Michael Golabek, Pavel Pugach, P. J. Klasse, John P. Moore, Rogier W. Sanders, Andrew B. Ward, and Ian A. Wilson. Design and Structure of Two HIV-1 Clade C SOSIP.664 Trimers That Increase the Arsenal of Native-Like Env Immunogens. Proc. Natl. Acad. Sci. U.S.A., 112(38):11947-11952, 22 Sep 2015. PubMed ID: 26372963.
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Sannula Kesavardhana, Raksha Das, Michael Citron, Rohini Datta, Linda Ecto, Nonavinakere Seetharam Srilatha, Daniel DiStefano, Ryan Swoyer, Joseph G. Joyce, Somnath Dutta, Celia C. LaBranche, David C. Montefiori, Jessica A. Flynn, and Raghavan Varadarajan. Structure-Based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies. J. Biol. Chem., 292(1):278-291, 6 Jan 2017. PubMed ID: 27879316.
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Joshua S. Klein and Pamela J. Bjorkman. Few and Far Between: How HIV May Be Evading Antibody Avidity. PLoS Pathog., 6(5):e1000908, May 2010. PubMed ID: 20523901.
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James M. Kovacs, Joseph P. Nkolola, Hanqin Peng, Ann Cheung, James Perry, Caroline A. Miller, Michael S. Seaman, Dan H. Barouch, and Bing Chen. HIV-1 Envelope Trimer Elicits More Potent Neutralizing Antibody Responses than Monomeric gp120. Proc. Natl. Acad. Sci. U.S.A., 109(30):12111-12116, 24 Jul 2012. PubMed ID: 22773820.
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Kreer2020
Christoph Kreer, Henning Gruell, Thierry Mora, Aleksandra M. Walczak, and Florian Klein. Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies. Vaccines (Basel), 8(1):13 doi, Jan 2020. PubMed ID: 31906351
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Kulp2017
Daniel W. Kulp, Jon M. Steichen, Matthias Pauthner, Xiaozhen Hu, Torben Schiffner, Alessia Liguori, Christopher A. Cottrell, Colin Havenar-Daughton, Gabriel Ozorowski, Erik Georgeson, Oleksandr Kalyuzhniy, Jordan R. Willis, Michael Kubitz, Yumiko Adachi, Samantha M. Reiss, Mia Shin, Natalia de Val, Andrew B. Ward, Shane Crotty, Dennis R. Burton, and William R. Schief. Structure-Based Design of Native-Like HIV-1 Envelope Trimers to Silence Non-Neutralizing Epitopes and Eliminate CD4 Binding. Nat. Commun., 8(1):1655, 21 Nov 2017. PubMed ID: 29162799.
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Kumar2018
Amit Kumar, Claire E. P. Smith, Elena E. Giorgi, Joshua Eudailey, David R. Martinez, Karina Yusim, Ayooluwa O. Douglas, Lisa Stamper, Erin McGuire, Celia C. LaBranche, David C. Montefiori, Genevieve G. Fouda, Feng Gao, and Sallie R. Permar. Infant Transmitted/Founder HIV-1 Viruses from Peripartum Transmission Are Neutralization Resistant to Paired Maternal Plasma. PLoS Pathog., 14(4):e1006944, Apr 2018. PubMed ID: 29672607.
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Kwon2012
Young Do Kwon, Andrés Finzi, Xueling Wu, Cajetan Dogo-Isonagie, Lawrence K. Lee, Lucas R. Moore, Stephen D. Schmidt, Jonathan Stuckey, Yongping Yang, Tongqing Zhou, Jiang Zhu, David A. Vicic, Asim K. Debnath, Lawrence Shapiro, Carole A. Bewley, John R. Mascola, Joseph G. Sodroski, and Peter D. Kwong. Unliganded HIV-1 gp120 Core Structures Assume the CD4-Bound Conformation with Regulation by Quaternary Interactions and Variable Loops. Proc. Natl. Acad. Sci. U.S.A., 109(15):5663-5668, 10 Apr 2012. PubMed ID: 22451932.
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Young Do Kwon, Marie Pancera, Priyamvada Acharya, Ivelin S. Georgiev, Emma T. Crooks, Jason Gorman, M. Gordon Joyce, Miklos Guttman, Xiaochu Ma, Sandeep Narpala, Cinque Soto, Daniel S. Terry, Yongping Yang, Tongqing Zhou, Goran Ahlsen, Robert T. Bailer, Michael Chambers, Gwo-Yu Chuang, Nicole A. Doria-Rose, Aliaksandr Druz, Mark A. Hallen, Adam Harned, Tatsiana Kirys, Mark K. Louder, Sijy O'Dell, Gilad Ofek, Keiko Osawa, Madhu Prabhakaran, Mallika Sastry, Guillaume B. E. Stewart-Jones, Jonathan Stuckey, Paul V. Thomas, Tishina Tittley, Constance Williams, Baoshan Zhang, Hong Zhao, Zhou Zhou, Bruce R. Donald, Lawrence K. Lee, Susan Zolla-Pazner, Ulrich Baxa, Arne Schön, Ernesto Freire, Lawrence Shapiro, Kelly K. Lee, James Arthos, James B. Munro, Scott C. Blanchard, Walther Mothes, James M. Binley, Adrian B. McDermott, John R. Mascola, and Peter D. Kwong. Crystal Structure, Conformational Fixation and Entry-Related Interactions of Mature Ligand-Free HIV-1 Env. Nat. Struct. Mol. Biol., 22(7):522-531, Jul 2015. PubMed ID: 26098315.
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Peter D. Kwong, John R. Mascola, and Gary J. Nabel. Mining the B Cell Repertoire for Broadly Neutralizing Monoclonal Antibodies to HIV-1. Cell Host Microbe, 6(4):292-294, 22 Oct 2009. PubMed ID: 19837366.
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Peter D. Kwong, John R. Mascola, and Gary J. Nabel. Rational Design of Vaccines to Elicit Broadly Neutralizing Antibodies to HIV-1. Cold Spring Harb. Perspect. Med., 1(1):a007278, Sep 2011. PubMed ID: 22229123.
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Peter D. Kwong and John R. Mascola. Human Antibodies that Neutralize HIV-1: Identification, Structures, and B Cell Ontogenies. Immunity, 37(3):412-425, 21 Sep 2012. PubMed ID: 22999947.
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Kwong2013
Peter D. Kwong, John R. Mascola, and Gary J. Nabel. Broadly Neutralizing Antibodies and the Search for an HIV-1 Vaccine: The End of the Beginning. Nat. Rev. Immunol., 13(9):693-701, Sep 2013. PubMed ID: 23969737.
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Peter D. Kwong and John R. Mascola. HIV-1 Vaccines Based on Antibody Identification, B Cell Ontogeny, and Epitope Structure. Immunity, 48(5):855-871, 15 May 2018. PubMed ID: 29768174.
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Lavine2012
Christy L. Lavine, Socheata Lao, David C. Montefiori, Barton F. Haynes, Joseph G. Sodroski, Xinzhen Yang, and NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI). High-Mannose Glycan-Dependent Epitopes Are Frequently Targeted in Broad Neutralizing Antibody Responses during Human Immunodeficiency Virus Type 1 Infection. J. Virol., 86(4):2153-2164, Feb 2012. PubMed ID: 22156525.
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Daniel P. Leaman and Michael B. Zwick. Increased Functional Stability and Homogeneity of Viral Envelope Spikes through Directed Evolution. PLoS Pathog., 9(2):e1003184, Feb 2013. PubMed ID: 23468626.
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Jeong Hyun Lee, Raiees Andrabi, Ching-Yao Su, Anila Yasmeen, Jean-Philippe Julien, Leopold Kong, Nicholas C. Wu, Ryan McBride, Devin Sok, Matthias Pauthner, Christopher A. Cottrell, Travis Nieusma, Claudia Blattner, James C. Paulson, Per Johan Klasse, Ian A. Wilson, Dennis R. Burton, and Andrew B. Ward. A Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope Trimer Apex via a Long, Rigidified, and Anionic beta-Hairpin Structure. Immunity, 46(4):690-702, 18 Apr 2017. PubMed ID: 28423342.
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George K. Lewis. Challenges of Antibody-Mediated Protection against HIV-1. Expert Rev. Vaccines, 9(7):683-687, Jul 2010. PubMed ID: 20624038.
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Hongru Li, Chati Zony, Ping Chen, and Benjamin K. Chen. Reduced Potency and Incomplete Neutralization of Broadly Neutralizing Antibodies against Cell-to-Cell Transmission of HIV-1 with Transmitted Founder Envs. J. Virol., 91(9), 1 May 2017. PubMed ID: 28148796.
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Yu Liang, Miklos Guttman, James A. Williams, Hans Verkerke, Daniel Alvarado, Shiu-Lok Hu, and Kelly K. Lee. Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan. J. Virol., 90(20):9224-9236, 15 Oct 2016. PubMed ID: 27489265.
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Liao2013b
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Liao2013c
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Lihong Liu, Michael Wen, Weiming Wang, Shumei Wang, Lifei Yang, Yong Liu, Mengran Qian, Linqi Zhang, Yiming Shao, Jason T. Kimata, and Paul Zhou. Potent and Broad Anti-HIV-1 Activity Exhibited by a Glycosyl-Phosphatidylinositol-Anchored Peptide Derived from the CDR H3 of Broadly Neutralizing Antibody PG16. J. Virol., 85(17):8467-8476, Sep 2011. PubMed ID: 21715497.
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Liu2014
Pinghuang Liu, Latonya D. Williams, Xiaoying Shen, Mattia Bonsignori, Nathan A. Vandergrift, R. Glenn Overman, M. Anthony Moody, Hua-Xin Liao, Daniel J. Stieh, Kerrie L. McCotter, Audrey L. French, Thomas J. Hope, Robin Shattock, Barton F. Haynes, and Georgia D. Tomaras. Capacity for Infectious HIV-1 Virion Capture Differs by Envelope Antibody Specificity. J. Virol., 88(9):5165-5170, May 2014. PubMed ID: 24554654.
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Lovelace2011
Erica Lovelace, Hengyu Xu, Catherine A. Blish, Roland Strong, and Julie Overbaugh. The Role of Amino Acid Changes in the Human Immunodeficiency Virus Type 1 Transmembrane Domain in Antibody Binding and Neutralization. Virology, 421(2):235-244, 20 Dec 2011. PubMed ID: 22029936.
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Carsten Magnus, Lucia Reh, and Alexandra Trkola. HIV-1 Resistance to Neutralizing Antibodies: Determination of Antibody Concentrations Leading to Escape Mutant Evolution. Virus Res., 218:57-70, 15 Jun 2016. PubMed ID: 26494166.
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Malherbe2014
Delphine C. Malherbe, Franco Pissani, D. Noah Sather, Biwei Guo, Shilpi Pandey, William F. Sutton, Andrew B. Stuart, Harlan Robins, Byung Park, Shelly J. Krebs, Jason T. Schuman, Spyros Kalams, Ann J. Hessell, and Nancy L. Haigwood. Envelope variants circulating as initial neutralization breadth developed in two HIV-infected subjects stimulate multiclade neutralizing antibodies in rabbits. J Virol, 88(22):12949-67 doi, Nov 2014. PubMed ID: 25210191
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Mannar2021
Dhiraj Mannar, Karoline Leopold, and Sriram Subramaniam. Glycan Reactive Anti-HIV-1 Antibodies bind the SARS-CoV-2 Spike Protein But Do Not Block Viral Entry. Sci. Rep., 11(1):12448, 14 Jun 2021. PubMed ID: 34127709.
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Youdong Mao, Liping Wang, Christopher Gu, Alon Herschhorn, Shi-Hua Xiang, Hillel Haim, Xinzhen Yang, and Joseph Sodroski. Subunit Organization of the Membrane-Bound HIV-1 Envelope Glycoprotein Trimer. Nat. Struct. Mol. Biol., 19(9):893-899, Sep 2012. PubMed ID: 22864288.
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John R. Mascola and David C. Montefiori. The Role of Antibodies in HIV Vaccines. Annu. Rev. Immunol., 28:413-444, Mar 2010. PubMed ID: 20192810.
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Andrew T. McGuire, Jolene A. Glenn, Adriana Lippy, and Leonidas Stamatatos. Diverse Recombinant HIV-1 Envs Fail to Activate B Cells Expressing the Germline B Cell Receptors of the Broadly Neutralizing Anti-HIV-1 Antibodies PG9 and 447-52D. J. Virol., 88(5):2645-2657, Mar 2014. PubMed ID: 24352455.
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McLellan2011
Jason S. McLellan, Marie Pancera, Chris Carrico, Jason Gorman, Jean-Philippe Julien, Reza Khayat, Robert Louder, Robert Pejchal, Mallika Sastry, Kaifan Dai, Sijy O'Dell, Nikita Patel, Syed Shahzad-ul-Hussan, Yongping Yang, Baoshan Zhang, Tongqing Zhou, Jiang Zhu, Jeffrey C. Boyington, Gwo-Yu Chuang, Devan Diwanji, Ivelin Georgiev, Young Do Kwon, Doyung Lee, Mark K. Louder, Stephanie Moquin, Stephen D. Schmidt, Zhi-Yong Yang, Mattia Bonsignori, John A. Crump, Saidi H. Kapiga, Noel E. Sam, Barton F. Haynes, Dennis R. Burton, Wayne C. Koff, Laura M. Walker, Sanjay Phogat, Richard Wyatt, Jared Orwenyo, Lai-Xi Wang, James Arthos, Carole A. Bewley, John R. Mascola, Gary J. Nabel, William R. Schief, Andrew B. Ward, Ian A. Wilson, and Peter D. Kwong. Structure of HIV-1 gp120 V1/V2 Domain with Broadly Neutralizing Antibody PG9. Nature, 480(7377):336-343, 15 Dec 2011. PubMed ID: 22113616.
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McLinden2013
Robert J. McLinden, Celia C. LaBranche, Agnès-Laurence Chenine, Victoria R. Polonis, Michael A. Eller, Lindsay Wieczorek, Christina Ochsenbauer, John C. Kappes, Stephen Perfetto, David C. Montefiori, Nelson L. Michael, and Jerome H. Kim. Detection of HIV-1 Neutralizing Antibodies in a Human CD4+/CXCR4+/CCR5+ T-Lymphoblastoid Cell Assay System. PLoS One, 8(11):e77756, 2013. PubMed ID: 24312168.
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Miglietta2014
Riccardo Miglietta, Claudia Pastori, Assunta Venuti, Christina Ochsenbauer, and Lucia Lopalco. Synergy in Monoclonal Antibody Neutralization of HIV-1 Pseudoviruses and Infectious Molecular Clones. J. Transl. Med., 12:346, 2014. PubMed ID: 25496375.
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Iliyana Mikell and Leonidas Stamatatos. Evolution of Cross-Neutralizing Antibody Specificities to the CD4-BS and the Carbohydrate Cloak of the HIV Env in an HIV-1-Infected Subject. PLoS One, 7(11):e49610, 2012. PubMed ID: 23152926.
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Mishra2020
Nitesh Mishra, Shaifali Sharma, Ayushman Dobhal, Sanjeev Kumar, Himanshi Chawla, Ravinder Singh, Bimal Kumar Das, Sushil Kumar Kabra, Rakesh Lodha, and Kalpana Luthra. A Rare Mutation in an Infant-Derived HIV-1 Envelope Glycoprotein Alters Interprotomer Stability and Susceptibility to Broadly Neutralizing Antibodies Targeting the Trimer Apex. J. Virol., 94(19), 15 Sep 2020. PubMed ID: 32669335.
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Mishra2020a
Nitesh Mishra, Shaifali Sharma, Ayushman Dobhal, Sanjeev Kumar, Himanshi Chawla, Ravinder Singh, Muzamil Ashraf Makhdoomi, Bimal Kumar Das, Rakesh Lodha, Sushil Kumar Kabra, and Kalpana Luthra. Broadly Neutralizing Plasma Antibodies Effective against Autologous Circulating Viruses in Infants with Multivariant HIV-1 Infection. Nat. Commun., 11(1):4409, 2 Sep 2020. PubMed ID: 32879304.
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Moore2011
Penny L. Moore, Elin S. Gray, Daniel Sheward, Maphuti Madiga, Nthabeleng Ranchobe, Zhong Lai, William J. Honnen, Molati Nonyane, Nancy Tumba, Tandile Hermanus, Sengeziwe Sibeko, Koleka Mlisana, Salim S. Abdool Karim, Carolyn Williamson, Abraham Pinter, Lynn Morris, and CAPRISA 002 Study. Potent and Broad Neutralization of HIV-1 Subtype C by Plasma Antibodies Targeting a Quaternary Epitope Including Residues in the V2 loop. J. Virol., 85(7):3128-3141, Apr 2011. PubMed ID: 21270156.
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Moore2012
Penny L. Moore, Elin S. Gray, C. Kurt Wibmer, Jinal N. Bhiman, Molati Nonyane, Daniel J. Sheward, Tandile Hermanus, Shringkhala Bajimaya, Nancy L. Tumba, Melissa-Rose Abrahams, Bronwen E. Lambson, Nthabeleng Ranchobe, Lihua Ping, Nobubelo Ngandu, Quarraisha Abdool Karim, Salim S. Abdool Karim, Ronald I. Swanstrom, Michael S. Seaman, Carolyn Williamson, and Lynn Morris. Evolution of an HIV Glycan-Dependent Broadly Neutralizing Antibody Epitope through Immune Escape. Nat. Med., 18(11):1688-1692, Nov 2012. PubMed ID: 23086475.
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Javier F. Morales, Bin Yu, Gerardo Perez, Kathryn A. Mesa, David L. Alexander, and Phillip W. Berman. Fragments of the V1/V2 Domain of HIV-1 Glycoprotein 120 Engineered for Improved Binding to the Broadly Neutralizing PG9 antibody. Mol. Immunol., 77:14-25, Sep 2016. PubMed ID: 27449907.
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Morgand2015
Marion Morgand, Mélanie Bouvin-Pley, Jean-Christophe Plantier, Alain Moreau, Elodie Alessandri, François Simon, Craig S. Pace, Marie Pancera, David D. Ho, Pascal Poignard, Pamela J. Bjorkman, Hugo Mouquet, Michel C. Nussenzweig, Peter D. Kwong, Daniel Baty, Patrick Chames, Martine Braibant, and Francis Barin. A V1V2 Neutralizing Epitope Is Conserved in Divergent Non-M Groups of HIV-1. J. Acquir. Immune Defic. Syndr., 21 Sep 2015. PubMed ID: 26413851.
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Mouquet2011
Hugo Mouquet, Florian Klein, Johannes F. Scheid, Malte Warncke, John Pietzsch, Thiago Y. K. Oliveira, Klara Velinzon, Michael S. Seaman, and Michel C. Nussenzweig. Memory B Cell Antibodies to HIV-1 gp140 Cloned from Individuals Infected with Clade A and B Viruses. PLoS One, 6(9):e24078, 2011. PubMed ID: 21931643.
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Mouquet2012a
Hugo Mouquet, Louise Scharf, Zelda Euler, Yan Liu, Caroline Eden, Johannes F. Scheid, Ariel Halper-Stromberg, Priyanthi N. P. Gnanapragasam, Daniel I. R. Spencer, Michael S. Seaman, Hanneke Schuitemaker, Ten Feizi, Michel C. Nussenzweig, and Pamela J. Bjorkman. Complex-Type N-Glycan Recognition by Potent Broadly Neutralizing HIV Antibodies. Proc. Natl. Acad. Sci. U.S.A, 109(47):E3268-E3277, 20 Nov 2012. PubMed ID: 23115339.
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Moyo2018
Thandeka Moyo, June Ereño-Orbea, Rajesh Abraham Jacob, Clara E. Pavillet, Samuel Mundia Kariuki, Emily N. Tangie, Jean-Philippe Julien, and Jeffrey R. Dorfman. Molecular Basis of Unusually High Neutralization Resistance in Tier 3 HIV-1 Strain 253-11. J. Virol., 92(14), 15 Jul 2018. PubMed ID: 29618644.
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Nie2020
Jianhui Nie, Weijin Huang, Qiang Liu, and Youchun Wang. HIV-1 Pseudoviruses Constructed in China Regulatory Laboratory. Emerg. Microbes Infect., 9(1):32-41, 2020. PubMed ID: 31859609.
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Nkolola2014
Joseph P. Nkolola, Christine A. Bricault, Ann Cheung, Jennifer Shields, James Perry, James M. Kovacs, Elena Giorgi, Margot van Winsen, Adrian Apetri, Els C. M. Brinkman-van der Linden, Bing Chen, Bette Korber, Michael S. Seaman, and Dan H. Barouch. Characterization and Immunogenicity of a Novel Mosaic M HIV-1 gp140 Trimer. J. Virol., 88(17):9538-9552, 1 Sep 2014. PubMed ID: 24965452.
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Nogal2020
Bartek Nogal, Laura E. McCoy, Marit J. van Gils, Christopher A. Cottrell, James E. Voss, Raiees Andrabi, Matthias Pauthner, Chi-Hui Liang, Terrence Messmer, Rebecca Nedellec, Mia Shin, Hannah L. Turner, Gabriel Ozorowski, Rogier W. Sanders, Dennis R. Burton, and Andrew B. Ward. HIV Envelope Trimer-Elicited Autologous Neutralizing Antibodies Bind a Region Overlapping the N332 Glycan Supersite. Sci. Adv., 6(23):eaba0512, Jun 2020. PubMed ID: 32548265.
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ORourke2012
Sara M. O'Rourke, Becky Schweighardt, Pham Phung, Kathryn A. Mesa, Aaron L. Vollrath, Gwen P. Tatsuno, Briana To, Faruk Sinangil, Kay Limoli, Terri Wrin, and Phillip W. Berman. Sequences in Glycoprotein gp41, the CD4 Binding Site, and the V2 Domain Regulate Sensitivity and Resistance of HIV-1 to Broadly Neutralizing Antibodies. J. Virol., 86(22):12105-12114, Nov 2012. PubMed ID: 22933284.
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Overbaugh2012
Julie Overbaugh and Lynn Morris. The Antibody Response against HIV-1. Cold Spring Harb. Perspect. Med., 2(1):a007039, Jan 2012. PubMed ID: 22315717.
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Pancera2010
Marie Pancera, Jason S. McLellan, Xueling Wu, Jiang Zhu, Anita Changela, Stephen D. Schmidt, Yongping Yang, Tongqing Zhou, Sanjay Phogat, John R. Mascola, and Peter D. Kwong. Crystal Structure of PG16 and Chimeric Dissection with Somatically Related PG9: Structure-Function Analysis of Two Quaternary-Specific Antibodies That Effectively Neutralize HIV-1. J. Virol., 84(16):8098-8110, Aug 2010. PubMed ID: 20538861.
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Pancera2013
Marie Pancera, Syed Shahzad-ul-Hussan, Nicole A. Doria-Rose, Jason S. McLellan, Robert T. Bailer, Kaifan Dai, Sandra Loesgen, Mark K. Louder, Ryan P. Staupe, Yongping Yang, Baoshan Zhang, Robert Parks, Joshua Eudailey, Krissey E. Lloyd, Julie Blinn, S. Munir Alam, Barton F. Haynes, Mohammed N. Amin, Lai-Xi Wang, Dennis R. Burton, Wayne C. Koff, Gary J. Nabel, John R. Mascola, Carole A. Bewley, and Peter D. Kwong. Structural Basis for Diverse N-Glycan Recognition by HIV-1-Neutralizing V1-V2-Directed Antibody PG16. Nat. Struct. Mol. Biol., 20(7):804-813, Jul 2013. PubMed ID: 23708607.
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Pantophlet2010
Ralph Pantophlet. Antibody Epitope Exposure and Neutralization of HIV-1. Curr. Pharm. Des., 16(33):3729-3743, 2010. PubMed ID: 21128886.
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Pegu2017
Amarendra Pegu, Ann J. Hessell, John R. Mascola, and Nancy L. Haigwood. Use of Broadly Neutralizing Antibodies for HIV-1 Prevention. Immunol. Rev., 275(1):296-312, Jan 2017. PubMed ID: 28133803.
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Pejchal2010
Robert Pejchal, Laura M. Walker, Robyn L. Stanfield, Sanjay K. Phogat, Wayne C. Koff, Pascal Poignard, Dennis R. Burton, and Ian A. Wilson. Structure and Function of Broadly Reactive Antibody PG16 Reveal an H3 Subdomain That Mediates Potent Neutralization of HIV-1. Proc. Natl. Acad. Sci. U.S.A., 107(25):11483-11488, 22 Jun 2010. PubMed ID: 20534513.
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Pejchal2011
Robert Pejchal, Katie J. Doores, Laura M. Walker, Reza Khayat, Po-Ssu Huang, Sheng-Kai Wang, Robyn L. Stanfield, Jean-Philippe Julien, Alejandra Ramos, Max Crispin, Rafael Depetris, Umesh Katpally, Andre Marozsan, Albert Cupo, Sebastien Maloveste, Yan Liu, Ryan McBride, Yukishige Ito, Rogier W. Sanders, Cassandra Ogohara, James C. Paulson, Ten Feizi, Christopher N. Scanlan, Chi-Huey Wong, John P. Moore, William C. Olson, Andrew B. Ward, Pascal Poignard, William R. Schief, Dennis R. Burton, and Ian A. Wilson. A Potent and Broad Neutralizing Antibody Recognizes and Penetrates the HIV Glycan Shield. Science, 334(6059):1097-1103, 25 Nov 2011. PubMed ID: 21998254.
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Pollara2013
Justin Pollara, Mattia Bonsignori, M. Anthony Moody, Marzena Pazgier, Barton F. Haynes, and Guido Ferrari. Epitope Specificity of Human Immunodeficiency Virus-1 Antibody Dependent Cellular Cytotoxicity (ADCC) Responses. Curr. HIV Res., 11(5):378-387, Jul 2013. PubMed ID: 24191939.
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Prevost2018
Jérémie Prévost, Jonathan Richard, Shilei Ding, Beatriz Pacheco, Roxanne Charlebois, Beatrice H Hahn, Daniel E Kaufmann, and Andrés Finzi. Envelope Glycoproteins Sampling States 2/3 Are Susceptible to ADCC by Sera from HIV-1-Infected Individuals. Virology, 515:38-45, Feb 2018. PubMed ID: 29248757.
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Provine2012
Nicholas M. Provine, Valerie Cortez, Vrasha Chohan, and Julie Overbaugh. The Neutralization Sensitivity of Viruses Representing Human Immunodeficiency Virus Type 1 Variants of Diverse Subtypes from Early in Infection Is Dependent on Producer Cell, as Well as Characteristics of the Specific Antibody and Envelope Variant. Virology, 427(1):25-33, 25 May 2012. PubMed ID: 22369748.
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Pugach2015
Pavel Pugach, Gabriel Ozorowski, Albert Cupo, Rajesh Ringe, Anila Yasmeen, Natalia de Val, Ronald Derking, Helen J. Kim, Jacob Korzun, Michael Golabek, Kevin de Los Reyes, Thomas J. Ketas, Jean-Philippe Julien, Dennis R. Burton, Ian A. Wilson, Rogier W. Sanders, P. J. Klasse, Andrew B. Ward, and John P. Moore. A Native-Like SOSIP.664 Trimer Based on an HIV-1 Subtype B env Gene. J. Virol., 89(6):3380-3395, Mar 2015. PubMed ID: 25589637.
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Qi2016
Yifei Qi, Sunhwan Jo, and Wonpil Im. Roles of Glycans in Interactions between gp120 and HIV Broadly Neutralizing Antibodies. Glycobiology, 26(3):251-260, Mar 2016. PubMed ID: 26537503.
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Rademeyer2016
Cecilia Rademeyer, Bette Korber, Michael S. Seaman, Elena E. Giorgi, Ruwayhida Thebus, Alexander Robles, Daniel J. Sheward, Kshitij Wagh, Jetta Garrity, Brittany R. Carey, Hongmei Gao, Kelli M. Greene, Haili Tang, Gama P. Bandawe, Jinny C. Marais, Thabo E. Diphoko, Peter Hraber, Nancy Tumba, Penny L. Moore, Glenda E. Gray, James Kublin, M. Juliana McElrath, Marion Vermeulen, Keren Middelkoop, Linda-Gail Bekker, Michael Hoelscher, Leonard Maboko, Joseph Makhema, Merlin L. Robb, Salim Abdool Karim, Quarraisha Abdool Karim, Jerome H. Kim, Beatrice H. Hahn, Feng Gao, Ronald Swanstrom, Lynn Morris, David C. Montefiori, and Carolyn Williamson. Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization. PLoS Pathog., 12(7):e1005742, Jul 2016. PubMed ID: 27434311.
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Ren2018
Yanqin Ren, Maria Korom, Ronald Truong, Dora Chan, Szu-Han Huang, Colin C. Kovacs, Erika Benko, Jeffrey T. Safrit, John Lee, Hermes Garbán, Richard Apps, Harris Goldstein, Rebecca M. Lynch, and R. Brad Jones. Susceptibility to Neutralization by Broadly Neutralizing Antibodies Generally Correlates with Infected Cell Binding for a Panel of Clade B HIV Reactivated from Latent Reservoirs. J. Virol., 92(23), 1 Dec 2018. PubMed ID: 30209173.
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Ringe2011
Rajesh Ringe, Deepak Sharma, Susan Zolla-Pazner, Sanjay Phogat, Arun Risbud, Madhuri Thakar, Ramesh Paranjape, and Jayanta Bhattacharya. A Single Amino Acid Substitution in the C4 Region in gp120 Confers Enhanced Neutralization of HIV-1 by Modulating CD4 Binding Sites and V3 Loop. Virology, 418(2):123-132, 30 Sep 2011. PubMed ID: 21851958.
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Ringe2012
Rajesh Ringe, Sanjay Phogat, and Jayanta Bhattacharya. Subtle Alteration of Residues Including N-Linked Glycans in V2 Loop Modulate HIV-1 Neutralization by PG9 and PG16 Monoclonal Antibodies. Virology, 426(1):34-41, 25 Apr 2012. PubMed ID: 22314018.
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Roark2021
Ryan S. Roark, Hui Li, Wilton B. Williams, Hema Chug, Rosemarie D. Mason, Jason Gorman, Shuyi Wang, Fang-Hua Lee, Juliette Rando, Mattia Bonsignori, Kwan-Ki Hwang, Kevin O. Saunders, Kevin Wiehe, M. Anthony Moody, Peter T. Hraber, Kshitij Wagh, Elena E. Giorgi, Ronnie M. Russell, Frederic Bibollet-Ruche, Weimin Liu, Jesse Connell, Andrew G. Smith, Julia DeVoto, Alexander I. Murphy, Jessica Smith, Wenge Ding, Chengyan Zhao, Neha Chohan, Maho Okumura, Christina Rosario, Yu Ding, Emily Lindemuth, Anya M. Bauer, Katharine J. Bar, David Ambrozak, Cara W. Chao, Gwo-Yu Chuang, Hui Geng, Bob C. Lin, Mark K. Louder, Richard Nguyen, Baoshan Zhang, Mark G. Lewis, Donald D. Raymond, Nicole A. Doria-Rose, Chaim A. Schramm, Daniel C. Douek, Mario Roederer, Thomas B. Kepler, Garnett Kelsoe, John R. Mascola, Peter D. Kwong, Bette T. Korber, Stephen C. Harrison, Barton F. Haynes, Beatrice H. Hahn, and George M. Shaw. Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth. Science, 371(6525), 8 Jan 2021. PubMed ID: 33214287.
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Rolland2012
Morgane Rolland, Paul T. Edlefsen, Brendan B. Larsen, Sodsai Tovanabutra, Eric Sanders-Buell, Tomer Hertz, Allan C. deCamp, Chris Carrico, Sergey Menis, Craig A. Magaret, Hasan Ahmed, Michal Juraska, Lennie Chen, Philip Konopa, Snehal Nariya, Julia N. Stoddard, Kim Wong, Hong Zhao, Wenjie Deng, Brandon S. Maust, Meera Bose, Shana Howell, Adam Bates, Michelle Lazzaro, Annemarie O'Sullivan, Esther Lei, Andrea Bradfield, Grace Ibitamuno, Vatcharain Assawadarachai, Robert J. O'Connell, Mark S. deSouza, Sorachai Nitayaphan, Supachai Rerks-Ngarm, Merlin L. Robb, Jason S. McLellan, Ivelin Georgiev, Peter D. Kwong, Jonathan M. Carlson, Nelson L. Michael, William R. Schief, Peter B. Gilbert, James I. Mullins, and Jerome H. Kim. Increased HIV-1 Vaccine Efficacy against Viruses with Genetic Signatures in Env V2. Nature, 490(7420):417-420, 18 Oct 2012. PubMed ID: 22960785.
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Rosenberg2015
Yvonne Rosenberg, Markus Sack, David Montefiori, Celia Labranche, Mark Lewis, Lori Urban, Lingjun Mao, Rainer Fischer, and Xiaoming Jiang. Pharmacokinetics and Immunogenicity of Broadly Neutralizing HIV Monoclonal Antibodies in Macaques. PLoS One, 10(3):e0120451, 25 Mar 2015. PubMed ID: 25807114.
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Rudometova2022
N. B. Rudometova, N. S. Shcherbakova, D. N. Shcherbakov, O. S. Taranov, B. N. Zaitsev, and L. I. Karpenko. Construction and Characterization of HIV-1 env-Pseudoviruses of the Recombinant Form CRF63_02A and Subtype A6. Bull Exp Biol Med, 172(6):729-733 doi, Apr 2022. PubMed ID: 35501651
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Rusert2016
Peter Rusert, Roger D. Kouyos, Claus Kadelka, Hanna Ebner, Merle Schanz, Michael Huber, Dominique L. Braun, Nathanael Hozé, Alexandra Scherrer, Carsten Magnus, Jacqueline Weber, Therese Uhr, Valentina Cippa, Christian W. Thorball, Herbert Kuster, Matthias Cavassini, Enos Bernasconi, Matthias Hoffmann, Alexandra Calmy, Manuel Battegay, Andri Rauch, Sabine Yerly, Vincent Aubert, Thomas Klimkait, Jürg Böni, Jacques Fellay, Roland R. Regoes, Huldrych F. Günthard, Alexandra Trkola, and Swiss HIV Cohort Study. Determinants of HIV-1 Broadly Neutralizing Antibody Induction. Nat. Med., 22(11):1260-1267, Nov 2016. PubMed ID: 27668936.
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Saha2012
Piyali Saha, Sanchari Bhattacharyya, Sannula Kesavardhana, Edward Roshan Miranda, P. Shaik Syed Ali, Deepak Sharma, and Raghavan Varadarajan. Designed Cyclic Permutants of HIV-1 gp120: Implications for Envelope Trimer Structure and Immunogen Design. Biochemistry, 51(9):1836-1847, 6 Mar 2012. PubMed ID: 22329717.
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Sajadi2012
Mohammad M. Sajadi, George K. Lewis, Michael S. Seaman, Yongjun Guan, Robert R. Redfield, and Anthony L. DeVico. Signature Biochemical Properties of Broadly Cross-Reactive HIV-1 Neutralizing Antibodies in Human Plasma. J. Virol., 86(9):5014-5025, May 2012. PubMed ID: 22379105.
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Sanchez-Merino2016
V. Sanchez-Merino, A. Fabra-Garcia, N. Gonzalez, D. Nicolas, A. Merino-Mansilla, C. Manzardo, J. Ambrosioni, A. Schultz, A. Meyerhans, J. R. Mascola, J. M. Gatell, J. Alcami, J. M. Miro, and E. Yuste. Detection of Broadly Neutralizing Activity within the First Months of HIV-1 Infection. J. Virol., 90(11):5231-5245, 1 Jun 2016. PubMed ID: 26984721.
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Sanders2013
Rogier W. Sanders, Ronald Derking, Albert Cupo, Jean-Philippe Julien, Anila Yasmeen, Natalia de Val, Helen J. Kim, Claudia Blattner, Alba Torrents de la Peña, Jacob Korzun, Michael Golabek, Kevin de los Reyes, Thomas J. Ketas, Marit J. van Gils, C. Richter King, Ian A. Wilson, Andrew B. Ward, P. J. Klasse, and John P. Moore. A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but not Non-Neutralizing Antibodies. PLoS Pathog., 9(9):e1003618, Sep 2013. PubMed ID: 24068931.
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Sather2014
D. Noah Sather, Sara Carbonetti, Delphine C. Malherbe, Franco Pissani, Andrew B. Stuart, Ann J. Hessell, Mathew D. Gray, Iliyana Mikell, Spyros A. Kalams, Nancy L. Haigwood, and Leonidas Stamatatos. Emergence of Broadly Neutralizing Antibodies and Viral Coevolution in Two Subjects during the Early Stages of Infection with Human Immunodeficiency Virus Type 1. J. Virol., 88(22):12968-12981, Nov 2014. PubMed ID: 25122781.
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Quentin J. Sattentau and Andrew J. McMichael. New Templates for HIV-1 Antibody-Based Vaccine Design. F1000 Biol. Rep., 2:60, 2010. PubMed ID: 21173880.
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Schorcht2020
Anna Schorcht, Tom L. G. M. van den Kerkhof, Christopher A. Cottrell, Joel D. Allen, Jonathan L. Torres, Anna-Janina Behrens, Edith E. Schermer, Judith A. Burger, Steven W. de Taeye, Alba Torrents de la Peña, Ilja Bontjer, Stephanie Gumbs, Gabriel Ozorowski, Celia C. LaBranche, Natalia de Val, Anila Yasmeen, Per Johan Klasse, David C. Montefiori, John P. Moore, Hanneke Schuitemaker, Max Crispin, Marit J. van Gils, Andrew B. Ward, and Rogier W. Sanders. Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers. J. Virol., 94(24), 23 Nov 2020. PubMed ID: 32999024.
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Scott2015
Yanille M. Scott, Seo Young Park, and Charlene S. Dezzutti. Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo. Antimicrob. Agents Chemother., 60(2):904-912, Feb 2016. PubMed ID: 26596954.
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Shang2011
Hong Shang, Xiaoxu Han, Xuanling Shi, Teng Zuo, Mark Goldin, Dan Chen, Bing Han, Wei Sun, Hao Wu, Xinquan Wang, and Linqi Zhang. Genetic and Neutralization Sensitivity of Diverse HIV-1 env Clones from Chronically Infected Patients in China. J. Biol. Chem., 286(16):14531-14541, 22 Apr 2011. PubMed ID: 21325278.
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Shivatare2013
Sachin S. Shivatare, Shih-Huang Chang, Tsung-I Tsai, Chien-Tai Ren, Hong-Yang Chuang, Li Hsu, Chih-Wei Lin, Shiou-Ting Li, Chung-Yi Wu, and Chi-Huey Wong. Efficient Convergent Synthesis of Bi-, Tri-, and Tetra-Antennary Complex Type N-Glycans and Their HIV-1 Antigenicity. J. Am. Chem. Soc., 135(41):15382-15391, 16 Oct 2013. PubMed ID: 24032650.
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Sliepen2015
Kwinten Sliepen, Max Medina-Ramirez, Anila Yasmeen, John P. Moore, Per Johan Klasse, and Rogier W. Sanders. Binding of Inferred Germline Precursors of Broadly Neutralizing HIV-1 Antibodies to Native-Like Envelope Trimers. Virology, 486:116-120, Dec 2015. PubMed ID: 26433050.
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Sliepen2019
Kwinten Sliepen, Byung Woo Han, Ilja Bontjer, Petra Mooij, Fernando Garces, Anna-Janina Behrens, Kimmo Rantalainen, Sonu Kumar, Anita Sarkar, Philip J. M. Brouwer, Yuanzi Hua, Monica Tolazzi, Edith Schermer, Jonathan L. Torres, Gabriel Ozorowski, Patricia van der Woude, Alba Torrents de la Pena, Marielle J. van Breemen, Juan Miguel Camacho-Sanchez, Judith A. Burger, Max Medina-Ramirez, Nuria Gonzalez, Jose Alcami, Celia LaBranche, Gabriella Scarlatti, Marit J. van Gils, Max Crispin, David C. Montefiori, Andrew B. Ward, Gerrit Koopman, John P. Moore, Robin J. Shattock, Willy M. Bogers, Ian A. Wilson, and Rogier W. Sanders. Structure and immunogenicity of a stabilized HIV-1 envelope trimer based on a group-M consensus sequence. Nat Commun, 10(1):2355 doi, May 2019. PubMed ID: 31142746
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Stefic2019
Karl Stefic, Mélanie Bouvin-Pley, Asma Essat, Clara Visdeloup, Alain Moreau, Cécile Goujard, Marie-Laure Chaix, Martine Braibant, Laurence Meyer, and Francis Barin. Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02\_AG Viruses with a Focus on Evolution over Time. J. Virol., 93(2), 15 Jan 2019. PubMed ID: 30404804.
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Stewart-Jones2016
Guillaume B. E. Stewart-Jones, Cinque Soto, Thomas Lemmin, Gwo-Yu Chuang, Aliaksandr Druz, Rui Kong, Paul V. Thomas, Kshitij Wagh, Tongqing Zhou, Anna-Janina Behrens, Tatsiana Bylund, Chang W. Choi, Jack R. Davison, Ivelin S. Georgiev, M. Gordon Joyce, Young Do Kwon, Marie Pancera, Justin Taft, Yongping Yang, Baoshan Zhang, Sachin S. Shivatare, Vidya S. Shivatare, Chang-Chun D. Lee, Chung-Yi Wu, Carole A. Bewley, Dennis R. Burton, Wayne C. Koff, Mark Connors, Max Crispin, Ulrich Baxa, Bette T. Korber, Chi-Huey Wong, John R. Mascola, and Peter D. Kwong. Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G. Cell, 165(4):813-826, 5 May 2016. PubMed ID: 27114034.
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Thenin2012
Suzie Thenin, Tanawan Samleerat, Elsa Tavernier, Nicole Ngo-Giang-Huong, Gonzague Jourdain, Marc Lallemant, Francis Barin, and Martine Braibant. Envelope Glycoproteins of Human Immunodeficiency Virus Type 1 Variants Issued from Mother-Infant Pairs Display a Wide Spectrum of Biological Properties. Virology, 426(1):12-21, 25 Apr 2012. PubMed ID: 22310702.
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Thenin2012a
Suzie Thenin, Emmanuelle Roch, Tanawan Samleerat, Thierry Moreau, Antoine Chaillon, Alain Moreau, Francis Barin, and Martine Braibant. Naturally Occurring Substitutions of Conserved Residues in Human Immunodeficiency Virus Type 1 Variants of Different Clades Are Involved in PG9 and PG16 Resistance to Neutralization. J. Gen. Virol., 93(7):1495-1505, Jul 2012. PubMed ID: 22492917.
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Tomaras2010
Georgia D. Tomaras and Barton F. Haynes. Strategies for Eliciting HIV-1 Inhibitory Antibodies. Curr. Opin. HIV AIDS, 5(5):421-427, Sep 2010. PubMed ID: 20978384.
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Tomaras2011
Georgia D. Tomaras, James M. Binley, Elin S. Gray, Emma T. Crooks, Keiko Osawa, Penny L. Moore, Nancy Tumba, Tommy Tong, Xiaoying Shen, Nicole L. Yates, Julie Decker, Constantinos Kurt Wibmer, Feng Gao, S. Munir Alam, Philippa Easterbrook, Salim Abdool Karim, Gift Kamanga, John A. Crump, Myron Cohen, George M. Shaw, John R. Mascola, Barton F. Haynes, David C. Montefiori, and Lynn Morris. Polyclonal B Cell Responses to Conserved Neutralization Epitopes in a Subset of HIV-1-Infected Individuals. J. Virol., 85(21):11502-11519, Nov 2011. PubMed ID: 21849452.
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Tong2012
Tommy Tong, Ema T. Crooks, Keiko Osawa, and James M. Binley. HIV-1 Virus-Like Particles Bearing Pure Env Trimers Expose Neutralizing Epitopes but Occlude Nonneutralizing Epitopes. J. Virol., 86(7):3574-3587, Apr 2012. PubMed ID: 22301141.
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Upadhyay2014
Chitra Upadhyay, Luzia M. Mayr, Jing Zhang, Rajnish Kumar, Miroslaw K. Gorny, Arthur Nádas, Susan Zolla-Pazner, and Catarina E. Hioe. Distinct Mechanisms Regulate Exposure of Neutralizing Epitopes in the V2 and V3 Loops of HIV-1 Envelope. J. Virol., 88(21):12853-12865, Nov 2014. PubMed ID: 25165106.
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vandenKerkhof2013
Tom L. G. M. van den Kerkhof, K. Anton Feenstra, Zelda Euler, Marit J. van Gils, Linda W. E. Rijsdijk, Brigitte D. Boeser-Nunnink, Jaap Heringa, Hanneke Schuitemaker, and Rogier W. Sanders. HIV-1 Envelope Glycoprotein Signatures That Correlate with the Development of Cross-Reactive Neutralizing Activity. Retrovirology, 10:102, 23 Sep 2013. PubMed ID: 24059682.
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Tom L. G. M. van den Kerkhof, Steven W. de Taeye, Brigitte D. Boeser-Nunnink, Dennis R. Burton, Neeltje A. Kootstra, Hanneke Schuitemaker, Rogier W. Sanders, and Marit J. van Gils. HIV-1 escapes from N332-directed antibody neutralization in an elite neutralizer by envelope glycoprotein elongation and introduction of unusual disulfide bonds. Retrovirology, 13(1):48, 7 Jul 2016. PubMed ID: 27388013.
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Veillette2014
Maxime Veillette, Anik Désormeaux, Halima Medjahed, Nour-Elhouda Gharsallah, Mathieu Coutu, Joshua Baalwa, Yongjun Guan, George Lewis, Guido Ferrari, Beatrice H. Hahn, Barton F. Haynes, James E. Robinson, Daniel E. Kaufmann, Mattia Bonsignori, Joseph Sodroski, and Andres Finzi. Interaction with Cellular CD4 Exposes HIV-1 Envelope Epitopes Targeted by Antibody-Dependent Cell-Mediated Cytotoxicity. J. Virol., 88(5):2633-2644, Mar 2014. PubMed ID: 24352444.
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vonBredow2016
Benjamin von Bredow, Juan F. Arias, Lisa N. Heyer, Brian Moldt, Khoa Le, James E. Robinson, Susan Zolla-Pazner, Dennis R. Burton, and David T. Evans. Comparison of Antibody-Dependent Cell-Mediated Cytotoxicity and Virus Neutralization by HIV-1 Env-Specific Monoclonal Antibodies. J. Virol., 90(13):6127-6139, 1 Jul 2016. PubMed ID: 27122574.
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Voss2017
James E. Voss, Raiees Andrabi, Laura E. McCoy, Natalia de Val, Roberta P. Fuller, Terrence Messmer, Ching-Yao Su, Devin Sok, Salar N. Khan, Fernando Garces, Laura K. Pritchard, Richard T. Wyatt, Andrew B. Ward, Max Crispin, Ian A. Wilson, and Dennis R. Burton. Elicitation of Neutralizing Antibodies Targeting the V2 Apex of the HIV Envelope Trimer in a Wild-Type Animal Model. Cell Rep., 21(1):222-235, 3 Oct 2017. PubMed ID: 28978475.
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Voss2019
James E. Voss, Alicia Gonzalez-Martin, Raiees Andrabi, Roberta P. Fuller, Ben Murrell, Laura E. McCoy, Katelyn Porter, Deli Huang, Wenjuan Li, Devin Sok, Khoa Le, Bryan Briney, Morgan Chateau, Geoffrey Rogers, Lars Hangartner, Ann J. Feeney, David Nemazee, Paula Cannon, and Dennis R. Burton. Reprogramming the Antigen Specificity of B Cells Using Genome-Editing Technologies. eLife, 8, 17 Jan 2019. PubMed ID: 30648968.
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Wagh2016
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Displaying record number 2163
Download this epitope
record as JSON.
MAb ID |
VRC01 (VRC01d45, VRC-HIVMAB060-00-AB) |
HXB2 Location |
Env |
Env Epitope Map
|
Author Location |
gp120 |
Epitope |
(Discontinuous epitope)
|
Subtype |
B |
Ab Type |
gp120 CD4bs |
Neutralizing |
tier 2 View neutralization details |
Contacts and Features |
View contacts and features |
Species
(Isotype)
|
human(IgG1) |
Patient |
NIH45 |
Immunogen |
HIV-1 infection |
Keywords |
acute/early infection, adjuvant comparison, anti-idiotype, antibody binding site, antibody gene transfer, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autoantibody or autoimmunity, autologous responses, binding affinity, bispecific/trispecific, broad neutralizer, CD4+ CTL, chimeric antibody, co-receptor, complement, computational prediction, contact residues, dynamics, early treatment, effector function, elite controllers and/or long-term non-progressors, enhancing activity, escape, genital and mucosal immunity, germline, glycosylation, HAART, ART, HIV reservoir/latency/provirus, HIV-2, immunoprophylaxis, immunotherapy, junction or fusion peptide, kinetics, memory cells, mimics, mother-to-infant transmission, mutation acquisition, neutralization, novel epitope, polyclonal antibodies, rate of progression, responses in children, review, SIV, structure, subtype comparisons, therapeutic vaccine, transmission pair, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity, viral fitness and/or reversion |
Notes
Showing 280 of
280 notes.
-
VRC01: N6/PGDM1400-10E8v4, a trispecific bnAb with variable domains from 3 different Abs (CD4bs-targeting N6 on a monospecific Ab arm, and V2-glycan-targeting PGDM1400 plus MPER-targeting 10E8v4 on a bispecific arm) demonstrated potent, yet transient, in vivo anti-viral activity in 6 SHIVBG505-infected naive Indian rhesus macaques. VRC01 demonstrated ADCC, ADCP, and ADCML Fc-mediated effector functions.
Pegu2022
(effector function)
-
VRC01: Eighty clusters of overlapping epitopes that could bind to MHC Class II HLA-DR1*01:01 (DR1) allele were identified by LC-MS/MS using a cell-free processing system that incorporated soluble DR1, HLA-DM (DM), cathepsins, and full-length protein antigens (Gag, Pol, Env, Vif, Tat, Rev, and Nef). Sixteen of Env CD4+ T cell epitopes identified in this study, which were primarily located in the vicinity of the gp120/gp41 interface or the CD4bs, were assessed for overlap with bnAb binding footprints. 5/16 overlapped with the binding footprint of CD4bs-targeting bnAb VRC01: EEE267-283 (EEEVMIRSENITNNAKN), EQF351-371 (EQFGNNKTIIFKQSSGGDPEIV), SDN274-287 (SDNFTNNAKTIIVQ), ETF466-476 (ETFRPGGGDMR) and EEF91-103 (EEFNMWKNNMVEQ). The first 2 were identified as glycosylated forms, while the latter 2 were identified as unglycosylated forms, and SDN274-287 was identified with both glycosylated and unglycosylated forms.
Sengupta2023
(antibody binding site)
-
VRC01: This article reviews how B cell receptor sequence analyses and repertoires can be used in vaccine stratagem. Passive immunization trials with VRC01 are underway in humans as it has proven to be a bnAb suppressing viremia and viral rebound. Overall, multiple immunogens and their interactions driving bnAb development to generate Abs with special genetic characteristics of V gene restriction, long CDRH3 and high load SHM are the current effective strategy being used.
Kreer2020
(antibody generation, neutralization, therapeutic vaccine, review, antibody sequence)
-
VRC01: This preview summarizes the findings of Doud2017, Dingens2017, and Dingens2019 where all possible point mutation escapes from binding nAbs were mapped using a screen of single amino acid changes of soluble Env ectodomain that were then grown and exposed to bnAbs. A loss of interaction/binding to the bnAb suggested neutralization resistant Env and these were deep sequenced, giving an atlas of escape pathways the virus might take. Escape mutants were found to mostly overlap with the 5 structural epitopes (antigen binding regions) of Env even though many of them are not reported in nature. Two additional sets of mutations were found in (1) contact residues that do not affect neutralization and (2) residues outside the 5 structural epitopes. These studies will provide a third characteristic to add to successful bnAb generation besides breadth and potency - "non-susceptibility to escape". Combination therapy trials like those of VRC01 and 3BNC117, both CD4bs bnAbs, would also benefit from an understanding of their antigenic escape profile.
Ward2019
(review)
-
VRC01: The study describes the generation, crystal structure, and immunogenic properties of a native-like Env SOSIP trimer based on a group M consensus (ConM) sequence. A crystal structure of ConM SOSIP.v7 trimer together with nAbs PGT124 and 35O22 revealed that ConM SOSIP.v7 is structurally similar to other Env trimers. In rabbits, the ConM SOSIP trimer induced serum nAbs that neutralized the autologous Tier 1A virus (ConM from 2004) and a related Tier 1B ConS virus (ConM from 2001). These responses target the trimer apex and were enhanced when the trimers were presented on ferritin nanoparticles. The neutralization of ConM and ConS pseudoviruses was tested against a large panel of nAbs and non-nAbs (2219, 2557, 3074, 3869, 447-52D, 830A, 654-30D, 1008-30D, 1570D, 729-30D, F105, 181D, 246D, 50-69D, sCD4, VRC01, 3BNC117, CH31, PG9, PG16, CH01, PGDM1400, PGT128, PGT121, 10-1074, PGT151, VRC43.01, 2G12, DH511.2_K3, 10E8, 2F5, 4E10); most nAbs were able to neutralize these pseudoviruses. Soluble ConM trimers were able to weakly activate B cells expressing PGT121 and PG16 BCRs but were inactive against those expressing VRC01 and PGT145. In contrast, at the same molar amount of trimers, the ConM SOSIP.v7-ferritin nanoparticles activated all 4 B cells efficiently. Binding of bnAbs 2G12 and PGT145 and non-nAbs F105 and 19b to ConM SOSIP.v7 trimer and SOSIP showed that the ferritin-bound trimer bound more avidly than the soluble trimer. This study shows that native-like HIV-1 Env trimers can be generated from consensus sequences, and such immunogens might be suitable vaccine components to prime and/or boost desirable nAb responses.
Sliepen2019
(neutralization, vaccine antigen design)
-
VRC01: Following the VRC018 clinical trial of the BG505 DS-SOSIP immunogen, donor N751 showed the highest BG505-reactive ELISA responses. B cells from this donor were sorted for binding to a novel BG505 trimer construct (BG505 glycan base); 8 clones were identified that bound to glycan-base BG505, and 2 were selected for characterization (2C06 and 2C09). The epitopes of 2C06.01 and 2C09.01 were similar to each other, and have substantial overlap with the epitope of VRC34.01, and lower overlap with two other FP-targeting mAbs, PGT151 and ACS202. Binding of mAbs to BG505 DS-SOSIP was compared with binding to the glycan base construct; some mAbs bound to both BG505 DS-SOSIP and glycan base (PGT145, VRC26.25, VRC01, PGT151, VRC34.01, and 2G12), some bound to neither (PG05, 447-52D, and 2557), and 4 base-binding mAbs bound to BG505 DS-SOSIP, but not to BG505 glycan base (1E6, 5H3, 3H2, and 9B9).
Wang2023
(binding affinity)
-
VRC01: A SHIV carrying a highly neutralization-sensitive Env (SHIVCNE40) was passaged in macaques. SHIVCNE40 developed enhanced replication kinetics associated with neutralization resistance against autologous serum, CD4-Ig, and several nAbs (17b, 3BNC117, N6, PGT145, PGT121, PGT128, 35O22, 2F5, 10E8). A gp41 substitution, E658K, was the major determinant for this resistance. However, this mutation didn’t disrupt the binding of SHIVCNE40 with assayed nAbs (17b, N6, VRC01, b12, PGT145, 10-1074, 35O22). Structural modeling and functional verification indicate that the substitution disrupts an intermolecular salt bridge with the neighboring protomer, particularly K601, thereby promoting fusion and facilitating immune evasion. This effect is applicable across many HIV-1 viruses of diverse subtypes. These results highlight the critical role of gp41 in shaping the neutralization profile and conformation of Env during viral adaptation. The unique intermolecular salt bridge could potentially be utilized for rational vaccine design involving more stable HIV-1 Env trimers.
Wang2019
(mutation acquisition, neutralization, structure)
-
VRC01: A panel of 30 contemporary subtype B pseudoviruses (PSVs) was generated. Neutralization sensitivities of these PSVs were compared with subtype B strains from earlier in the pandemic using 31 nAbs (PG9, PG16, PGT145, PGDM1400, CH02, CH03, CH04, 830A, PGT121, PGT126, PGT128, PGT130, 10-1074, 2192, 2219, 3074, 3869, 447-52D, b12, NIH45-46, VRC01, VRC03, 3BNC117, HJ16, sCD4, 10E8, 4E10, 2F5, 7H6, 2G12, 35O22). A significant reduction in Env neutralization sensitivity was observed for 27 out of 31 nAbs for the contemporary, as compared to earlier-decade subtype B PSVs. A decline in neutralization sensitivity was observed across all Env domains; the nAbs that were most potent early in the pandemic suffered the greatest decline in potency over time. A metaanalysis demonstrated this trend across multiple subtypes. As HIV-1 Env diversification continues, changes in Env antigenicity and neutralization sensitivity should continue to be evaluated to inform the development of improved vaccine and antibody products to prevent and treat HIV-1.
Wieczorek2023
(neutralization, viral fitness and/or reversion)
-
VRC01: Pseudoviruses were made from 13 env sequences of subtypes A6 and CRF63_02A6, based on genetic variants of HIV-1 circulating in the Siberian Federal District. Neutralization of these viruses was tested for 8 bnAbs. Most of the pseudoviruses were sensitive to neutralization by VRC01, PGT126, and 10E8, moderately sensitive to PG9 and 4E10, and resistant to 2G12, PG16, and 2F5. All obtained variants of pseudoviruses were CCR5-tropic.
Rudometova2022
(co-receptor, neutralization, subtype comparisons)
-
VRC01:This study identified a B cell lineage of bNAbs in an HIV-1 elite post-treatment controller (ePTC; donor: PTC-005002). Circulating viruses in PTC escaped bNAb pressure but remained sensitive to autologous neutralization by other Ab populations. VRC01 was used as a reference control IgG. Neutralizing activity of EPTC112 was evaluated in the presence and absence of VRC01.
Molinos-Albert2023
(neutralization, binding affinity)
-
VRC01: A panel of 58 mAbs was cloned from a rhesus macaque immunized with envelope glycoprotein immunogens developed from HIV-1 clade B-infected human donor VC10014. Neutralizing mAbs predominantly targeted linear epitopes in the V3 region in the cradle orientation (V3C), with others targeting the V3 ladle orientation (V3L), the CD4 binding site, C1, C4, or gp41. Nonneutralizing mAbs bound C1, C5, or undetermined gp120 conformational epitopes. Neutralization potency strongly correlated with the magnitude of binding to infected primary macaque splenocytes and to the level of ADCC, but did not correlate with ADCP. MAbs were traced to 23 of 72 functional IgHV germline alleles. Neutralizing V3C mAbs displayed minimal nucleotide SHM in the H chain V region (3.77%), indicating that relatively little affinity maturation was needed to achieve in-clade neutralization breadth. This study underscores the polyfunctional nature of vaccine-elicited tier 2-neutralizing V3 Abs and demonstrates partial reproduction of a human donor’s Ab response through nonhuman primate vaccination. Several previously-isolated mAbs were used in binding assays: b12, VRC01, N6, 3BNC117, 2558, 2219, 1006-15D, 447-52D, 10-1074, 830A, 2F5, F240, PGDM1400, 2219.
Spencer2021
(vaccine antigen design, binding affinity)
-
VRC01: This study analyzed Env sequences of early HIV-1 clonal variants from 31 individuals from the Amsterdam Cohort Studies with diverse levels of heterologous neutralization at 2-4 years post-seroconversion. A number of Env signatures coincided with neutralization development. These included a statistically shorter variable region 1 and a lower probability of glycosylation. Induction of neutralization was associated with a lower probability of glycosylation at position 332, which is involved in the epitopes of many bnAbs. 2G12 and PGT126 were tested for their ability to block infectivity by patient viruses with predicted glycosylation at N332; the NLS glycosylation motif was associated with resistance to these mAbs more often than the NIS glycosylation motif. Sequence Harmony software identified amino acid changes associated with the development of heterologous neutralization. These residues mapped to various Env subdomains, but in particular to the first and fourth variable region, as well as the underlying α2 helix of the third constant region. These findings imply that the development of heterologous neutralization might depend on specific characteristics of early Env. Env signatures that correlate with the induction of neutralization might be relevant for the design of effective HIV-1 vaccines. Primary virus isolates from 21 of the patients were assayed for neutralization by 11 well-known nAbs (b12, VRC01, 447-52D, 2G12, PGT121, PGT126, PG9, PG16, PGT145, 2F5, 4E10).
vandenKerkhof2013
(glycosylation, neutralization, vaccine antigen design, polyclonal antibodies)
-
VRC01: The polyclonal response of human subjects VC20013 and VC10014 demonstrated increasing neutralization breadth against a panel of HIV-1 isolates over time. Full-length functional env genes were cloned longitudinally from these subjects from months after infection through 2.6 to 5.8 years of infection. Motifs associated with the development of breadth in published, cross-sectional studies were found in the viral sequences of both subjects. To test the immunogenicity of envelope vaccines derived from time points obtained during and after broadening of neutralization activity within these subjects, rabbits were coimmunized 4 times with selected multiple gp160 DNAs and gp140-trimeric envelope proteins. In an assay of rabbit polyclonal responses, the most rapid and persistent neutralization of multiclade tier 1 viruses was elicited by envelopes that were circulating in plasma at time points prior to the development of 50% neutralization breadth in both human subjects. The breadth elicited in rabbits was not improved by exposure to later envelope variants. Env immunogen sequences were tested for binding to a panel of well studied mAbs of various binding types (VRC01, HJ16, b12, b6, PG9, PGT121, 2G12, 2F5, F240); all gp140s bound to weak or non-neutralizing antibodies b6 and F240. MAb b6 also bound BG505 SOSIP, while F240 did not, suggesting that cluster I gp41 epitopes, which become exposed during gp120 shedding, are more easily accessed on these trimers than on BG505-SOSIP. These data have implications for vaccine development in describing a target time point to identify optimal env immunogens.
Malherbe2014
(vaccine antigen design, vaccine-induced immune responses, binding affinity, polyclonal antibodies)
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VRC01: Two conserved tyrosine (Y) residues within the V2 loop of gp120, Y173 and Y177, were mutated individually or in combination, to either phenylalanine (F) or alanine (A) in several strains of diverse subtypes. In general, these mutations increased neutralization sensitivity, with a greater impact of Y177 over Y173 single mutations, of double over single mutations, and of A over F substitutions. The Y173A Y177A double mutation in HIV-1 BaL increased sensitivity to most of the weakly neutralizing MAbs tested (2158, 447-D, 268-D, B4e8, D19, 17b, 48d, 412d) and even rendered the virus sensitive to non-neutralizing antibodies against the CD4 binding site (F105, 654-30D, and b13). In the case of V2 mAb 697-30D, residue Y173 is part of its epitope, and thus abrogates its binding and has no effect on neutralization; the Y177A mutant alone did increase neutralization sensitivity to this mAb. When the double mutant was tested against bnAbs, there was a large decrease in neutralization sensitivity compared to WT for many bnAbs that target V1, V2, or V3 (PG9, PG16, VRC26.08, VRC38, PGT121, PGT122, PGT123, PGT126, PGT128, PGT130, PGT135, VRC24, CH103). The double mutation had lesser or no effect on neutralization by one V3 bnAb (2G12) and by most bnAbs targeting the CD4 binding site (VRC01, VRC07, VRC03, VRC-PG04, VRC-CH31, 12A12, 3BNC117, N6), the gp120-gp41 interface (35O22, PGT151), or the MPER (2F5, 4E10, 10E8).
Guzzo2018
(antibody binding site, neutralization)
-
VRC01: This study explored the basis of the neutralization resistance of tier 3 virus 253-11 (subtype CRF02_AG). Virus 253-11 was resistant to neutralization by 17b, b12, VRC03, F105, SCD4, CH12, Z13e1, PG16, PGT145, 2G12, PGT121, PGT126, PGT128, PGT130, 39F, F240, and 35O22; the virus was sensitive to 3BNC117, NIH45-46G54W, VRC01, 10E8, 2F5, 4E10, PG9, VRC26.26, 10-1074, and PGT151. Virus 253-11 was strikingly resistant to most tested antibodies that target V3/glycans, despite possessing key potential N-linked glycosylation sites, especially N301 and N332, needed for the recognition of this class of antibodies. The resistance of 253-11 was not associated with an unusually long V1/V2 loop, nor with polymorphisms in the V3 loop and N-linked glycosylation sites. The 253-11 MPER was rarely recognized by sera, but was more often recognized in a chimera consisting of a HIV-2 backbone with the 253-11 MPER, suggesting steric or kinetic hindrance of the MPER. Mutations in the 253-11 MPER previously reported to increase the lifetime of the prefusion Env conformation (Y681H, L669S), decreased the resistance of 253-11 to several mAbs, presumably destabilizing its otherwise stable, closed trimer structure. A crystal structure of a recombinant 253-11 SOSIP trimer revealed that the heptad repeat helices in gp41 are drawn in close proximity to the trimer axis and that gp120 protomers also showed a relatively compact form around the trimer axis.
Moyo2018
(neutralization, structure)
-
VRC01: This study assessed the ability of single bNAbs and triple bNAb combinations to mediate polyfunctional antiviral activity against a panel of cross-clade simian-human immunodeficiency viruses (SHIVs), which are commonly used as tools for validation of therapeutic strategies in nonhuman primate models. Most bnAbs assayed were capable of mediating both neutralizing and nonneutralizing effector functions (ADCC and ADCP) against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs was highly strain dependent. Several triple bNAb combinations were identified comprising of CD4 binding site-, V2-glycan-, and gp120-gp41 interface-targeting bNAbs that are capable of mediating synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. In assays using the transmitted/founder SHIV.C.CH505, there was a correlation between the neutralization potencies and nonneutralizing effector functions of bnAbs: VRC01 was positive for neutralization and binding to infected cells, but negative for ADCC.
Berendam2021
(effector function, neutralization, binding affinity, broad neutralizer)
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VRC01: This study used directed evolution to overcome the instability and heterogeneity of a primary Env isolate (ADA) in order to design better immunogens. HIV-1 virions were subjected to iterative cycles of destabilization and replication to select for Envs with enhanced stability. Several mutations in Env were associated with increased trimer stability, primarily in the heptad repeat regions of gp41 and V1 of gp120. Mutations from the most stable Envs were combined into a variant Env, termed "comb-mut", with superior homogeneity and stability. Comb-mut had greater binding affinity for PGT128, PG9, PG16, 2G12, VRC01, b12, and CD4-IgG2, but decreased binding to 4E10, 2F5, b6, 19b, 17b, 7B2, and D50. Comb-mut was more sensitive to neutralization by PG9. One specific mutation (K574) was shown to decrease the neutralization IC50 of mAbs b12, 2F5, 4E10, b6, 2G12, 8K8 and inhibitors sCD4, T-20, and PF-68742. Several of the Env substitutions were shown to stabilize Env spikes from HIV-1 clades A, B, and C. Spike stabilizing mutations may be useful in the development of Env immunogens that stably retain native, trimeric structure.
Leaman2013
(mimics, vaccine antigen design, binding affinity)
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VRC01: The Antibody Mediated Prevention (AMP) trials showed that VRC01 treatment prevented acquisition of strains of HIV-1 sensitive to VRC01. VRC01 dose and serum concentration were shown to be inversely correlated with risk of acquiring HIV. Prevention efficacy (PE) was strongly dependent on the neutralization sensitivity of an HIV-1 isolate to VRC01, measured as in vitro IC80 or IC50. Statistical tests showed that PE is significantly greater against viruses with lower IC80 or IC50, and the result was replicated across two AMP trial cohorts. In HVTN 704/HPTN 085, which enrolled 2,699 transgender individuals and men who have sex with men in Brazil, Peru and the United States, PE was 73.0% against viruses with IC80 < 1 μg/ml. In HVTN 703/HPTN 081, which enrolled 1,924 heterosexual women in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania and Zimbabwe, PE was 78.6% against viruses with IC80 < 1 μg/ml. AMP data were used to calculate a predicted PT80 (serum neutralization 80% inhibitory dilution titer), which quantifies the neutralization potency of antibodies in an individual's serum against an HIV-1 isolate. An average PT80 of 200 (a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. This study suggests that the goal of sustained PT80 >200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. The PT80 biomarker is proposed as a surrogate endpoint for evaluation of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines. A predicted triple bnAb regimen of PGDM1400LS + PGT121.414LS + VRC07-523LS was predicted to provide levels of HIV prevention with over 7-fold higher efficacy than VRC01.
Gilbert2022
(autologous responses, immunoprophylaxis, computational prediction)
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VRC01: The phase 2b Antibody Mediated Prevention (AMP) trials showed that VRC01, prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, this study investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data. The case–control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. Estimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients, but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy. These findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs.
Seaton2023
(immunoprophylaxis, kinetics, immunotherapy)
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VRC01: VRC01-class mAbs were isolated from chronically subtype-C infected patient PC063. The neutralization of these mAbs was compared with VRC01, 12A21, minVRC01, and min12A21.
Umotoy2019
(neutralization, antibody lineage)
-
VRC01: Reduction in exposure of non-neutralizing Ab (nnAb) epitopes on native-like Env trimer immunogens results in bnAbs being elicited that have autologous tier 2 neutralization instead of tier 1. The design of trimer modifications to silence nnAb reactivity were directed towards (1) the V3 loop (2) epitopes exposed through CD4-induced conformational changes (CD4i epitopes) and (3) the exposed SOSIP trimer base that is usually buried within virus membrane. (1) In Steichen2016 2 Env variants of BG505 SOSIP.664 with reduced V3 nnAb-generating activity were created, one using mammalian display screens, BG505 MD39, and the other with an engineered disulfide bond, BG505 SOSIP.DS21. MD39's trimer design was improved by using the Rosetta Design platform and inserting 6 buried mutations to form BG505 Olio6, and both this trimer as well as the DS21 were shown to have reduced antigenicity for nnAb generation in a rabbit vaccine model. (2) To reduce CD4i epitope elicitation of nnAbs, saturation mutagenesis of Olio6 was performed, in search of the trimer that binds VRC01-class bnAbs but not CD4. BG505 Olio6.CD4KO containing the G473T mutation was identified. In addition, for the purposes of nucleic acid-based vaccine platform designs, the natural furin cleavage site between gp120 and gp41 was removed to abolish protease cleavage, by swapping the order of gp14 and gp120 in the gp160 gene, giving the trimer BG505 MD39.CP (circular permutation). (3) The exposed trimer base was masked with glycan in 3 under-glycosylated regions in order to direct bnAb responses to the distal regions (CD4bs, V2 apex, N332 superset) of the trimer instead, generating the GRSF (glycan resurfaced) MD39 and GRSF MD39.CP variants. Furthermore, variants with improved thermostability over MD39 were created, MD37 and MD64. All of these stabilizing mutations were transferred to diverse HIV isolates from different subtypes. Finally 3 subtype C (isolate 327c) trimers were assessed for binding to bnAbs, VRC01, PGT121, PGT151, PGT145, PG9 and to nnAbs, F105 and 17b - VRC01 does bind all three.
Kulp2017
(antibody binding site, antibody generation, antibody interactions, assay or method development, autologous responses, vaccine antigen design, structure)
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VRC01: The VRC01 Antibody Mediated Prevention (AMP) vaccine trials (2016-2020) showed that passively administered bnAbs could prevent HIV-1 acquisition of bnAb-sensitive viruses. Viruses isolated from AMP participants who acquired infection during the study were used to make a panel of 218 HIV-1 pseudoviruses. The majority of viruses identified were clade B and C, with clades A, D, F, G and recombinants present at lower frequencies. BnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10–1074 and 10E8v4) were tested for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998–2010), the AMP clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best antibody mixture against clade C viruses, and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. The AMP placebo virus panel represents a resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs.
Mkhize2023
(assay or method development, neutralization, immunotherapy)
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VRC01: Using subtype A BG505 Env structural information, improved variants of subtype B JRFL and subtype C 16055 Env native flexibly linked (NFL) trimers were generated. The trimer-derived (TD) residues that increased well-ordered, homogeneous, stable, and soluble trimers did not require positive or negative selection as previously needed [Guenaga2015, PLoS Pathos. 11(1):e1004570]. VRC01 recognition and avidity to the CD4bs was high, with binding to the JRFL NFL TD15 trimer being higher than to the 16055 NFL TD8 as was the case for other CD4bs-bnAbs tested, viz. VRC03 and VRC06.
Guenaga2015a
(antibody interactions, assay or method development, vaccine antigen design, structure)
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VRC01: Two potent VRC01-class bNAbs, MinVRC01 and Min12A21, were engineered using minimal mutations. The mutations could be clustered spatially based on epitope interaction, and this was coupled to a neutralization readout. With the definition of VRC01-class epitope and paratope interaction and which of these interactions drives neutralization, the authors developed a tool (AFF, Antibody Features Frequency) to estimate which Ab sequence correlates with certain features. A yeast surface display method (using libraries mutated in residues of VH and VL genes as well as reversions, insertions and deletions) was used to assess the mutations and find heavily mutation-enriched genes. Min12A21 had the highest AFF in this study, while MinVRC01 had a high AFF, as well as polyreactivity.
Jardine2016a
(assay or method development, mutation acquisition, neutralization, structure, antibody polyreactivity)
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VRC01: Most published structures of bnAbs, yet none of non- or poorly-neutralizing mAbs, were structurally compatible with a newly generated crystal structure of a mature ligand-free endoglycosidase H-treated BG505 SOSIP.664 Env trimer. Robust binding of the structurally incompatible V3- and CD4-bs targeting nAbs could be induced with CD4. A “DS” variant of BG505 SOSIP.664, containing a stabilizing disulfide bond between 201C and 433C mutations, was developed and appeared to represent an obligate intermediate in that it bound only a single CD4 and remained in a prefusion closed conformation. BnAb VRC01 was structurally compatible with BG505 SOSIP.664 and had a breadth of 89% (IC50 < 50 μg/ml) in a panel of 170 diverse HIV-1 pseudoviruses. VRC01 binding of the Env trimer was drastically reduced (<25% vs. wildtype) with some mutations that stabilized the closed prefusion state. VRC01 had KD values of 1.72 and 1.43 nM, respectively, when binding to BG505 SOSIP.664 wildtype and DS variant.
Kwon2015
(neutralization, vaccine antigen design, binding affinity, structure)
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VRC01: Cryo-electron microscopy (EM) of the cleaved, soluble SOSIP gp140 trimer complexed with CD4bs-binding bnAb PGV04 was studied at 5.8Å, facilitating study of Env V1/V2, V3, HR1 and HR2 domains and some shielding glycans. This provides further information on trimer assembly, gp120-gp41 interactions and the three-dimensional CD4bs epitope cluster. Glycan N276 prevents binding of VRC01 to the gp120 monomer. When the heavy chain of VRC01 binds the trimer at the CD4bs, it is within 5Å of a loop (residues 61–62) that precedes a short α-helix (α-0) in C1 of a neighboring gp120 protomer (similar to CD4 binding to CD4bs).
Lyumkis2013
(vaccine antigen design, structure)
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VRC01: Native, well-ordered, soluble mimetics of the Env trimer from subtypes B (JRFL) and C (16055) were obtained from genetically identical samples of heterogeneous mixture of disordered Env SOSIPs. Negative selection by non-nAbs was used to remove disordered oligomers, leaving well-ordered trimers that were able to bind sCD4, a panel of bnAbs that bind CD4bs, and PGT15 which is a bnAb that binds only cleavage-dependent, well-ordered, Env trimer. Several biophysical techniques were used to interrogate the structure of the purified subtype B and C trimers. Trimer antigenicity was assessed by bio-layer interferometry against F105-like non-neutralizing Abs, and some bnAbs in solution. Non-trimer-preferring Ab VRC01 recognizes monomers, but recognizes these non-nAb negatively selected trimers as well.
Guenaga2015
(vaccine antigen design, subtype comparisons, structure)
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VRC01: The study characterized viral evolution and changes in neutralizing activity and sensitivity of a long-term non-progressing patient (GX2016EU01) with HIV-1 CRF07_BC infection. Four plasma samples were derived from the patient between 2016 and 2020, and 59 full-length env gene fragments were obtained, revealing that potential N-linked glycosylation sites in V1 and V5 significantly increased over time. While 24 Env-pseudotyped viruses from the patient remained sensitive to autologous plasma, all were resistant to bNAbs 2G12, PGT121, and PGT135. The pseudoviruses were sensitive to 10E8, VRC01, and 12A21, but became more resistant to these bnAbs and to autologous plasma at later timepoints. The neutralization breadth of plasma from all 4 sequential samples was 100% against the global HIV-1 reference panel. Immune escape mutants resulted in increased resistance to bNAbs targeting different epitopes. The study identified known mutations F277W in gp41 and previously uncharacterized mutation S465T in V5 which may be associated with increased viral resistance to bNAbs.
Wang2022
(autologous responses, glycosylation, mutation acquisition, neutralization, escape, rate of progression, polyclonal antibodies)
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VRC01: To characterize the persistence and phenotypic properties of HIV Env over time, blood and lymphoid samples were obtained at 2 timepoints from 8 people with HIV on suppressive ART. Single genome amplification and sequencing was performed on env to understand genetic diversity clonal expansion. A subset of envs were used to generate pseudovirus particles to assess sensitivity to autologous plasma IgG and bnAbs, and neutralization was assayed against a panel of 5 bnAbs (VRC01, 10E8, PGT121, 10-1074, 3BNC117) and the trispecific N6/PGDM1400x10E8. Identical env sequences indicating clonal expansion persisted between timepoints and within multiple T-cell subsets. At both timepoints, CXCR4-tropic (X4) Envs were more prevalent in naive and central memory cells; the proportion of X4 Envs did not significantly change in each subset between timepoints. Autologous purified plasma IgG showed variable neutralization of Envs, with no significant difference in neutralization between R5 and X4 Envs. X4 Envs were more sensitive to neutralization with clinical bnAbs, with CD4-binding site bnAbs demonstrating high breadth and potency against Envs. These data suggest the viral reservoir was predominantly maintained over time through proliferation of infected cells. The humoral immune response to Envs within the latent reservoir was variable between persons. The study also found that coreceptor usage can influence bNAb sensitivity and may need to be considered for future bNAb immunotherapy approaches.
Gartner2023
(co-receptor, neutralization, HAART, ART, HIV reservoir/latency/provirus, polyclonal antibodies)
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VRC01: N-linked glycosylation of antibodies can increase their chemical heterogeneity, complicating their manufacture. VRC01-like antibodies were assessed for the presence of light chain (LC) glycosylation, with some showing the presence of LC glycosylation (N6, VRC01, 3BNC117, VRC-CH31,) and some not (12A12, VRC18, VRC-PG04, VRC-PG20, VRC23, DRVIA7). This study developed a method to remove variable domain (Fv) glycans from nAbs, and used this method to develop engineered versions of 4 antibodies (VRC26.25, N6, PGT121, and VRC07-523).
Chuang2020
(assay or method development, glycosylation)
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VRC01: Some CD4-binding site Abs have greater env trimer binding due to quaternary contacts. This study engrafted the extended heavy-chain framework region 3 (FR3) loop of VRC03, which mediates quaternary interaction, onto several potent bnAbs, enabling them to reach an adjacent gp120 protomer. The interactive quaternary surface was delineated by solving the crystal structure of 2 of the chimeric antibodies. Chimerization enhances the neutralizing activity of several potent bNAbs against a majority of global HIV-1 strains. Compared to unmodified antibodies, the chimeric antibodies displayed lower autoreactivity and prolonged in vivo half-life in huFcRn mice and macaques. Thus, paratope engraftment may be used to expand the epitope repertory of natural antibodies, improving their functionality. VRC01-FR3-03 had more potent neutralization than VRC01; neither Ab was autoreactive in either of two assays.
Liu2019
(autoantibody or autoimmunity, neutralization)
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VRC01: This study reported isolation of 263A9 with low neutralizing activity. 263A9 in particular, was a VRC01-like antibody whose VH and VL were derived from IGHV1–2*04 and IGKV1–33*01,respectively, and both had significant SHM rates. It was found that the VL of 263A9 hindered the neutralizing activity of the Ab, and that replacing its LCDR1 and LCDR3 with VRC01 increased the neutralizing breadth of the chimeric Abs. An antibodyomics research revealed that the VL of 263A9 lineage was remote from VRC01-class antibodies. this study also looked at the envelope sequence characteristics of donor CBJC263 and discovered that N276 in the D loop and N460/N463 glycans in the V5 region of gp120 potentially interact with VL of 263A9 at the structural level.
Hu2023
(neutralization, germline)
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VRC01: This paper comprehensively defined the effect of every viable single aa mutation in the ectodomain and transmembrane domain of BG505.T332N Env on binding by 9 individual bnAbs targeting 5 epitope classes (VRC01, 3BNC117, PGT121, 10-1074, PG9, PGT145, PGT151, VRC34.01, and 10E8), as well as by a mixture of 3BNC117 and 10-1074. Escape mutations mostly occurred in a small subset of structurally-defined contacts within <4 Å and at near-contact sites within 5-10 Å of the Ab. Escape from both CD4bs-targeting bnAbs, VRC01 and 3BNC117, occurred at sites including 197 (glycosylation motif), 279 (loop D) and 369 (CD4 binding loop), but there were Ab-specific differences as well. Env sites with the largest cumulative mutational impact on VRC01 binding were N197, N279, and I326. Of 19 point mutations assessed on a BG505.T332N background, the greatest effects on neutralization were mediated by N279K and N197S, with respective fold-change decreases of >175 and 26.1, and N197E with ˜50 fold increase in neutralization potency. While both N197S and N197E eliminate the N197 glycan, N197S also introduces an N-linked glycosylation site at N195 which may be required for escape mediated by N197 mutations. See LANL Features and Contacts database for more details. Strain-specific differences were also identified through mapping escape of a lab-derived Env (strain LAI) from VRC01.
Dingens2019
(antibody binding site, neutralization, escape, contact residues)
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VRC01: Primary HIV-1 Envs were expressed as SHIVs, and responses from infected rhesus macaques showed patterns of Env-antibody coevolution similar to those in humans. This included conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions, and deletions leading to virus persistence. A total of 22 macaques were infected with one of the following: SHIV.CH505, SHIV.CH848, or SHIV.CAP256SU. Seven of the animals’ sera showed heterologous neutralization against tier 1A pseudoviruses: 2 were infected by SHIV.CH505 (RM5695 and RM6070), 2 by SHIV.CH848 (RM6163 and RM6167), and 3 by SHIV.CAP256SU (RM40591, RM42056 and RM6727). The remaining 15 animals showed either no or very limited, low titer neutralization of heterologous tier 2 viruses. Escape mutations from the macaque sera and mAbs closely resembled those of human mAb of the same binding type. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design. Several mAbs were isolated from RM6072 (infected with SHIV.CH505); these included DH650UCA, various intermediates, DH650, and DH650.2 - DH650.14. DH650 bound the CD4-binding site by CD4 mimicry, mirroring human bnAbs 8ANC131, CH235, or VRC01. The crystal structure of DH650 bound to the gp120 Env core of the CH505 T/F virus showed that its interactions with the gp120 CD4bs closely resembled those of the human CD4bs mAbs CH235, 8ANC131 and VRC01. None of the DH650 lineage mAbs neutralized heterologous viruses; on a panel of 117 multi-clade viruses, DH650.8 neutralized none.
Roark2021
(mutation acquisition, neutralization, vaccine antigen design, escape, structure)
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VRC01: The study used an immunization regimen incorporating targeted N-glycan removal and heterologous prime:boosting in rabbits to elicit neutralizing responses to epitopes conserved across strains. This multi-faceted approach elicited cross-neutralizing IgG mAbs in a subset of rabbits, with much of the response directed to the CD4bs. From rabbit C3, a mixture of 3 mAbs (A10, E70 and 1C2) reconstituted most of the neutralizing ability of C3 serum or purified IgG. The binding site of mAb E70 was determined by cross-competition ELISA and cryoEM, and it was directed to the CD4bs. E70 contacts with Env were compared with those of VRC01 and VRC-PG19; a set of 8 Env positions were contacted by all three mAbs. E70 structure was compared with that of VRC01, CH103, and CH235. E70 was able to neutralize 25% of a 40-virus tier 2 panel. Deletion of the N-glycan at N234 rendered viruses resistant to E70. MAb 1C2 was directed to the gp120:gp41 interface and resembled the human bnAb 3BC315, both in its binding site and its neutralization specificity. CryoEM and crystal structure revealed a complex interface recognition.
Dubrovskaya2019
(structure, contact residues)
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VRC01: This study examined whether HIV-1-specific bnAbs are capable of cross-neutralizing simian immunodeficiency viruses (SIVs) from chimpanzees (n=11) or western gorillas (n=1). BnAbs directed against the epitopes at the CD4 binding site (VRC01, VRC03, VRC-PG04, VRC-CH03, VRC-CH31, F105, b13, NIH45-46G54W, 45-46m2, 45-46m7), V3 (10-1074, PGT121, PGT128, PGT135, and 2G12), and gp41-gp120 interface (8ANC195, 35O22, PGT151, PGT152, PGT158) failed to neutralize SIVcpz and SIVgor strains. V2-directed bNabs (PG9, PG16, PGT145) as well as llama-derived heavy-chain only antibodies recognizing the CD4 binding site or gp41 epitopes (JM4, J3, 3E3, 2E7, 11F1F, Bi-2H10) were either completely inactive or neutralized only a fraction of SIVcpz strains. In contrast, neutralization of SIVcpz and SIVgor strains was achieved with low-nanomolar potency by one antibody targeting the MPER region of gp41 (10E8), as well as functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Igmim2, CD4-218.3-E51, CD4-218.3-E51-mim2), mono- and bispecific anti-human CD4 mAbs (iMab, PG9-iMab, PG16-iMab, LM52, LM52-PGT128), and CCR5 receptor mAbs (PRO140, PRO140-10E8). Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5, and neutralized SIVcpz in chimpanzee CD4+ T cells. These findings provide new insight into the protective capacity of anti-HIV-1 bnAbs and identify candidates for further development to combat SIV infection.
Barbian2015
(neutralization, SIV, binding affinity)
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VRC01: A recombinant native-like Env SOSIP trimer, AMC009, was developed based on viral founder sequences of elite neutralizer H18877. The subtype B AMC009 Env was defined as a Tier 2 virus based on a neutralization assay against well known nAbs (VRC01, 3BNC117, CH31, CH01, PG9, PG16, PGDM1400, 10-1074, PGT128, PGT121, PGT151, VRC34.01, 2G12, 2F5, 4E10, DH511.2.K3_4, 10E8, and the mAb mixture CH01-31).The AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bnAb epitopes. Its overall structure was similar to that of BG505 SOSIP.664, and it resembled one from another elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, AMC009 trimers did not induce autologous neutralizing antibody responses efficiently, while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous tier 2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009, and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the nAb activity from rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers.
Schorcht2020
(neutralization, vaccine-induced immune responses, structure)
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VRC01: The study looked at the neutralization of subtype C Env sequences from 9 South African individuals followed longitudinally. A total of 43 Env sequences were cloned and assayed for neutralization by 12 bnAbs of various binding types (VRC07-LS, N6.LS, VRC01, PGT151, 10-1074 and PGT121, 10E8, 3BNC117, CAP256.VRC26.25, 4E10, PGDM1400, and N123-VRC34.01). Features associated with resistance to bNAbs were higher potential glycosylation sites, relatively longer V1 and V4 domains, and known signature mutations. The study found significant variability in the breadth and potency of bnAbs against circulating HIV-1 subtype C envelopes. In particular, VRC07-LS, N6.LS, VRC01, PGT151, 10-1074, and PGT121 display broad activity against subtype C variants. The results suggest that these 6 bnAbs are potent antibodies that should be considered for future antibody therapy and treatment studies targeting HIV-1 subtype C.
Mandizvo2022
(glycosylation, mutation acquisition, neutralization, immunotherapy)
-
VRC01: HIV-1 bnAbs require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations. Probable mutations occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. The paper introduced the ARMADiLLO program, which estimates how probable a particular mAb mutation is, and thus the key improbable mutations were defined for a panel of 26 bnAbs. The number of improbable mutations ranged from 7 (PGT128) to 23 (VRC01 and 35O22); VRC01 had 23 improbable mutations out of 71 total AA mutations, and 3 indels. Single-amino acid reversion mutants were made for key improbable mutations of 3 bnAbs (CH235, VRC01, and BF520.1), and these mutant mAbs were tested for their neutralization ability. The study also noted that bnAbs that had relatively small numbers of improbable single somatic mutations had other unusual characteristics that were due to additional improbable events, such as indels (PGT128) or extraordinary CDR H3 lengths (VRC26.25).
Wiehe2018
(neutralization)
-
VRC01: The study assessed the breadths and potencies of 14 bnAbs against 36 viruses reactivated from peripheral blood CD4+ T cells from ARV-treated HIV-infected individuals by using paired neutralization and infected cell binding assays. Infected cell binding correlated with virus neutralization for 10 of 14 antibodies (VRC01, VRC07-523, 3BNC117, N6, PGT121, 10-1074, PGDM1400, PG9, 10E8, and 10E8v4-V5R-100cF). For example, the correlation for 3BNC117 had r=0.82 and P<0.0001. Heterogeneity was observed, however, with a lack of significant correlation for 2G12, CAP256.VRC26.25, 2F5, and 4E10. The study also performed paired infected cell binding and ADCC assays by using two reservoir virus isolates in combination with 9 bNAbs, and the results were consistent with previous studies indicating that infected cell binding is moderately predictive of ADCC activity for bNAbs with matched Fc domains. These data provide guidance on the selection of antibodies for clinical trials.
Ren2018
(effector function, neutralization, binding affinity, HIV reservoir/latency/provirus)
-
VRC01: A panel of 33 CRF02_AG pseudoviruses was generated from HIV-1-infected individuals during early stages of infection. Samples represented a 15-year period 1997-2012. These viruses were best neutralized by the CD4bs-directed bnAbs (VRC01, 3BNC117, NIH45-46G54W, and N6) and the MPER-directed bnAb 10E8 in terms of both potency and breadth. There was a higher resistance to bnAbs targeting the V1V2-glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Neutralization by 8ANC195 was also assayed. Combinations of antibodies were predicted by the CombiNaber tool to achieve full coverage across this subtype. There was increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the timespan sampled.
Stefic2019
(neutralization, acute/early infection, subtype comparisons)
-
VRC01: Isolation of human MPER-targeting mAb, E10, from an HIV-1-infected patient sample by single B cell sorting and single cell PCR has been reported. E10 had lower neutralization activity than mAb b12 but higher ADCC activity than mAb 2F5 at low concentrations. MAb VRC01 did not show a positive response to any of 60 overlapping consensus B-clade 15mer linear peptides spanning gp160 from HXB2 aa position 485-735. Assessed peptides included #121-180 (catalog #8883-8942) from NIH ARRP.
Yang2018
-
VRC01: The study found variations in the neutralization susceptibility of 71 Indian clade C viruses to 4 bnAbs (VRC01, VRC26.25, PGDM1400 and PGT121). Based on the neutralization data, the resistance signatures of the 4 bnAbs were determined. Using the CombiNAber tool, two possible combinations of three bnAbs (VRC01/VRC26.25/PGT121 and PGDM1400/VRC26.25/PGT121) were predicted to have 100% neutralization of the panel of Indian clade C viruses.
Mullick2021
(antibody interactions, neutralization)
-
VRC01: The authors review Fc effector functions, which cooperatively with Fab neutralization functions, could be used passively as immunotherapeutic or immunoprophylactic agents of HIV reservoir control or even infection prevention. One effector function, antibody-dependent complement-mediated lysis (ADCML), is seen with IgG1 and IgG3 anti-V1/V2 glycan bnAbs, PG9, PG16, PGT145; but not with 2F5, 4E10, 2G12, VRC01 and 3BNC117 unless they are delivered with anti-regulators of complement activation (RCA) antibodies. Another effector function, antibody-dependent cellular cytotoxicity (ADCC) can slow disease progression by NK-mediated degranulation of infected cells that are coated by bnAbs whose Fc region is recognized by the low affinity NK receptor, FcγRIIIA (or CD16). Strong ADCC was induced by NIH45-46, 3BNC117, 10-1074, PGT121 and 10E8, with intermediate activity for PG16 and VRC01, but no ADCC activation for 12A12, 8ANC195 and 4E10. A final effector function, antibody-dependent phagocytosis (ADP) also eliminates infected cells but through phagocytosis mediated by Fc portions of coating anti-HIV antibodies interacting with other FcγR (or FcαR) on the surface of granulocytes, monocytes or macrophages. This protective mode is less well studied but bnAbs like VRC01 have been engineered to increase phagocytosis by neutrophils. Protein engineering of bispecifics against the surface of infected or reservoir virus cells has potential in the future.
Danesh2020
(antibody interactions, assay or method development, complement, effector function, immunoprophylaxis, neutralization, immunotherapy, early treatment, review, broad neutralizer, HIV reservoir/latency/provirus)
-
VRC01: To understand early bnAb responses, 51 HIV-1 clade C infected infants were assayed for neutralization of a 12-virus multi-clade panel. Plasma bnAbs targeting V2-apex on Env were predominant in infant elite and broad neutralizers. In infant elite neutralizers, multi-variant infection was associated with plasma bnAbs targeting diverse autologous viruses. A panel of mAbs (PG9, PG16, PGT145, PGDM1400, VRC26.25, 10-1074, BG18, AIIMS-P01, PGT121, PGT128, PGT135, VRC01, N6, 3BNC117, PGT151, 35O22, 10E8, 4E10, F105, 17b, A32, 48d, b6, 447-52d) was assayed for their ability to neutralize Env clones from infant elite neutralizers; circulating viral variants in infant elite neutralizers were most susceptible to V2-apex bnAbs.
Mishra2020a
(neutralization, polyclonal antibodies)
-
VRC01: In vertically-infected infant AIIMS731, a rare HIV-1 mutation in hypervariable loop 2 (L184F) was studied. In patient sequences, this mutation was present in the majority of clones. A panel of 6 V2 bnAbs (PG9, PG16, PGT145, PGDM1400, CAP256.25, and CH01) was assayed for neutralization of 6 patient viral clones. The AIIMS731 viral variants segregated into 4 neutralization-sensitive and 2 resistant clones; sensitive clones carried 184F, while resistant clones carried the rare 184L mutation. A large panel of bnAbs targeting non-V2 epitopes was used to assess the neutralization of the 6 patient viral variants. The bnAb panel consisted of V3/N332 glycan supersite bnAbs (10-1074, BG18, AIIMS-P01, PGT121, PGT128, and PGT135), CD4bs bnAbs (VRC01, VRC03, VRC07-523LS, N6, 3BNC117, and NIH45-46 G54W), a silent face-targeting bnAb (PG05), fusion peptide and gp120-gp41 interface bnAbs (PGT151, 35O22, and N123-VRC34.01), and MPER bnAbs (10E8, 4E10, and 2F5). All of these bnAbs had similar neutralization efficiencies for all 6 clones, suggesting that the L184F mutation was specific for viral escape from neutralization by V2 apex bnAbs. A panel of non-neutralizing mAbs (V3 loop-targeting non-nAbs 447-52D and 19b, and CD4-induced non-nAbs 17b, A32, 48d, and b6), were also assessed; 2 of the variants (the same 2 susceptible to the V2 bnAbs) showed moderate neutralization by 447-52D, 19b, 17b, and 48d. The structure of ligand-free BG505 SOSIP trimer revealed that the side chain of L184 was outward facing and did not make significant intraprotomeric interactions, but upon mutating L184 to F184, a disruption of the accessible surface between the bulky side chain of F184 on one protomer and R165 on the neighboring protomer was seen. Thus, the L184F mutation resulted in increased susceptibility to neutralization by antibodies known to target the relatively more open conformation of Env on tier 1 viruses, suggesting that the rare L184F mutation allowed Env to sample more open states resembling the CD4-bound conformation where the CCR5 binding site is exposed.
Mishra2020
(neutralization, polyclonal antibodies)
-
VRC01: This report characterizes an additional antiviral activity of some bnAbs to block HIV-1 release by tethering viral particles at the surface of infected cells in vitro in a bivalency-dependent manner. After cultivation of infected primary CD4+ T cells with individual bnAbs, supernatant p24 levels were negatively correlated with cell-associated Gag levels, Env binding and neutralization potency while cell-associated Gag levels and Env binding positively correlated with each other and individually with neutralization potency. The capacity to mediate this tethering activity varied among different classes of mAbs: 0/3 non-neutralizing mAbs, 1/5 bnAbs targeting the MPER or gp120/gp41 interface and 9/9 of the bnAbs targeting the V3 and V1/V1 loops or the CD4bs demonstrated this activity against at least 1/3 diverse viral strains (AD8, CH058 and vKB18). Five of these latter 9 bnAbs displayed tethering activity against all 3 strains. Surface aggregation of mature virions and bnAb 10-1074 was observed in CH058-infected primary CD4+ T cells and CHME macrophage-like cells. CD4bs-targeting bnAb VRC01 displayed tethering activity against 2/3 HIV-1 strains (AD8 and vKB18).
Dufloo2022
(binding affinity)
-
VRC01: Five novel functional HIV-1/HCV cross-reactive monoclonal antibodies (180, 692, 688, 803, and KP1-8) with diverse epitope specificities were isolated from a chronically HIV-1/HCV co-infected donor, VC10014, and characterized. MAb VRC01 was used as positive control for binding to clade A BG505 gp140, clade B B41 gp140, clade C ConC gp120, and clade AE A244 gp120.
Pilewski2023
-
VRC01: Env clones were obtained from donor CBJC515 plasma. The neutralization of these clones was tested against 3 donor serum samples (2005, 2006, 2008) and 6 bnAbs (10E8, 2G12, PGT121, PGT135, VRC01, 12A21). In phylogeny, the sequences clustered into 2 major clusters. Cluster I viruses vanished in 2006 and then appeared as recombinants in 2008. In Cluster II viruses, the V1 length and N-glycosylation sites increased over the four years of the study period. Most viruses were sensitive to concurrent and subsequent autologous plasma, and to bNAbs 10E8, PGT121, VRC01, and 12A21, but all viruses were resistant to PGT135. Overall, 90% of Cluster I viruses were resistant to 2G12, while 94% of Cluster II viruses were sensitive to 2G12. The study confirmed that HIV-1 continued to evolve even in the presence of bnAbs, and two virus clusters in this donor adopted different escape mechanisms under the same humoral immune pressure.
Hu2021
(autologous responses, glycosylation, neutralization, escape, polyclonal antibodies)
-
VRC01: A family of CD4BS antibodies was isolated from donor 391370, whose serum had broad neutralization. Among this family, BG24, BG5, BG33, and BG38 were studied, and BG24 had the lowest neutralization IC50. Compared to other VRC01-class antibodies, BG24 is much less mutated, while achieving comparable breadth and potency. Several mutational variants of BG24 were also studied, including BG24-G54W and BG24-Y100DW. Two BG24 constructs were designed that substituted CDRH2 residues from VRC-PG20; these constructs (BG24-CDR2-v1 and BG24-CDR2-v2) had a 2 to 5-fold improvement in IC50 relative to unmodified BG24. VH and VL germline gene usage and phylogeny were determined for sequences of the BG24 family mAbs. BG24 was negative for autoreactivity and polyreactivity. Following intravenous injection of BG24 into nonhumanized mice, BG24 showed a similar decline in serum to other VRC01-class antibodies indicating an acceptable pharmacokinetic profile. In humanized mice injected with HIV YU-2, treatment with BG24 or VRC01 showed a comparable peak drop in average viral load, with rebound of viremia by 3 weeks after treatment initiation. An x-ray crystal structure of a BG24-BG505 Env trimer complex revealed conserved contacts at the gp120 interface characteristic of the VRC01-class Abs, despite lacking common CDR3 sequence motifs. Relative to VRC01-class bNAbs, BG24 maintained a similar gp120-binding orientation.
Barnes2022
(neutralization, immunotherapy, broad neutralizer)
-
VRC01: This study inferred a high-probability unmutated common ancestor (UCA) of the VRC01 lineage and reconstructed the stages of lineage maturation, including a phylogeny of 45 naturally-paired mAbs from donor NIH45. Nine new lineage members were isolated from donor NIH45, named DH651.1 - DH561.9. The study also derived VH and VL reverted forms of several VRC01-class mAbs derived from other donors (12A12, 3BNC60, 3BNC117, VRC20, VRC23, and VRC18b). Early mutations within the VRC01 lineage defined maturation pathways toward limited or broad neutralization, suggesting that focusing the immune response is likely required to steer B-cell maturation toward the development of neutralization breadth. VRC01 lineage bnAbs with long CDR H3s overcame the HIV-1 N276 glycan barrier without shortening their CDR L1, revealing a solution for broad neutralization in which the heavy chain, not CDR L1, is the determinant to accommodate the N276 glycan. An X-ray structure and molecular dynamics simulation of VRC08 were studied to elucidate this process.
Bonsignori2018
(neutralization, structure, antibody lineage)
-
VRC01: A plant-based expression system was used to produce different glycoforms of the bnAbs PG9, PG16, 10–1074, NIH45–46G54W, 10E8, PGT121, PGT128, PGT145, PGT135, and b12. Also produced were mutated forms (N92T) of VRC01 (mVRC01) and NIH45–46G54W (mNIH45–46G54W). The in vivo properties of these mAbs were assessed in macaques to distinguish those most likely to comprise or become a component of an affordable and efficacious immunotherapeutic cocktails. N-glycans within the VL domain impaired the plasma stability of plant-derived bnAbs. While PGT121 and b12 exhibited no immunogenicity in rhesus macaques, VRC01, 10-1074 and NIH45-46G54W elicited high titer anti-idiotypic antibodies. The results indicated that that specific mutations in certain bnAbs caused immunogenicity in macaques. Such immunogenicity in humans would potentially compromise their value for immunotherapy. CHO1-31 was used as a positive control in a neutralization assay.
Rosenberg2015
(anti-idiotype, neutralization, immunotherapy)
-
VRC01: HIV-1 env genes were sequenced from 16 mother/infant transmitting pairs. Infant transmitted-founder (T/F) and representative maternal non-transmitted Env variants were identified and used to generate pseudoviruses for paired maternal plasma neutralization analysis. Eighteen out of 21 (85%) infant T/F Env pseudoviruses were neutralization resistant to paired maternal plasma, while all infant T/F viruses were neutralization sensitive to a panel of HIV-1 broadly neutralizing antibodies (2G12, CH01, PG9, PG16, PGT121, PGT126, DH429, b12, VRC01, NIH45-46, CH31, 4E10, 2F5, 10E8, DH512) and variably sensitive to heterologous plasma neutralizing antibodies. Antibody mixture CH01/31 was used as a positive control for neutralization. The infant T/F pseudoviruses were overall more neutralization resistant to paired maternal plasma in comparison to pseudoviruses from maternal non-transmitted variants. These findings suggest that autologous neutralization of circulating viruses by maternal plasma antibodies select for neutralization-resistant viruses that initiate peripartum transmission, raising the speculation that enhancement of this response at the end of pregnancy could reduce infant HIV-1 infection risk.
Kumar2018
(neutralization, acute/early infection, mother-to-infant transmission, transmission pair)
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VRC01: This study reported the results of the Antibody Mediated Prevention trials such as HIV Vaccine Trials Network (HVTN), 704/HIV Prevention Trials Network (HPTN) 085 and HVTN 703/HPTN 081. These were designed as proof-of-concept trials to determine whether VRC01 is capable of preventing HIV-1 acquisition. Cohorts include At-risk cisgender men and transgender persons in the Americas and Europe for HVTN 704/HPTN 085 and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081. Participants were randomly selected to receive infusions of VRC01 at a dose of either 10mg/kg (low-dose) or 30mg/Kg (high-dose) or placebo, for 10 infusions in total, every 8 weeks. HIV-1 testing was performed every 4 weeks. Estimated prevention efficacy was 26.6% (95% confidence interval) in HVTN 704/HPTN 085 and 8.8% (95% confidence interval) in HVTN 703/HPTN 081. VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective.
Corey2021
(vaccine-induced immune responses)
-
VRC01: Since cross-reactive antibodies can interfere in immunoassays, HIV-1 mAbs were tested for binding to the SARS-COV-2 spike (S) protein (SARS-COV-2 S cross-reactivity). The following 9 gp120-epitope binding HIV-1 mAbs are cross-reactive with COV-2 S: 2G12, PGT121, PGT126, PGT128, PGT145, PG9, PG16, 10-1074, and 35O22. CD4bs Abs VRC01 and VRC03 are not cross-reactive. Cross-reactivity of the 9 HIV-1 Abs was through glycoepitopes. Glycan-dependent, V3-loop-binding PGT126 and PGT128 as well as 2G12 were the strongest binders of COV-2 S and were found to be immunoreactive but incapable of neutralization or antibody-dependent enhancement (ADE).
Mannar2021
(antibody interactions, effector function, glycosylation, computational prediction, antibody polyreactivity)
-
VRC01: To improve the potency and breadth of bNAbs, structure-based design methods were used to generate engineered variants of 6 VRC01-class mAbs (VRC01, VRC07-523LS, VRC08, N6, 3BNC117 and N49P7). Several of the engineered variant mAbs had improved potency, breadth, and pharmacokinetics. The specific mutations introduced, singly or in combination, included mutation of heavy chain (HC) amino acid 54, replacement of the native HC FR3 with FR3 from VRC03 (03FR3), introduction of the "LS" HC mutations (M428L and N434S in the Fc region), and light chain truncation of the first 2 or 3 residues. In previous studies, the LS mutation has been shown to improve antibody half-life without significantly affecting potency, while alteration of LC residues 1, 2, and 3 can improve the potency of some mAbs.
Kwon2021
(neutralization, broad neutralizer)
-
VRC01: Analyses of all PDB HIV1-Env trimer (prefusion, closed) structures fulfilling certain parameters of resolution were performed to classify them on the basis of (a) antibody class which was informed by parental B cells as well as structural recognition, and (b) Env residues defining recognized HIV epitopes. Structural features of the 206 HIV epitope and bNAb paratopes were correlated with functional properties of the breadth and potency of neutralization against a 208-strain panel. Broadly nAbs with >25% breadth of neutralization belonged to 20 classes of antibodies with a large number of protruding loops and high degree of somatic hypermutation (SHM). Analysis of recognized HIV epitopes placed the bNAbs into 6 categories (viz. V1V2, glycan-V3, CD4-binding site, silent face center, fusion peptide and subunit interface). The epitopes contained high numbers of independent sequence segments and glycosylated surface area. VRC01-Env formed a distinct group within the CD4bs category, Class VRC01. Crystal structure data at 3.4A resolution of fully glycosylated Clade G X1193.ct SOSIP.664 prefusion trimer with VRC01 as well as PGT122 and 35O22 was found in PDB ID: 5FYJ.
Chuang2019
(antibody binding site, antibody interactions, binding affinity, antibody sequence, structure, antibody lineage, broad neutralizer)
-
VRC01: In an effort to identify new Env immunogens able to elicit bNAbs, this study looked at Envs derived from rare individuals who possess bNAbs and are elite viral suppressors, hypothesizing that in at least some people the antibodies may mediate durable virus control. The Env proteins recovered from these individuals may more closely resemble the Envs that gave rise to bNAbs compared to the highly diverse viruses isolated from normal progressors. This study identified a treatment-naive elite suppressor, EN3 (patient record #4929), whose serum had broad neutralization. The Env sequences of EN3 had much fewer polymorphisms, compared to those of a normal progressor, EN1 (patient record #4928), who also had broad serum neutralization. This result confirmed other reports of slower virus evolution in elite suppressors. EN3 Envelope proteins were unusual in that most possessed two extra cysteines within an elongated V1 region. The impact of the extra cysteines on the binding to bNAbs, virus infectivity, and sensitivity to neutralization suggested that structural motifs in V1 can affect infectivity, and that rare viruses may be prevented from developing escape. As part of this study, the neutralization of pseudotype viruses for EN3 Env clones was assayed for several bNAbs (PG9, PG16, PGT145, PGT121, PGT128, VRC01, 4E10, and 35O22).
Hutchinson2019
(elite controllers and/or long-term non-progressors, neutralization, vaccine antigen design, polyclonal antibodies)
-
VRC01: This review focuses on the potential for bNAbs to induce HIV-1 remission, either alone or in combination with latency reversing agents, therapeutic vaccines, or other novel therapeutics. Ongoing human trials aimed at HIV therapy or remission are utilizing the following antibodies, alone or in combination: VRC01, VRC01-LS, VRC07-523-LS, 3BNC117, 10-1074, 10-1074-LS, PGT121, PGDM1400, 10E8.4-iMab, and SAR441236 (trispecific VRC01/PGDM1400-10E8v4). Ongoing non-human primate studies aimed to target, control, or potentially eliminate the viral reservoir are utilizing the following antibodies, alone or in combination: 3BNC117, 10-1074, N6-LS, PGT121, and the GS9721 variant of PGT121.
Hsu2021
(antibody interactions, immunotherapy, review, HIV reservoir/latency/provirus)
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VRC01: A series of mutants was produced in the CAP256-VRC26.25 heavy chain for the purpose of avoiding the previously-identified proteolytic cleavage at position K100m. Neutralization of the mutants was tested, and the cleavage-resistant variant that showed the greatest potency was K100mA. In addition to the K100mA mutation, an LS mutation was added to the Fc portion of the heavy chain, as this change has been shown to improve the half-life of antibodies used for passive administration without affecting neutralization potency. The resulting construct was named CAP256V2LS. The pharmacokinetics of CAP256V2LS were assessed in macaques and mice, and it showed a profile similar to other antibodies used for immunotherapy. The antibody lacked autoreactivity. Structural analysis of wild-type CAP256-VRC26.25 showed that the K100m residue is not involved in interaction with the Env trimer. Previously-published neutralization data for VRC01 and VRC01-LS were used for comparison purposes.
Zhang2022
(neutralization, immunotherapy, broad neutralizer)
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VRC01: Rabbits were immunized with a DNA vaccine encoding JR-CSF gp120. Five sera with potent autologous neutralizing activity were selected and compared with a human neutralizing plasma (Z23) and monoclonal antibodies targeting various regions of gp120 (VRC01, b12, b6, F425, 2F5, 2G12, and X5). The rabbit sera contained different neutralizing activities dependent on C3 and V5, C3 and V4, or V4 regions of the glycan-rich outer domain of gp120. All sera showed enhanced neutralizing activity toward an Env variant that lacked a glycosylation site in V4. The JR-CSF gp120 epitopes recognized by the sera were distinct from those of the mAbs. The activity of one serum required specific glycans that are also important for 2G12 neutralization, and this serum blocked the binding of 2G12 to gp120. The findings show that different fine specificities can achieve potent neutralization of HIV-1, yet this strong activity does not result in improved breadth.
Narayan2013
(neutralization, polyclonal antibodies)
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VRC01: The study compared well-characterized nAbs (2G12, b12, VRC01, 10E8, 17b) with 4 mAbs derived from a Japanese patient (4E9C, 49G2, 916B2, 917B11) in their neutralization and ADCC activity against viruses of subtypes B and CRF01. CRF01 viruses were less susceptible to neutralization by 2G12 and b12, while VRC01 was highly effective in neutralizing CRF01 viruses. 49G2 showed better neutralization breadth against CRF01 than against B viruses. CRF01_AE viruses from Japan also showed a slightly higher susceptibility to anti-CD4i Ab 4E9C than the subtype B viruses, and to CRF01_AE viruses from Vietnam. Neutralization breadth of other anti-CD4i Abs 17b, 916B2 and 917B11 was low against both subtype B and CRF01_AE viruses. Anti-CD4bs Ab 49G2, which neutralized only 22% of the viruses, showed the broadest coverage of Fc-mediated signaling activity against the same panel of Env clones among the Abs tested. The CRF01_AE viruses from Japan were more susceptible to 49G2-mediated neutralization than the CRF01_AE viruses from Vietnam, but Fc-mediated signaling activity of 49G2was broader and stronger in the CRF01_AE viruses from Vietnam than the CRF01_AE viruses from Japan.
Thida2019
(effector function, neutralization, subtype comparisons)
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VRC01: An R5 virus isolated from chronic patient NAB01 (Patient Record# 4723) was adapted in culture to growth in the presence of target cells expressing reduced levels of CD4. Entry kinetics of the virus were altered, and these alterations resulted in extended exposure of CD4-induced neutralization-sensitive epitopes to CD4. Adapted and control viruses were assayed for their neutralization by a panel of neutralizing antibodies targeting several different regions of Env (PGT121, PGT128, 1-79, 447-52d, b6, b12, VRC01, 17b, 4E10, 2F5, Z13e1). Adapted viruses showed greater sensitivity to antibodies targeting the CD4 binding site and the V3 loop. This evolution of Env resulted in increased CD4 affinity but decreased viral fitness, a phenomenon seen also in the immune-privileged CNS, particularly in macrophages.
Beauparlant2017
(neutralization, viral fitness and/or reversion, dynamics, kinetics)
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VRC01: The Chinese HIV Reference Laboratory produced 124 pseudoviruses from patients with subtype B, BC, and CRF01 infections. These viruses were assigned to tiers based on their neutralization by a panel of patient sera. Their neutralization sensitivities were also measured against a panel of well-characterized mAbs (2F5, b12, 2G12, 4E10, 10E8, VRC01, VRC-CH31, CH01, PG9, PG16, PGT121, PGT126).
Nie2020
(assay or method development, neutralization)
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VRC01: In 8 ART-treated patients, latent viruses were induced by a viral outgrowth assay and assayed for their sensitivity to neutralization by 8 broadly neutralizing antibodies (VRC01, VRC07-523, 3BNC117, PGT121, 10-1074, PGDM1400, VRC26.25, 10E8v4-V5F-100cF). The patients' inducible reservoir of autologous viruses was generally refractory to neutralization, and higher Env diversity correlated with greater resistance to neutralization.
Wilson2021
(autologous responses, neutralization, HAART, ART, HIV reservoir/latency/provirus)
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VRC01: Extensive structural and biochemical analyses demonstrated that PGT145 achieves recognition and neutralization by targeting quaternary structure of the cationic trimer apex with long and unusually stabilized anionic β-hairpin HCDR3 loops. In BG505.Env.C2 alanine-scanning neutralization assays, VRC01 had more similar results to hammerhead-class antibodies PG9 & CH01 than to PGT145-like antibodies.
Lee2017
(antibody binding site, neutralization)
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VRC01: Novel Env pseudoviruses were derived from 22 patients in China infected with subtype CRF01_AE viruses. Neutralization IC50 was determined for 11 bNAbs: VRC01, NIH45-46G54W, 3BNC117, PG9, PG16, 2G12, PGT121, 10-1074, 2F5, 4E10, and 10E8. The CRF01_AE pseudoviruses exhibited different susceptibility to these bNAbs. Overall, 4E10, 10E8, and 3BNC117 neutralized all 22 env-pseudotyped viruses, followed by NIH45-46G54W and VRC01, which neutralized more than 90% of the viruses. 2F5, PG9, and PG16 showed only moderate breadth, while the other three bNAbs neutralized none of these pseudoviruses. Specifically, 10E8, NIH45-46G54Wand 3BNC117 showed the highest efficiency, combining neutralization potency and breadth. Mutations at position 160, 169, 171 were associated with resistance to PG9 and PG16, while loss of a potential glycan at position 332 conferred insensitivity to V3-glycan-targeting bNAbs. These results may help in choosing bNAbs that can be used preferentially for prophylactic or therapeutic approaches in China.
Wang2018a
(assay or method development, neutralization, subtype comparisons)
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VRC01: A novel CD4bs bnAb, 1-18, is identified with breadth (97% against a 119-strain multiclade panel) and potency exceeding (IC50 = 0.048 µg/mL) most VH1-46 and VH1-2 class bnAbs like 3BNC117, VRC01, N6, 8ANC131, 10-1074, PGT151, PGT121, 8ANC195, PG16 and PGDM1400. 1-18 effectively restricts viral escape better than bnAbs 3BNC117 and VRC01. As with VRC01-like Abs, 1-18 targets the CD4bs but it recognizes the epitope differently. Neutralizing activity against VRC01 Ab-class escapes is maintained by 1-18. In humanized mice infected by strain HIV-1YU2, viral suppression is also maintained by 1-18. VH1-46-derived B cell clone 4.1 from patient IDC561 produced potent, broadly active mAbs. Subclone 4.1 is characterized by a 6 aa CDRH1 insertion lengthening it from 8 to 14 aa and produces bNAbs 1-18 and 1-55. Cryo-EM at 2.5A of 1-18 in complex with BG505SOSIP.664 suggests their insertion increases inter-protomer contacts by a negatively charged DDDPYTDDD motif, resulting in an enlargement of the buried surface on HIV-1 gp120. Variations in glycosylation is thought to confer higher neutralizing activity on 1-18 over 1-55.
Schommers2020
(neutralization)
-
VRC01: Soluble versions of HIV-1 Env trimers (sgp140 SOSIP.664) stabilized by a gp120-gp41 disulfide bond and a change (I559P) in gp41 have been structurally characterized. Cross-linking/mass spectrometry to evaluate the conformations of functional membrane Env and sgp140 SOSIP.664 has been reported. Differences were detected in the gp120 trimer association domain and C terminus and in the gp41 HR1 region which can guide the improvement of Env glycoprotein preparations and potentially increase their effectiveness as a vaccine. VRC01 broadly neutralized HIV-1AD8 full-length and cytoplasmic tail-deleted Envs.
Castillo-Menendez2019
(vaccine antigen design, structure)
-
VRC01: HIV Env glycoproteins were expressed by incorporation into live attenuated rubella viral vectors strain RA27/3. These vectors can stably express Env core derived glycoproteins ranging in size up to 363 amino acids from HIV clade C strain 426c. By themselves, the vectors elicited modest Ab titers to the Env insert. But the combination of rubella/env prime followed by a homologous protein boost gave a strong response. MAb VRC01 was used as a positive control in neutralization assays.
Virnik2018
(vaccine antigen design)
-
VRC01: An engineered Env outer domain(OD) eOD-GT8 60-mer nanoparticle has been reported as a priming immunogen for eliciting VRC01-class precursors. N-linked glycans were introduced into non-CD4bs surfaces of eOD-GT8 to mask irrelevant epitopes, and these mutants were evaluated in a mouse model that expressed diverse IgG heavy chains containing human IGHV1-2*02, the germline VRC01 VH segment. Compared to the parental eOD-GT8, a mutant with 5 added glycans stimulated significantly higher proportions of CD4bs-specific serum responses and VRC01-class precursors. The antibodies used to evaluate the antigens included VRC01, its V gene germline revertant VRC01 gl, the VRC-PG04 V gene germline revertant VRC-PG04 gl, a polyclonal rabbit anti-gp120 serum, two non-CD4bs monoclonal antibodies (X1A2 and X1C6) isolated from eOD-GT6 60-mer-immunized XenoMouse, and two non-CD4bs mAbs (mA9 and mE4) isolated from eOD-GT8 60-mer-immunized IGHV1-2 knockin mice.
Duan2018
(glycosylation, vaccine antigen design)
-
VRC01: In an attempt to engage appropriate germline B cells that give rise to bNAbs, a combination of Env glycan modifications that permit far greater neutralization potency by near germline forms of multiple VRC01-class bNAbs were tested. The authors assessed CD4bs bNAbs for neutralizing activity against of Env-pseudotyped viruses (EPV) that were either Man5-enrichment and/or had targeted glycan deletion and concluded that neutralization by germline-reverted forms of VRC01-class bNAbs requires a combination of both Man5-enrichment and glycan deletion. In particular, Man5-enrichment increased the sensitivity of 426c by 8–12 fold when assayed with mature VRC01, 3BNC117, VRC-CH31 and CH103, and this sensitivity increased further by targeted glycan deletion. Furthermore, Man5-enrichment increased the sensitivity of subtype C transmitted-founder 426c EPV that lacked glycan N276, and those that lacked two glycans at N460 and N463, to mature VRC01 by ˜10-fold.
LaBranche2018
(antibody interactions, antibody lineage)
-
VRC01: Expanding on previous work aimed at understanding the germline VRC01-class antibody-recognition potential of the previously described 426c Env, the authors characterize the crystal structure, binding and contacts to the germline VRC01 of two C Env constructs: the previously described soluble trimeric 426c SOSIP with three NLGSs removed at positions Asn276, Asn460, and Asn463; and a monomeric 426c core containing all wild-type NLGSs (including those at positions Asn276, Asn460, and Asn463), but lacking variable loops 1, 2, and 3. The authors test and characterize various glycan-deleted combinations and NLGS backbones and demonstrate that germline VRC01 could bind to a 426c core construct in the presence of all naturally occurring NLGSs surrounding the CD4BS, including the NLGS at position Asn276 and with its associated glycan.
Borst2018
(antibody interactions, antibody lineage)
-
VRC01: Lipid-based nanoparticles for the multivalent display of trimers have been shown to enhance humoral responses to trimer immunogens in the context of HIV vaccine development. After immunization with soluble MD39 SOSIP trimers (a stabilized version of BG505), trimer-conjugated liposomes improved both germinal center B cell and trimer-specific T follicular helper cell responses. In particular, MD39-liposomes showed high levels of binding by bNAbs such as V3 glycan specific PGT121, V1/V2 glycan specific PGT145, gp120/gp41 interface specific PGT151, CD4 binding site specific VRC01, and showed minimal binding by non-NAbs like CD4 binding site specific B6, and V3 specific 4025 or 39F.
Tokatlian2018
(vaccine antigen design, binding affinity)
-
VRC01: Without SOSIP changes, cleaved Env trimers disintegrate into their gp120 and gp41-ectodomain (gp41_ECTO) components. This study demonstrates that the gp41_ECTO component is the primary source of this Env metastability and that replacing wild-type gp41_ECTO with BG505 gp41_ECTO of the uncleaved prefusion-optimized design is a general and effective strategy for trimer stabilization. A panel of 11 bNAbs, including the CD4-binding site (CD4bs) recognized by VRC01 and b12, was used to assess conserved neutralizing epitopes on the trimer surface, and the main result was that the substitution was found to significantly improve trimer binding to bNAbs VRC01, PGT151, and 35O22, with P values (paired t test) of 0.0229, 0.0269, and 0.0407, respectively.
He2018
(antibody interactions, glycosylation, vaccine antigen design)
-
VRC01: To reduce local V2 flexibility and improve the binding of V2-dependent bNAbs and germline precursor bNAbs, the authors designed BG505 SOSIP.664 trimer variants whose V1 and V2 domains were stabilized by introducing disulfide bonds either within the V2 loop or between the V1 and V2 loops. The resulting SOSIP trimer variants — E153C/K178C, E153C/K178C/G152E and I184C/E190C — have improved reactivity with V2 bNAbs and their inferred germline precursors and are more sensitive to neutralization by V2 bNAbs. Compared with BG505 SOSIP.664, the E153C/R178C V1-V2 disulfide mutant bound the VRC01, PGT151, and 2G12 slightly less well and the G152E compensatory mutation improved VRC01, PGT151, and 2G12 binding. However, there was no change in sensitivity to VRC01 for either mutant virus E153C/K178C/G152E or I184C/E190C.
deTaeye2019
(neutralization, vaccine antigen design, binding affinity)
-
VRC01: This study looks at the role of somatic mutations within antibody variable and framework regions (FWR) in bNAbs and how these mutations alter thermostability and neutralization as the Ab lineage reaches maturation. The emergence and selection of different mutations in the complementarity-determining and framework regions are necessary to maintain a balance between antibody function and stability. The study shows that all major classes of bNAbs (DH270, CH103, CH235, VRC01, PGT lineage etc.) have lower thermostability than their corresponding inferred UCA antibodies. Fab interdomain flexibility mutations are selected early in Ab development.
Henderson2019
(neutralization, antibody lineage, broad neutralizer)
-
VRC01: The authors used nuclear magnetic resonance (NMR) to define the structure of the HIV-1 MPER when linked to the transmembrane domain (MPER-TMD) in the context of a lipid bilayer. In particular, they looked at the accessibility of the MPER-TMD to 2F5, 4E10, 10E8 and DH570. The MPER appears to be accessible up to ∼10% of the time to the 2F5, 4E10, and 10E8 Fabs but ∼40% of time to the DH570 Fab. To assess possible functional roles for the MPER in membrane fusion, they generated 17 Env mutants using the sequence of a clade A isolate, 92UG037.8, mutating each of the three structural elements: hydrophobic core, turn, and kink. Mutants W670A (hydrophobic core), F673A (turn), and W680A (kink), while still sensitive to VRC01, became much more resistant to the trimer-specific bNAbs and also gained sensitivity to b6, 3791, and 17b. All mutants with changes at W666 in the hydrophobic core and K683 at the kink lost infectivity almost completely. For the rest of the mutants, infectivity ranged from 4.3 to 50.8% of that of the wild type, showing that key residues important for stabilizing the MPER structure are also critical for Env-induced membrane fusion activity, especially in the context of viral infection.
Fu2018
(antibody binding site, antibody interactions, neutralization, variant cross-reactivity, binding affinity, structure)
-
VRC01: Two HIV-1-infected individuals, VC10014 and VC20013, were monitored from early infection until well after they had developed broadly neutralizing activity. The bNAb activity developed about 1 year after infection and mapped to a single epitope in both subjects. Isolates from each subject, taken at five different time points, were tested against monoclonal bNAbs: VRC01, B12, 2G12, PG9, PG16, 4E10, and 2F5. In subject VC10014, the bNAb activity developed around 1 year postinfection and targeted an epitope that overlaps the CD4-BS and is similar to (but distinct from) bNAb HJ16. In the case of VC20013, the bNAb activity targeted a novel epitope in the MPER that is critically dependent on residue 677 (mutation K677N). All of the isolates from subject VC20013 were very susceptible to bNAbs that target the CD4 binding site (CD4-BS), including b12 and VRC01.
Sather2014
(neutralization, broad neutralizer)
-
VRC01: This study demonstrated that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens eliciting Ab responses with greater neutralization breadth. Data from four large virus panels were used to comprehensively map viral signatures associated with bNAb sensitivity, hypervariable region characteristics, and clade effects. The bNAb signatures defined for the V2 epitope region were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine which resulted in increased breadth of nAb responses compared with Env 459C alone. The G458Y signature mutation conferred complete resistance (IC50 > 25 mg/mL) to VRC01 and can neutralize the CH505 TF (IC50 of 0.14mg/mL).VRC01 has reduced breadth and potency against C clade viruses.
Bricault2019
(antibody binding site, neutralization, vaccine antigen design, computational prediction, broad neutralizer)
-
VRC01: In vitro neutralization data against 25 subtype A, 100 C, and 20 D pseudoviruses of 8 bNAbs (3BNC117, N6, VRC01, VRC07-523LS, CAP256-VRC26.25, PGDM1400, 10–1074, PGT121) and 2 bispecific Abs under clinical development (10E8-iMAb, 3BNC117-PGT135) was studied to assess the antibodies’ potential to prevent infection by dominant HIV-1 subtypes in sub-Saharan Africa. In vivo protection of these Abs and their 2-Ab combination was predicted using a function of in vitro neutralization based on data from a macaque simian-human immunodeficiency virus (SHIV) challenge study. Conclusions were that 1. bNAb combinations outperform individual bNAbs 2. Different bNAb combinations were optimal against different HIV subtypes 3. Bispecific 10E8-iMAb outperformed all combinations, and 4. 10E8-iMAb in combination with other conventional Abs was predicted to be the best combination against HIV-infection.
Wagh2018
(neutralization, computational prediction, immunotherapy)
-
VRC01: A novel antibody, Y498, was derived from donor XJ1981, whose serum had potent and broad neutralization activity. Y498 neutralized 30% of 70 tested HIV-1 isolates and targeted an epitope overlapping the CD4bs of gp120. The neutralization of Y498 was compared to that of 3 other CD4BS antibodies: VRC01, b12, and A16.
Sun2017
(antibody generation, neutralization, broad neutralizer)
-
VRC01: This review summarizes current advances in antibody lineage-based design and epitope-based vaccine design. Antibody lineage-based design is described for VRC01, PGT121 and PG9 antibody classes, and epitope-based vaccine design is described for the CD4-binding site, as well as fusion peptide and glycan-V3 cites of vulnerability.
Kwong2018
(antibody binding site, vaccine antigen design, vaccine-induced immune responses, review, antibody lineage, broad neutralizer, junction or fusion peptide)
-
VRC01: VRC 606 (clinicaltrials.gov NCT02599896) was a single-site Phase I open-label dose-escalation study that evaluated a variant of VRC01, VRC01LS for safety and pharmacokinetic (PK) parameters. VRC01LS has mutations M428L and N434S in the Fc region intended to extend serum half-life, these LS mutations result in enhanced IgG-FcRn binding but do not affect binding to the Fc-gamma receptor and thus do not impair Fc-mediated effector functions, such as antibody dependent cellular cytotoxicity (ADCC). It was observed that VRC01LS was safe and well tolerated and displayed a serum half-life more than four times longer than wild-type VRC01. The VRC01LS Ab retained its neutralizing activity in serum for the 48-week duration of this study, and no Abs were detected to it.
Gaudinski2018
(enhancing activity, therapeutic vaccine, immunotherapy, broad neutralizer)
-
VRC01: This review discusses the identification of super-Abs, where and how such Abs may be best applied, and future directions for the field. VRC01, a prototype super-Ab, was isolated from direct functional screening of thousands of B cell clones. VRC01 is in Phase I clinical development and the Antibody-Mediated Prevention (AMP) study will assess the ability of the VRC01 mAb specific for CD4 binding site to decrease the risk of HIV acquisition in humans.
Walker2018
(antibody binding site, review, broad neutralizer)
-
VRC01: The authors selected an optimal panel of diverse HIV-1 envelope glycoproteins to represent the antigenic diversity of HIV globally in order to be used as antigen candidates. The selection was based on genetic and geographic diversity, and experimentally and computationally evaluated humoral responses. The eligibility of the envelopes as vaccine candidates was evaluated against a panel of antibodies for breadth, affinity, binding and durability of vaccine-elicited responses. The antigen panel was capable of detecting the spectrum of V2-specific antibodies that target epitopes from the V2 strand C (V2p), the integrin binding motif in V2 (V2i), and the quaternary epitope at the apex of the trimer (V2q).
Yates2018
(vaccine antigen design, vaccine-induced immune responses, binding affinity)
-
VRC01: Polyreactive properties of natural and artificially engineered HIV-1 bNAbs were studied, with almost 60% of the tested HIV-1 bNAbs (including this one) exhibiting low to high polyreactivity in different immunoassays. A previously unappreciated polyreactive binding for PGT121, PGT128, NIH45-46W, m2, and m7 was reported. Binding affinity, thermodynamic, and molecular dynamics analyses revealed that the co-emergence of enhanced neutralizing capacities and polyreactivity was due to an intrinsic conformational flexibility of the antigen-binding sites of bNAbs, allowing a better accommodation of divergent HIV-1 Env variants.
Prigent2018
(antibody polyreactivity)
-
VRC01: A systems glycobiology approach was applied to reverse engineer the relationship between bNAb binding and glycan effects on Env proteins. Glycan occupancy was interrogated across every potential N-glycan site in 94 recombinant gp120 antigens. Using a Bayesian machine learning algorithm, bNAb-specific glycan footprints were identified and used to design antigens that selectively alter bNAb antigenicity. The novel synthesized antigens unsuccessfully bound to target bNAbs with enhanced and selective antigenicity.
Yu2018
(glycosylation, vaccine antigen design)
-
VRC01: This review discusses current HIV bNAb immunogen design strategies, recent progress made in the development of animal models to evaluate potential vaccine candidates, advances in the technology to analyze antibody responses, and emerging concepts in understanding B cell developmental pathways that may facilitate HIV vaccine design strategies.
Andrabi2018
(vaccine antigen design, review)
-
VRC01: A panel of bnAbs were studied to assess ongoing adaptation of the HIV-1 species to the humoral immunity of the human population. Resistance to neutralization is increasing over time, but concerns only the external glycoprotein gp120, not the MPER, suggesting a high selective pressure on gp120. Almost all the identified major neutralization epitopes of gp120 are affected by this antigenic drift, suggesting that gp120 as a whole has progressively evolved in less than 3 decades.
Bouvin-Pley2014
(neutralization)
-
VRC01: Bispecific bNAbs containing anti-CD4bs VRC01 and anti-V3 glycan PGT121 were constructed by linking the single chain (Sc) bNAbs with flexible (G4S)n linkers at IgG Fc and were found to have greater neutralization breadth than parental bNAbs when optimal. The optimal bis-specific NAb, dVRC01-5X-PGT121, was one that crosslinked protomers within one Env spike. Combination of this bispecific with a third bNAb, anti-MPER 10E8, gave 99.5%, i.e. nearly pan-neutralization of a 208 virus panel with a geometric mean IC50 below 0.1 µg/ml.
Steinhardt2018
(neutralization, immunotherapy, bispecific/trispecific)
-
VRC01: The first cryo-EM structure of a cross-linked vaccine antigen was solved. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a bNAb PGV04 Fab fragment revealed how cross-linking affects key properties of the trimer. SOSIP and GLA-SOSIP trimers were compared for antigenicity by ELISA, using a large panel of mAbs previously determined to react with BG505 Env. Non-NAbs globally lost reactivity (7-fold median loss of binding), likely because of covalent stabilization of the cross-linked ‘closed’ form of the GLA-SOSIP trimer that binds non-NAbs weakly or not at all. V3-specific non-NAbs showed 2.1–3.3-fold reduced binding. Three autologous rabbit monoclonal NAbs to the N241/N289 ‘glycan-hole’ surface, showed a median ˜1.5-fold reduction in binding. V3 non-NAb 4025 showed residual binding to the GLA-SOSIP trimer. By contrast, bNAbs like VRC01 broadly retained reactivity significantly better than non-NAbs, with exception of PGT145 (3.3-5.3 fold loss of binding in ELISA and SPR).
Schiffner2018
(vaccine antigen design, binding affinity, structure)
-
VRC01: This study describes the generation of CHO cell lines stably expressing the following vaccine Env Ags: CRF01_AE A244 Env gp120 protein (A244.AE) and 6240 Env gp120 protein (6240.B). The antigenic profiles of the molecules were assessed with a panel of well-characterized mAbs recognizing critical epitopes and glycosylation analysis confirming previously identified sites and revealing unknown sites at non-consensus motifs. A244.AE gp120 bound to VRC01 in ELISA EC50 and Surface Plasmon Resonance (SPR) assays. 6240.B gp120 bound to VRC01. 6240.B gp120 exhibited binding to VRC01.
Wen2018
(glycosylation, vaccine antigen design)
-
VRC01: The prophylactic and therapeutic potential of an engineered single gene–encoded tandem bispecific immunoadhesin (IA) molecule BiIA-SG was studied. Before engineering BiIAs, codon-optimized scFvs of bNAbs PG9, PG16, PGT128, VRC01, and Hu5A8 were synthesized. The VL/VH domain of each scFv was engineered as a corresponding IA by fusion with human IgG1-Fc to generate IA-PG9, IA-PG16, IA-PGT128, IA-VRC01, and IA-Hu5A8. While all IAs exhibited specific anti–HIV-1 activity, only IA-PGT128 displayed similar potency and the same sigmoidal slope of 100% neutralization as previously described for the native PGT128, and IA-PGT128 in combination with IA-Hu5A8 exhibited the best synergistic effect based on computational synergy volumes. IA-PGT128 and IA-Hu5A8 were therefore used for BiIA construction.
Wu2018
-
VRC01: Prevention of HIV infection by intravenously-administered VRC01 was modeled to predict prevention efficacy (PE) of each 10 mg/kg or 30 mg/kg VRC01 dose. Nonhuman primates (NHPs) were administered high-dose intra-rectal simian-human immunodeficiency virus challenge two days post-VRC01 infusion (“NHP model”). As humans may require greater VRC01 concentration to achieve the same level of protection, it was assumed that 5-fold greater VRC01 serum concentration would be needed to provide the same level of per-exposure PE as seen in the NHP data (“5-fold model”). For the 10 mg/kg regimen, the 5-fold and NHP models predict an overall PE of 37% and 64%, respectively; for the 30 mg/kg regimen, the two models predict an overall PE of 53% and 82%, respectively.
Huang2018
(immunoprophylaxis)
-
VRC01: Assays of poly- and autoreactivity demonstrated that broadly neutralizing NAbs are significantly more poly- and autoreactive than non-neutralizing NAbs. VRC01 is autoreactive, but not polyreactive.
Liu2015a
(autoantibody or autoimmunity, antibody polyreactivity)
-
VRC01: This study was designed to evaluate the safety, pharmacological profile, and immune functions of VRC01 administered either subcutaneously or intravenously as a foundation for future efficacy trials. HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01. Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6 United States clinical research sites affiliated with the HVTN between September 9, 2014 and July 15, 2015. Participants were randomized to receive the following: a 40 mg/kg IV VRC01 loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment group 1 [T1], n = 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 [T3], n = 20); placebo (placebo group 3 [P3], n = 4)doses every 2 weeks; or three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 [T2], n = 20). Treatment groups T4 and T5 (n = 12 each) received three 10 or 30 mg/kg IV VRC01 doses every 8 weeks, respectively. Participants were followed for 32 weeks after their first VRC01 administration and received a total of 249 IV infusions and 208 SC injections, with no serious adverse events, dose-limiting toxicities, nor evidence for anti-VRC01 antibodies observed. The limitations of this study include the relatively small sample size of each VRC01 administration regimen and missing data from participants who were unable to complete all study visits. The antibody in serum after administration showed evidence of a number of immune functions that are known to inhibit HIV transmission and replication.
Mayer2017
(immunoprophylaxis, immunotherapy)
-
VRC01: Panels of C clade pseudoviruses were computationally downselected from the panel of 200 C clade viruses defined by Rademeyer et al. 2016. A 12-virus panel was defined for the purpose of screening sera from vaccinees. Panels of 50 and 100 viruses were defined as smaller sets for use in testing magnitude and breadth against C clade. Published neutralization data for 16 mAbs was taken from CATNAP for the computational selections: 10-1074, 10-1074V, PGT121, PGT128, VRC26.25, VRC26.08, PGDM1400, PG9, PGT145, VRC07-523, 10E8, VRC13, 3BNC117, VRC07, VRC01, 4E10.
Hraber2017
(assay or method development, neutralization)
-
VRC01: This study reports host tolerance mechanisms that limit the development of CD4bs and HCDR3-binder bNAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs bnAbs recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice Env + B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env- upon receptor editing. Stepwise immunization initiates CD4bs-bnAb responses, but immune tolerance mechanisms restrict their development. Crystal structure of DH522 showed footprints of VRC01 and CD4 attachment inhibitor N-(4-bromophenyl)-N′-(2,2,6,6-tetramethylpiperidin-4-yl)ethanediamide (NBD-557).
Williams2017a
(glycosylation, structure, antibody lineage, chimeric antibody)
-
VRC01: The immunologic effects of mutations in the Env cytoplasmic tail (CT) that included increased surface expression were explored using a vaccinia prime/protein boost protocol in mice. After vaccinia primes, CT- modified Envs induced up to 7-fold higher gp120-specific IgG, and after gp120 protein boosts, they elicited up to 16-fold greater Tier-1 HIV-1 neutralizing antibody titers. Envs with or without the TM1 mutations were expressed in HEK 293T cells and analyzed for the relative expression of Ab epitopes including the CD4 binding site for VRC01.
Hogan2018
(vaccine antigen design)
-
VRC01: The HIV Vaccine Trials Network and the HIV Prevention Trials Network conducted the first clinical test-of-concept, Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of VRC01, prevents HIV-1 infection. HIV-1 prevention efficacy trials were conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa. Participants were randomized 1:1:1 to receive an intravenous infusion of 10 mg/kg VRC01, 30 mg/kg VRC01, or a control preparation every 8 weeks for a total of 10 infusions. Each trial wasdesigned (1) to assess overall prevention efficacy (PE) pooled over the two VRC01 dose groups vs. control and (2) to assess VRC01 dose and laboratory markers as correlates of protection (CoPs) against overall and genotype- and phenotype-specific infection. Each AMP trial was designed to have 90% power to detect PE > 0% if PE is ≥ 60%. If affirmative, they will provide information for estimating the optimal dosage of VRC01 (or subsequent derivatives) and identify threshold levels of neutralization and Fc effector functions associated with high-level protection.
Gilbert2017
(immunoprophylaxis)
-
VRC01: SOSIP.664 trimer was modified at V3 positions 306 and 308 by Leucine substitution to create hydrophobic interactions with the tryptophan residue at position 316 and the V1V2 domain. These modifications stabilized the resulting SOSIP.v5.2 S306L R308L trimers. In vivo, the induction of V3 non-NAbs was significantly reduced compared with the SOSIP.v5.2 trimers. S306L plus R308L paired substitutions had no effect on the trimer reactivity of VRC01.
deTaeye2018
(broad neutralizer)
-
VRC01: Nanodiscs (discoidal lipid bilayer particles of 10-17 nm surrounded by membrane scaffold protein) were used to incorporate Env complexes for the purpose of vaccine platform generation. The Env-NDs (Env-NDs) were characterized for antigenicity and stability by non-NAbs and NAbs. Most NAb epitopes in gp41 MPER and in the gp120:gp41 interface were well exposed while non-NAb cell surface epitopes were generally masked. Anti-CD4bs NAb VRC01, had a Kd of 14.6 nM and bound the Env-ND well.
Witt2017
(vaccine antigen design, binding affinity)
-
VRC01: In the RV305 HIV-1 vaccine trial, two boosts of either ALVAC-HIV, AIDSVAX B/E gp120 or ALVAC-HIV + AIDSVAX B/E gp120 were given to HIV-1-uninfected RV144 vaccine-recipients. While no bNAb plasma activity was induced in this trial as well, an increased frequency of memory B cells that produce Env-specific anti-CD4bs antibodies with long HCDR3s was detected. In a binding assay, VRC01 binding was reduced by mutants of CRF01_AE Env protein A244.
Easterhoff2017
(binding affinity)
-
VRC01: DS-SOSIP.4mut (4mut) was identified as the most immunogenic and stable of 4 engineered, soluble, closed prefusion HIV-1 Env trimers. 4mut contained 4 mutations (M154, M300, M302 and L320) designed to form hydrophobic interactions between V1V1 and V3 loops. Both pre- and post-V3 negative selection, CD4bs-targeted bnAb VRC01 recognized 4mut, the other 3 designed trimers (DS-SOSIP.6mut containing 4mut mutations, Y177W and I420M, DS-SOSIP.I423F and DS-SOSIP.A316W), and related trimers DS-SOSIP and BG505 SOSIP.664. Each DS-SOSIP variant was able to elicit trimer-specific responses, comparable to BG505 SOSIP.664, in guinea pigs after 4 immunizations, but none elicited heterologous neutralizing activity. Crystal structures were generated for 4mut and 6mut.
Chuang2017
(vaccine antigen design, vaccine-induced immune responses)
-
VRC01: Libraries of BG505 gp120 containing mutations were displayed on yeast and screened for binding to a panel of VRC01-class mAbs. Boosted VRC01 gH mice showed broad neutralization on a panel of N276A viruses, neutralization of fully native virus containing the N276 glycan site was limited to a single heterologous tier 2 isolate and was substantially less potent. The progress of vaccine-induced somatic hyper mutation, SHM, toward mature VRC01 was tested. For each VH1-2 sequence, the total number of amino-acid mutations and the number of amino-acid mutations shared with a panel of VRC01-class mAbs like VRC01, PGV04, PGV20, VRC-CH31, 3BNC60, and 12A12 were determined. Extremely deep Ab repertoire sequencing on two healthy HIV-naive individuals were performed to compute the frequency of randomly incorporated VRC01-class mutations in human VH1-2 Ab sequence.
Briney2016
(HIV-2, neutralization, vaccine antigen design)
-
VRC01: Env variants that lack all 15 core glycan sites were produced. These variants retain conformational integrity and viral infectivity and bind to several bNAbs, including VRC01 and b12, suggesting that Env glycans are not essential to protein folding, and deglycosylated antigens may be useful as priming immunogens. A partially germline-reverted variant of VRC01 (GL-VRC01) was produced to compare its binding to that of VRC01.
Rathore2017
(glycosylation, vaccine antigen design)
-
VRC01: Env trimers were engineered with selective deglycosylation around the CD4 binding site to see if they could be useful vaccine antigens. The neutralization of glycan-deleted trimers was tested for a set of bnAbs (PG9, PGT122, PGT135, b12, CH103, HJ16, VRC01, VRC13, PGT151, 8ANC195, 35O22), and the antigens elicited potent neutralization based on the CD4 supersite. A crystal structure was made of one of these Env trimers bound to Fabs 35O22 and 3H+109L. Guinea pigs vaccinated with these antigens achieved neutralization of deglycosylated Envs. Glycan-deleted Env trimers may be useful as priming antigens to increase the frequency of CD4 site-directed antibodies.
Zhou2017
(glycosylation, neutralization, vaccine antigen design, vaccine-induced immune responses)
-
VRC01: Env from of a highly neutralization-resistant isolate, CH120.6, was shown to be very stable and conformationally-homogeneous. Its gp140 trimer retains many antigenic properties of the intact Env, while its monomeric gp120 exposes more epitopes. Thus trimer organization and stability are important determinants for occluding epitopes and conferring resistance to antibodies. Among a panel of 21 mAbs, CH120.6 was resistant to neutralization by all non-neutralizing and strain-specific mAbs, regardless of the location of their epitopes. It was weakly neutralized by several broadly-neutralizing mAbs (VRC01, NIH45-46, 12A12, PG9, PG16, PGT128, 4E10, and 10E8), and well neutralized by only 2 (PGT145 and 10-1074).
Cai2017
(neutralization)
-
VRC01: Mice twice-primed with DNA plasmids encoding HIV-1 gp120 and gag and given a double boost with HIV-1 virus-like particles (VLPs) i.e. DDVV immunization, elicited Env-specific antibody responses as well as Env- and Gag-specific CTL responses. In vivo electroporation (EP) was used to increase breadth and potency of response. Human anti-gp120 VRC01 was used to prove that the VLP spike included the broad neutralization epitope recognized by it.
Huang2017a
(therapeutic vaccine, variant cross-reactivity)
-
VRC01: This review discusses host controls of bNAb responses and why highly antigenic vaccine Envs do not induce bNAbs when used as vaccine immunogens. In Kl mice expressing 3BNC60 germline unmutated common ancestor (UCA), majority of the bone marrow B cell were deleted, and peripheral residual B cells were anergic. Vaccination resulted in GL B cells activated with minimal affinity maruration.
Kelsoe2017
(review)
-
VRC01: A panel of mAbs (2G12, VRC01, HJ16, 2F5, 4E10, 35O22, PG9, PGT121, PGT126, 10-1074) was tested to compare their efficacy in cell-free versus cell-cell transmission. Almost all bNAbs (with the exception of anti-CD4 mAb Leu3a) blocked cell-free infection with greater potency than cell-cell infection, and showed greater potency in neutralization of cell-free viruses. The lower effectiveness on neutralization was particularly pronounced for transmitted/founder viruses, and less pronounced for chronic and lab-adapted viruses. The study highlights that the ability of an antibody to inhibit cell-cell transmission may be an important consideration in the development of Abs for prophylaxis.
Li2017
(immunoprophylaxis, neutralization)
-
VRC01: Compared to patient-derived mAbs, vaccine-elicited mAbs are often less able to neutralize the virus, due to a less-effective angle of approach to the Env spike. This study engineered an immunogen consisting of the gp120 core in complex with a CD4bs mAb, 17b. Rabbits immunized with this antigen displayed earlier affinity maturation and better virus neutralization compared to those immunized with the gp120 core alone. The 17b antibody was shown to have a steric clash with two other CD4bs Abs, GE136 and GE148, but not with VRC01. VRC01 and 2G12 bound to the the 17b-gp120 complex more avidly than to the gp120 core alone.
Chen2016b
(antibody binding site, vaccine antigen design, vaccine-induced immune responses, structure)
-
VRC01: This study describes a computational method to calculate the binding affinities of antibodies and antigens. The method called free-energy perturbation (FEP) was developed using HIV-1 Env gp120 and 3 VRC01-class mAbs, VRC01, VRC03, and VRC-PG04.
Clark2017
(binding affinity, structure)
-
VRC01: The next generation of a computational neutralization fingerprinting (NFP) being used as a way to predict polyclonal Ab responses to HIV infection is presented. A new panel of 20 pseudoviruses, termed f61, was developed to aid in the assessment of experimental neutralization. This panel was used to assess 22 well-characterized bNAbs and mixtures thereof (HJ16, VRC01, 8ANC195, IGg1b12, PGT121, PGT128, PGT135, PG9, PGT151, 35O22, 10E8, 2F5, 4E10, VRC27, VRC-CH31, VRC-PG20, PG04, VRC23, 12A12, 3BNC117, PGT145, CH01). The new algorithms accurately predicted VRC01-like and PG9-like antibody specificities.
Doria-Rose2017
(neutralization, computational prediction)
-
VRC01: This review focuses on the potential role of HIV-1-specific NAbs in preventing HIV-1 infection. Several NAbs have provided protection from infection in SHIV challenge studies in primates: b12, VRC01, VRC07-523LS, 3BNC117, PG9, PGT121, PGT126, 10-1074, 2G12, 4E10, 2F5, 10E8. Engineered variant VRC01-LS had greater persistence and improved protection against SHIV challenge, compared to VRC01.
Pegu2017
(immunoprophylaxis, review)
-
VRC01: Prevalence, breadth, and potency of NAb responses in 98 CRF07_BC-infected individuals using a multi-subtype panel of 30 tier 2-3 Env-pseudotyped viruses were identified and the neutralization pattern of CRF07_BC-infected people was compared with that of subtype B'-infected individuals in China. 18% of 98 plasma samples neutralized >80% of viruses, and 53% neutralized >50%, suggesting the presence of broadly NAbs. CRF07_BC-infected individuals generated higher but less broad neutralization titers against intra-subtype viruses than subtype B'-infected individuals with longer infection length, indicating the transition from narrow autologous to broad heterologous neutralization over time. Neutralization activity of the top six plasmas from each cohort was attributable to the IgG fraction, and half of them developed CD4 binding site antibody reactivity. VRC01 and 2G12 were used as controls.
Hu2017
(broad neutralizer)
-
VRC01: First population pharmacokinetics (PK) analysis of VRC01 was conducted using 84 HIV-uninfected adults who received multiple-dose intravenous or subcutaneous VRC01 every several weeks. The study demonstrated that a robust PK model of VRC01 could be developed to reliably characterize the observed PK data and to estimate VRC01 concentration values and associated variabilities at any post-dose time-point.
Huang2017
(immunoprophylaxis)
-
VRC01: Novel bNAb, IOMA, combines features of VH1-2/VRC01-class bNAbs with CD4-mimetic CD4bs bNAbs. It is described in complex to BG505 SOSIP.664 Env trimer by 3.5A and 3.9A-resolution crystal structures. The IOMA-BG505 structure demonstrates that VH1-2*02-derived CD4-mimetic bNAbs are not limited to longer, five-residue CDRL3s as in the case of VRC01. This is the first full description of native glycosylated trimer (untrimmed high-mannose and complex-typle N-glycans) revealing Ab-vulnerable glycan holes. Though derived from VRC01, the shorter CDRL3 makes IOMA resemble am 8ANC131-class/VH1-46-derived CD4bs bNAb.
Gristick2016
(glycosylation)
-
VRC01: This review summarizes vaccine approaches to counter HIV diversity. A structural map illustrated the contact regions of several bNAbs: VRC26.09, PGT128, CH235.12, and 10E8. Structures illustrating the bNAbs' tolerance for sequence variation were illustrated for CH235.12, PGT128, VRC26.09, and 10E8. CD4BS bNAbs such as VRC01 and CH235.12 illustrate that bNAbs bind to both conserved and hypervariable regions of Env. These bNAbs aren't broad because their epitopes are highly conserved, but rather they arise due to selective pressures of the autologous viruses.
Korber2017
(antibody binding site, vaccine antigen design, review)
-
VRC01: In 33 individuals (14 uninfected and 19 HIV-1-infected), intravenous infusion of 10-1074 was well tolerated. In infected individuals with sensitive strains, 10-1074 decreased viremia, but escape variants and viral rebound occurred within a few weeks. Escape variants were also resistant to V3 antibody PGT121, but remained sensitive to antibodies targeting other epitopes (3BNC117, VRC01 or PGDM1400). Loss of the PNGS at position N332 or 324G(D/N)IR327 mutation was associated with resistance to 10-1074 and PGT121.
Caskey2017
(escape, immunotherapy)
-
VRC01: The results confirm that Nef and Vpu protect HIV-1-infected cells from ADCC, but also show that not all classes of antibody can mediate ADCC. Anti-cluster-A antibodies are able to mediate potent ADCC responses, whereas anti-coreceptor binding site antibodies are not. Position 69 in gp120 is important for antibody-mediated cellular toxicity by anti-cluster-A antibodies. The angle of approach of a given class of antibodies could impact its capacity to mediate ADCC. VRC01 and b12 were selected as Abs that recognize the CD4 binding site.
Ding2015
(effector function)
-
VRC01: The ability of neutralizing and nonneutralizing mAbs to block infection in models of mucosal transmission was tested. Neutralization potency did not fully predict activity in mucosal tissue. CD4bs-specific bNAbs, in particular VRC01, blocked HIV-1 infection across all cellular and tissue models. MPER (2F5) and outer domain glycan (2G12) bNAbs were also efficient in preventing infection of mucosal tissues, while bNAbs targeting V1-V2 glycans (PG9 and PG16) were more variable. Non-nAbs alone and in combinations, were poorly protective against mucosal infection. The protection provided by specific bNAbs demonstrates their potential over that of nonneutralizing antibodies for preventing mucosal entry. VRC01, b12, and CH31 were selected as representative mAbs of the CD4-BS class.
Cheeseman2017
(genital and mucosal immunity, immunoprophylaxis)
-
VRC01: To understand HIV neutralization mediated by the MPER, antibodies and viruses were studied from CAP206, a patient known to produce MPER-targeted neutralizing mAbs. 41 human mAbs were isolated from CAP206 at various timepoints after infection, and 4 macaque mAbs were isolated from animals immunized with CAP206 Env proteins. Two rare, naturally-occuring single-residue changes in Env were identified in transmitted/founder viruses (W680G in CAP206 T/F and Y681D in CH505 T/F) that made the viruses less resistant to neutralization. The results point to the role of the MPER in mediating the closed trimer state, and hence the neutralization resistance of HIV. CH58 was one of several mAbs tested for neutralization of transmitted founder viruses isolated from clade C infected individuals CAP206 and CH505, compared to T/F viruses containing MPER mutations that confer enhanced neutralization sensitivity.
Bradley2016a
(neutralization)
-
VRC01: A novel MHC-independent third-generation anti-HIV-1 CAR molecule (CD3ζ-CD28-CD137) has been reported.The extracellular domain is consisted of an scFv region derived from the bNAb VRC01 capable of redirecting the antigen specificity of primary CD8+ T cell populations against gp120. CAR cytoplasmic region, composed of a CD3ζ chain and multiple signaling domains (CD28 and CD137). The VC-CAR-T cells, were able to induce T cell-mediated cytolysis after coculture with gp120-expressing cells and wild-type HIV-1-infected CD4+ T cells. This also effectively induced the cytolysis of LRA-reactivated HIV-1-infected CD4 T lymphocytes isolated from infected individuals receiving sup-pressive cART. The data demonstrates that the special features of genetically engineered CAR-T cells make them a particularly suitable candidate for therapeutic application and constitute an improvement over existing CD4-based CAR-T technology.
Liu2016
(CD4+ CTL, immunotherapy)
-
VRC01: This study performed cyclical permutation of the V1 loop of JRFL in order to develop better gp120 trimers to elicit neutralizing antibodies. Some mutated trimers showed improved binding to several mAbs, including VRC01, VRC03, VRC-PG04, PGT128, PGT145, PGDM1400, b6, and F105. Guinea pigs immunized with prospective trimers showed improved neutralization of a panel of HIV-1 pseudoviruses. Binding of VRC01 to JRFL was abolished by mutation N279A.
Kesavardhana2017
(vaccine antigen design, vaccine-induced immune responses)
-
VRC01: This study investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit NAbs. Rabbits were immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). N197 glycan- and residue 230- removal conferred sensitivity to Trimer VLP sera and DNA trimer sera respectively, showing for the first time that strain-specific holes in the "glycan fence" can allow the development of tier 2 NAbs to native spikes. All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. VRC01 was 1 of 4 reference VRC01-like bNAbs - VRC01, 3BNC117, 8ANC131, CH103.
Crooks2015
(glycosylation, neutralization)
-
VRC01: 24 participants received VRC01 as immunotherapy during ART treatment interruption. VRC01 delayed viral rebound by approximately 4 to 6 weeks. VRC01 exerted pressure on the rebounding virus, resulting in selection for neutralization-resistant viruses.
Bar2016
(immunotherapy)
-
VRC01: Env residue N197 on the BG505-SOSIP trimer was mutated to test the effect of its glycosylation on the binding kinetics of CD4BS and other mAbs. Removal of the glycan had little effect on the overall structure of the molecule. Its removal resulted in increased binding of CD4 and CD4BS antibodies (VRC01, VRC03, V3-3074), but little effect on bNAbs targeting other epitopes (PG9, PG16, PGT145, 17b, A32, 2G12, PGT121, PGT126). Two CD4BS-binding antibodies tested (b12, F105) had insufficient breadth to bind the BG505-SOSIP trimer. Removal of the N197 glycan may allow for the development of better SOSIP immunogens, particularly to elicit CD4BS-specific Abs.
Liang2016
(glycosylation, vaccine antigen design)
-
VRC01: Chimeric antigen receptors, i.e., fusion proteins made from single-chain antibodies, may be a useful approach to immunotherapy. A set of mAbs were chosen based on their binding to a variety of sites on Env and availability of antibody sequences. The chimeric receptors were created by fusing the antibody's heavy chain, light chain, and two signaling domains into a single molecule. All 7 antibodies used to make the chimeric receptors (10E8, 3BNC117, PGT126, VRC01, X5, PGT128, PG9) showed specific killing of HIV-1 infected cells and suppression of viral replication against a panel of HIV-1 strains.
Ali2016
(immunotherapy, chimeric antibody)
-
VRC01: This review classified and mapped the binding regions of 32 bNAbs isolated 2010-2016.
Wu2016
(review)
-
VRC01: In neutralization assays of antibody mixtures, there was a modest synergy between the CD4bs VRC01 and either of the two CD4i MAbs E51 and 412d. The synergy is likely the result of the ability of CD4i antibodies (E51 or 412d) to induce the open state and facilitate access to the CD4 binding site. The presence of E51 enhanced the Env binding of VRC01, NIH45-46, NIH45-46G54W, and to a lesser extent 3BNC117.
Gardner2016
(antibody interactions)
-
VRC01: This study produced Env SOSIP trimers for clades A (strain BG505), B (strain JR-FL), and G (strain X1193). Based on simulations, the MAb-trimer structures of all MAbs tested needed to accommodate at least one glycan, including both antibodies known to require specific glycans (PG9, PGT121, PGT135, 8ANC195, 35O22) and those that bind the CD4-binding site (b12, CH103, HJ16, VRC01, VRC13). A subset of monoclonal antibodies bound to glycan arrays assayed on glass slides (VRC26.09, PGT121, 2G12, PGT128, VRC13, PGT151, 35O22), while most of the antibodies did not have affinity for oligosaccharide in the context of a glycan array (PG9, PGT145, PGDM1400, PGT135, b12, CH103, HJ16, VRC16, VRC01, VRC-PG04, VRC-CH31, VRC-PG20, 3BNC60, 12A12, VRC18b, VRC23, VRC27, 1B2530, 8ANC131, 8ANC134, 8ANC195).
Stewart-Jones2016
(antibody binding site, glycosylation, structure)
-
VRC01: This study assessed the ADCC activity of antibodies of varied binding types, including CD4bs (b6, b12, VRC01, PGV04, 3BNC117), V2 (PG9, PG16), V3 (PGT126, PGT121, 10-1074), oligomannose (2G12), MPER (2F5, 4E10, 10E8), CD4i (17b, X5), C1/C5 (A32, C11), cluster I (240D, F240), and cluster II (98-6, 126-7). ADCC activity was correlated with binding to Env on the surfaces of virus-infected cells. ADCC was correlated with neutralization, but not always for lab-adapted viruses such as HIV-1 NLA-3.
vonBredow2016
(effector function)
-
VRC01: This review summarizes representative anti-HIV MAbs of the first generation (2G12, b12, 2F5, 4E10) and second generation (PG9, PG16, PGT145, VRC26.09, PGDM1400, PGT121, PGT124, PGT128, PGT135, 10-1074, VRC01, 3BNC117, CH103, PGT151, 35O22, 8ANC195, 10E8). Structures, epitopes, VDJ usage, CDR usage, and degree of somatic hypermutation are compared among these antibodies. The use of SOSIP trimers as immunogens to elicit B-cell responses is discussed.
Burton2016
(review, structure)
-
VRC01: This study estimated intra-lineage longitudinal evolutionary rate changes for the VRC26 and CH103 lineages and compared these to the reported rate changes of the VRC01 lineage. Results confirmed that a decreasing evolutionary rate is common to all three lineages.
Sheng2016
(antibody lineage)
-
VRC01: Two stable homogenous gp140 Env trimer spikes, Clade A 92UG037.8 Env and Clade C C97ZA012 Env, were identified. 293T cells stably transfected with either presented fully functional surface timers, 50% of which were uncleaved. A panel of neutralizing and non-neutralizing Abs were tested for binding to the trimers. Consistent with CD4bs bNAbs, VRC01 bound cell surface tightly whether the trimer contained its C-terminal or not, and was competed out by sCD4. It was able to neutralize the 92UG037.8 HIV-1 isolate.
Chen2015
(neutralization, binding affinity)
-
VRC01: Factors that independently affect bNAb induction and evolution were identified as viral load, length of untreated infection, and viral diversity. Black subjects induced bNAbs more than white subjects, but this did not correlate with type of Ab response. Fingerprint analyses of induced bNAbs showed strong subtype dependency, with subtype B inducing significantly higher levels of CD4bs Abs and non-subtype B inducing V2-glycan specific Abs. Of the 239 bNAb antibody inducers found from 4,484 HIV-1 infected subjects,the top 105 inducers' neutralization fingerprint and epitope specificity was determined by comparison to the following antibodies - PG9, PG16, PGDM1400, PGT145 (V2 glycan); PGT121, PGT128, PGT130 (V3 glycan); VRC01, PGV04 (CD4bs) and PGT151 (interface) and 2F5, 4E10, 10E8 (MPER).
Rusert2016
(neutralization, subtype comparisons, broad neutralizer)
-
VRC01: PGT145 was used to positively isolate a subtype B Env trimer immunogen, B41 SOSIP.664-D7324, that exists in two conformations, closed and partially open. bNAbs tested against the trimer were able to neutralize the B41 pseudovirus with a wide range of potencies. All tested non-NAbs did not neutralize B41 (IC50 >50µg/ml). CD4bs bNAb, VRC01, was able to neutralize and bind B41 pseudovirus and trimer well.
Pugach2015
-
VRC01: The first generation of HIV trimer soluble immunogens, BG505 SOSIP.664 were tested in a mouse model for generation of nAb to neutralization-resistant circulating HIV strains. No such NAbs were induced, as mouse Abs targeted the bottom of soluble Env trimers, suggesting that the glycan shield of Env trimers is impenetrable to murine B cell receptors and that epitopes at the trimer base should be obscured in immunogen design in order to avoid non-nAb responses. Association and dissociation of known anti-trimer bNAbs (VRC01, PGT121, PGT128, PGT151, PGT135, PG9, 35O22, 3BC315 and PGT145) were found to be far greater than murine generated non-NAbs.
Hu2015
-
VRC01: A comprehensive antigenic map of the cleaved trimer BG505 SOSIP.664 was made by bNAb cross-competition. Epitope clusters at the CD4bs, quaternary V1/V2 glycan, N332-oligomannose patch and new gp120-gp41 interface and their interactions were delineated. Epitope overlap, proximal steric inhibition, allosteric inhibition or reorientation of glycans were seen in Ab cross-competition. Thus bNAb binding to trimers can affect surfaces beyond their epitopes. Among CD4bs binding bNAbs, VRC01 recognizes trimer similarly to CH103, CH106, 3BNC117 and 1NC9, and is inhibited by sCD4. VRC01 enhanced binding of non-NAb 17b. outer domain (OD)-glycan bNAbs, PGT135 and PGT136, though ˜ 5x less efficient binders of trimer, were able to unidirectionally inhibit binding of VRC01, as also other CD4bs bNAbs, 3BNC117, 2BNC60, NIH45-46.
Derking2015
(antibody interactions, neutralization, binding affinity, structure)
-
VRC01: Two clade C recombinant Env glycoprotein trimers, DU422 and ZM197M, with native-like structural and antigenic properties involving epitopes for all known classes of bNAbs, were produced and characterized. These Clade C trimers (10-15% of which are in a partially open form) were more like B41 Clade B trimers which have 50-75% trimers in the partially open configuration than like B505 Clade B trimers, almost 100% in the closed, prefusion state. The Clade C trimer ZM197M is strongly reactive to the CD4bs bNAb VRC01 but trimer DU442 and its pseudotyped virus are weakly reactive with VRC01. The structure of a complex of ZM197M SOSIP.664 with VRC01 Fab at 9.6 A by cryo-EM had a 0.96 correlation with the structure of the Clade A trimer.
Julien2015
(assay or method development, structure)
-
VRC01: Env trimer BG505 SOSIP.664 as well as the clade B trimer B41 SOSIP.664 were stabilized using a bifunctional aldehyde (glutaraldehye, GLA) or a heterobifunctional cross-linker, EDC/NHS with modest effects on antigenicity and barely any on biochemistry or structural morphology. ELISA, DSC and SPR were used to test recognition of the trimers by bNAbs, which was preserved and by weakly NAbs or non-NAbs, which was reduced. Cross-linking partially preserves quaternary morphology so that affinity chromatography by positive selection using quaternary epitope-specific bNAabs, and negative selection using non-NAbs, enriched antigenic characteristics of the trimers. Binding of the anti-CD4bs bNAb VRC01 to trimers was minimally affected by trimer cross-linking.
Schiffner2016
(assay or method development, binding affinity, structure)
-
VRC01: HIV-1 escape from the N332-glycan dependent bNAb, PGT135, developed in an elite controller but without change to the PGT135-binding Env epitope itself. Instead an insertion increasing V1 length by up to 21 residues concomitant with an additional 1-3 glycans and 2-4 cysteines shields the epitope from PGT135. The majority of viruses tested developed a 14-fold resistance to PGT135 from month 7 to 11. In contrast no significant difference in neutralization sensitivity was seen between HIV-1 and bNAb VRC01.
vandenKerkhof2016
(elite controllers and/or long-term non-progressors, neutralization, escape)
-
VRC01: The native-like, engineered trimer BG505 SOSIP.664 induced potent NAbs against conformational epitopes of neutralization-resistant Tier-2 viruses in rabbits and macaques, but induced cross-reactive NAbs against linear V3 epitopes of neutralization-sensitive Tier-1 viruses. A different trimer, B41 SOSIP.664 also induced strong autologous Tier-2 NAb responses in rabbits. Sera from 10/20 BG505 SOSIP.664-D7324 trimer-immunized rabbits were capable of inhibiting VRC01 binding to CD4bs, but gp140-immunized sera could not. 4/4 similarly trimer-immunized macaque sera also inhibited VRC01 binding. Serum inhibition of VRC01-trimer binding significantly correlated with rabbit autologous neutralization of the trimer-equivalent psuedovirus, BG505.T332N.
Sanders2015
(antibody generation, neutralization, binding affinity, polyclonal antibodies)
-
VRC01: A new trimeric immunogen, BG505 SOSIP.664 gp140, was developed that bound and activated most known neutralizing antibodies but generally did not bind antibodies lacking neuralizing activity. This highly stable immunogen mimics the Env spike of subtype A transmitted/founder (T/F) HIV-1 strain, BG505. Anti-CD4bs bNAb VRC01 neutralized BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, and was shown to recognize and bind the immunogen too.
Sanders2013
(assay or method development, neutralization, binding affinity)
-
VRC01: This review discusses the application of bNAbs for HIV treatment and eradication, focusing on bnAbs that target key epitopes, specifically: 2G12, 2F5, 4E10, VRC01, 3BNC117, PGT121, VRC26.08, VRC26.09, PGDM1400, and 10-1074. VRC01 was one of the first CD4bs antibodies identified, and it has been tested in both prophylactic and therapeutic human trials.
Stephenson2016
(immunotherapy, review)
-
VRC01: This paper describes modifications that expand the germ line VRC01-class antibody-recognition potential of the previously described 426c Env. The authors show that an optimized Env immunogen can engage multiple germ line VRC01-class antibodies.
McGuire2016
(antibody interactions, antibody lineage)
-
VRC01: This review discusses the breakthroughs in understanding of the biology of the transmitted virus, the structure and nature of its envelope trimer, vaccine-induced CD8 T cell control in primates, and host control of bnAb elicitation.
Haynes2016
(review)
-
VRC01: This study described a natural interaction between Abs and mucin protein, especially, MUC16 that is enhanced in chronic HIV infection. Agalactosylated (G0) Abs demonstrated the highest binding to MUC16. Binding of Abs to epithelial cells was diminished following MUC16 knockdown, and the MUC16 N-linked glycans were critical for binding.These point to a novel opportunity to enrich Abs at mucosal sites by targeting Abs to MUC16 through changes in Fc glycosylation, potentially blocking viral movement. Surface plasmon resonance (SPR) was performed to determine the binding affinity of Fc, Fab, and F(ab)2 of VRC01 to MUC16. They determined the relative percentage of G0, G1, and G2 glycan structures and the enhanced MUC16 binding with VRC01 was linked to higher G0 glycosylation.
Gunn2016
(antibody interactions, glycosylation)
-
VRC01: A panel of Env-specific mAbs was isolated from 6 HIV1-infected lactating women. Antibodies in colostrum may help prevent mucosal infection of the infant, so this study aimed to define milk IgGs for future vaccination strategies to reduce HIV transmission during lactation. Despite the high rate of VH 1-69 usage among colostrum Env specific B cells, it did not correlate with distinct gp120 epitope specificity or function. VRC01 was compared to the newly-derived mAbs; it tested positive in one assay of cross-reactivity with gut bacteria, and positive in one test of autoreactivity.
Jeffries2016
(antibody polyreactivity)
-
VRC01: The study detailed binding kinetics of the interaction between BG505 SOSIP.664 trimer or its variants (gp120 monomer; first study of disulfide-stabilized variant gp120-gp41ECTO protomer) and several mAbs, both neutralizing (VRC01, PGV04, PG9, PG16, PGT121, PGT122, PGT123, PGT145, PGT151, 2G12) and non-neutralizing (b6, b12, 14e, 19b, F240). CD4bs-directed VRC01 potently neutralizes BG505.T332N pseudovirus and binds strongly to all 3 antigens with slow dissociation.
Yasmeen2014
(antibody binding site, assay or method development)
-
VRC01: Neutralization breadth in 157 antiretroviral-naive individuals infected for less than 1 year post-infection was studied and compared to a cohort of 170 untreated chronic patients. A range of neutralizing activities was observed with a panel of six recombinant viruses from five different subtypes. Some sera were broadly reactive, predominantly targeting envelope epitopes within the V2 glycan-dependent region. The Env neutralization breadth was positively associated with time post infection. VRC01 has been used as a control in testing CD4 binding site neutralizing specificity of the sera.
Sanchez-Merino2016
(neutralization, acute/early infection)
-
VRC01: This review summarized the novel strategies for HIV vaccine discovery. Multiple therapeutic vaccines have failed in the past, in a non placebo controlled trial, a Tat vaccine demonstrated immune cell restoration, reduction of immune activation, and reduced HIV-1 DNA viral load. bNAbs offer both prevention potential and treatment. In early-phase clinical trials, VRC01 reduced viral load in HIV-1-infected individuals not on HAART.
Gray2016
(vaccine antigen design, vaccine-induced immune responses, HAART, ART, review)
-
VRC01: A new, current, mostly tier2 panel of 200 C-clade Env-psuedotyped viruses from early (< 100d) infection in southern Africa was used to assess antibody responses to natural infection and to vaccines. Viruses were assayed with bNAbs targeting the V2 glycan (PG9, VRC26.25), the MPER site (4E10), the CD4 binding site (VRC01), and the V3/C3 glycan site (PGT128). For VRC01 (and all other Abs besides PGT128) there was no significant difference in neutralization between pre-seroconversion and post-seroconversion viruses. When viruses from 3 time periods were compared, breadth remained constant, but potency decreased, indicating that the C clade epidemic is becoming increasingly resistant to VRC01. Viruses collected pre-seroconversion were more resistant to neutralization by serum than those post-seroconversion. As the epidemic matured over 13 years, viruses also became more resistant to mAbs tested.
Rademeyer2016
(assay or method development, neutralization)
-
VRC01: Ten mAbs were isolated from a vertically-infected infant BF520 at 15 months of age. Ab BF520.1 neutralized pseudoviruses from clades A, B and C with a breadth of 58%, putting it in the same range as second-generation bNAbs derived from adults, but its potency was lower. BF520.1 was shown to target the base of the V3 loop at the N332 supersite. CD4 bs-binding, second-generation mAb, VRC01 when compared had a geometric mean of IC50=2.13 µg/ml for 11/12 viruses it neutralized at a potency of 92%. The infant-derived antibodies had a lower rate of somatic hypermutation (SHM) and no indels compared to adult-derived anti-V3 mAbs. This study shows that bnAbs can develop without SHM or prolonged affinity maturation.
Simonich2016
(antibody binding site, neutralization, responses in children, structure)
-
VRC01: This study examined the neutralization of group N, O, and P primary isolates of HIV-1 by diverse antibodies. Cross-group neutralization was observed only with the bNAbs targeting the N160 glycan-V1/V2 site. Four group O isolates, 1 group N isolate, and the group P isolates were neutralized by PG9 and/or PG16 or PGT145 at low concentrations. None of the non-M primary isolates were neutralized by bNAbs targeting other regions, except 10E8, which weakly neutralized 2 group N isolates, and 35O22 which neutralized 1 group O isolate. Bispecific bNAbs (PG9-iMab and PG16-iMab) very efficiently neutralized all non-M isolates with IC50 below 1 ug/mL, except for 2 group O strains. Anti-CD4bs bNAb VRC01 was able to neutralize only 1/16 tested non-M primary isolates at an IC50< 10µg/ml, RBF208,M/O at 3.64 µg/ml.
Morgand2015
(neutralization, subtype comparisons)
-
VRC01: The neutralization of 14 bnAbs was assayed against a global panel of 12 or 17 Env pseudoviruses. From IC50, IC80, IC90, and IC99 values, the slope of the dose-response curve was calculated. Each class of Ab had a fairly consistent slope. Neutralization breadth was strongly correlated with slope. An IIP (Instantaneous Inhibitory Potential) value was calculated, based on both the slope and IC50, and this value may be predictive of clinical efficacy. VRC01, a CD4bs bnAb belonged to a group with slopes >1.
Webb2015
(neutralization)
-
VRC01: This study evaluated the binding of 15 inferred germline (gl) precursors of bNAbs that are directed to different epitope clusters, to 3 soluble native-like SOSIP.664 Env trimers - BG505, B41 and ZM197M. The trimers bound to some gl precursors, particularly those of V1V2-targeted Abs. These trimers may be useful for designing immunogens able to target gl precursors. CD4bs-binding gl-VRC01 precursor did not bind to any trimers.
Sliepen2015
(binding affinity, antibody lineage)
-
VRC01: This study presented structures of germline-reverted VRC01-class bNAbs alone and complexed with 426c-based gp120 immunogens. Germline bNAb–426c gp120 complexes showed preservation of VRC01-class signature residues and gp120 contacts, but detectably different binding modes compared to mature bNAb-gp120 complexes. It reported that unlike most antibodies, the overall final structures of VRC01 class antibodies are formed before the antibodies mature. NIH45-46GL and 3BNC60GL make all predicted HC VRC01-class signature contacts with the CD4-binding loop, the V5 loop, and loop D to bind to gp120.
Scharf2016
(structure)
-
VRC01: This study reported that early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs. HIV-1–specific human neutralizing mAbs (NmAbs) were used as a post-exposure therapy in an infant macaque model for intrapartum MTCT, inoculated orally with the SHIV SF162P3. On days 1, 4, 7 and 10 post virus exposure, animals were injected with NmAbs and quantified systemic distribution 24 h after Ab administration. Replicating virus was found in multiple tissues by day 1 in untreated animals. For VRC01 The time to maximal concentration in the plasma was 24 h, independent of dose, and the serum (plasma) half-life of VRC01 was 3.9–4.2 d. All NmAb-treated macaques were free of virus in blood and tissues at 6 months after exposure.
Hessell2016
(neutralization, acute/early infection, immunotherapy, mother-to-infant transmission)
-
VRC01: Donor EB179 was a long-term non-progressor with high serum neutralization breadth and potency. 8 B-cell clones produced Abs, including 179NC75 which had the highest neutralization, especially to Clade B virus, neutralizing 70% of a clade-B pseudovirus panel and 6 out of 9 cross-clade Env pseudoviruses as opposed to bNAb VRC01's neutralizing 7/9 of the same psuedoviral panel. 179NC75 was also more potent than VRC01 against 8 viruses of a 22 Tier-2 clade B panel.
Freund2015
(neutralization, broad neutralizer)
-
VRC01: A panel of antibodies was tested for binding, stability, and ADCC activity on HIV-infected cells. The differences in killing efficiency were linked to changes in binding of the antibody and the accessibility of the Fc region when bound to infected cells. Ab VRC01 had weak ADCC.
Bruel2016
(effector function, binding affinity)
-
VRC01: This review discusses the structural characteristics of bNAbs, how they recognize the virus, and new vaccination strategies that aim to guide B cells to produce protective Abs. The evolutionary lineage of VRC01 in the donor has been extensively studied. Although VRC01 had a 5-fold lower mutation rate than other bNAbs, such as CA256-VRC26 and CH103, it seems likely that the principles that guide VRC01 bNAb development will apply to other bNAb ontogenies.
Sadanand2016
(vaccine antigen design, review)
-
VRC01: To test whether NAbs can inhibit viral transmission through mucosal tissue, 4 bNAbs (PG9, PG16, VRC01, 4E10) were tested in tissue culture models of human colonic and ectocervical tissues. All 4 nAbs reduced HIV transmission, with a relative efficacy of PG16 > PG9 > VRC01 >> 4E10. The nAbs had a good safety profile and were not affected by the presence of semen.
Scott2015
(immunotherapy)
-
VRC01: The study's goal was to produce modified SOSIP trimers that would reduce the exposure - and, by inference, the immunogenicity - of non-NAb epitopes such as V3. The binding of several modified SOSIP trimers was compared among 12 neutralizing (PG9, PG16, PGT145, PGT121, PGT126, 2G12, PGT135, VRC01, CH103, CD4, IgG2, PGT151, 35O22) and 3 non-neutralizing antibodies (14e, 19b, b6). The V3 non-NAbs 447-52D, 39F, 14e, and 19b bound less well to all A316W variant trimers compared to wild-type trimers. Mice and rabbits immunized with modified, stabilized SOSIP trimers developed fewer V3 Ab responses than those immunized with native trimers.
deTaeye2015
(antibody binding site)
-
VRC01: In 5 years additional members of the CH235 clonal lineage were isolated based on deep sequencing of donor CH505's VL and VH chains at 17 timepoints in the donor's infection. Two of these had greater neutralization potency, CH235.9 and CH235.12. Study of crystal structures indicated a site of vulnerability near the Env CD4 binding site. The lineages of CH103 and CH235, both derived from Donor CH505 were compared - CH103 lineage Kd increased an order of magnitude each step of maturation but maintained a fast association rate; CH235 lineage however, had slower Kds and Kas over maturation. VRC01 was used as a control and neutralized 89% of a 202-multiclade Env-psuedovirus panel at a potency of <50 µg/ml. Despite using VH1-46, the CH235.9 and CH235.12 neutralizing profiles were more similar functionally to that of VH1-2-derived antibody VRC01. Structurally, both VRC01 and the CH235 bNAbs mimic CD4 to bind virus, preserving contacts with gp120 D368.
Bonsignori2016
(neutralization, binding affinity, antibody sequence)
-
VRC01: A germline-targeting immunogen (eOD-GT8) was developed to elicit VRC01-class bNAbs. HIV-naive humans were shown to have VRC01-class precursor naive B cells that responded to this immunogen; 27 such mAbs were isolated (Vrc01c-HuGL1 - Vrc01c-HuGL1). Not only are the eOD-GT8 isolated naïve B cells highly enriched for VRC01-class core characteristics of VH1-02 and a 5–amino acid L-CDR3, they possess further refined sequence attributes of VRC01-class bNAbs.
Jardine2016
(vaccine antigen design, immunotherapy, antibody lineage)
-
VRC01: HIV-1 strains were isolated from 60 patients infected with CRFs 01_AE, 07_BC, and 08_BC. Eight CRF01 strains that produced high-titer Env pseudoviruses were studied further. All were sensitive to neutralization by VRC01, PG9, PG16, and NIH45-46, but insensitive to 2G12. Mutations in either of the loop D or V5 regions (or both) may be critical for natural evasion of VRC01. However, the resistance mechanisms are currently unknown and four CRF01 AE viruses, CNAE08, CNAE14, CNAE17, and CNAE31, were demonstrated to be resistant to VRC01. Exchanging the V5 region alone did not affect the sensitivity of the viruses to VRC01.CNAE09, CNAE10, and CNAE11 strains containing the asparagine residue at position 461 were still highly sensitive to VRC01. CNAE17 demonstrated the highest levels of resistance may be due to the presence of mutation S365P in the CD4bs.
Chen2016
(neutralization, subtype comparisons)
-
VRC01: Four bNAbs (VRC01, VRC01-LS, 3BNC117, and 10-1074) were administered, singly or in combination, to macaques, followed by weekly challenges with clade B SHIVAD8. In all cases, the administration of MAbs delayed virus acquisition. Control animals required 2 to 6 challenges before becoming infected, while animals receiving VRC01 required 4–12 challenges; 3BNC117 required 7–20 challenges; 10-1074 required 6–23 challenges; and VRC01-LS required 9–18 challenges. Animals that received a single antibody infusion resisted infection for up to 23 weekly challenges.
Gautam2016
(immunotherapy)
-
VRC01: A large cross-sectional study of sera from 205 ART-naive patients infected with different HIV clades was tested against a panel of 219 cross-clade Env-pseudotyped viruses. Their neutralization was compared to the neutralization of 10 human bNAbs (10E8, 4E10, VRC01, PG9, PGT145, PGT128, 2F5, CH01, b12, 2G12) tested with a panel of 119 Env-pseudotyped viruses. Results from b12 and 2G12 suggested that these bnAbs may not be as broadly neutralizing as previously thought. VRC01 neutralized 89% of the 199 viruses tested.
Hraber2014
(neutralization)
-
VRC01: This study isolated 4 novel antibodies that bind the CD4 binding site of Env. Population-level analysis classified a diverse group of CD4bs antibodies into two types: CDR H3-dominated or VH-gene-restricted, each with distinct ontogenies. Structural data revealed that neutralization breadth was correlated with angle of approach of the antibodies to the CD4 binding region. VRC01 was one of the antibodies in the VH-gene-restricted class.
Zhou2015
(neutralization, structure, antibody lineage, broad neutralizer)
-
VRC01: Double, triple or quadruple combinations of fifteen bNAbs that target 4 distinct epitope regions: the CD4 binding site (3BNC117, VRC01, VRC07, VRC07-523, VRC13), the V3-glycan supersite (10–1074, 10-1074V, PGT121, PGT128), the V1/V2-glycan site (PG9, PGT145, PGDM1400, CAP256-VRC26.08, CAP256-VRC26.25), and the gp41 MPER epitope (10E8) were studied. Their neutralization potency and breadth were assayed against a panel of 200 acute/early subtype C strains, and compared to a novel, highly accurate predictive mathematical model (no-overlap Bliss Hill model, CombiNaber tool, LANL HIV Immunology database). These data were used to predict the best combinations of bNAbs for immunotherapy.
Wagh2016
(neutralization, immunotherapy)
-
VRC01: VRC07-523:BNabs were tested for their ability to suppress viremia during acute infection in rhesus macaques. Most effective by all virological parameters was dual therapy with VRC07-523 + PGT121. Therapy with VRC01 also curtailed viral replication, but less consistently. These finding support the use of MAbs for immunotherapy during early infection.
Bolton2015
(acute/early infection, immunotherapy)
-
VRC01: The rate of maturation and extent of diversity for the VRC01 lineage were characterized through longitudinal sampling of peripheral B cell transcripts from donor 45 over 15 years and co-crystal structures. VRC01-lineage clades underwent continuous evolution, with rates of ˜2 substitutions per 100 nucleotides per year, comparable with HIV-1 evolution. 39 VRC01-lineage Abs segregated into three major clades, and all Abs from donor 45 contained a cysteine at position 98 (99 in some sequences due to a 1-aa insertion) which was used as a signature to assess membership in the VRC01 lineage. Of 1,041 curated NGS sequences assigned to the VRC01 lineage, six did not contain the cysteine while 1,035 did (99.4%). For this Ab CDR H3 length is 12 and VH changes 32%, Vk nucleotide change is 18%.
Wu2015
(antibody lineage)
-
VRC01: A VRC01 drug product was administered to 23 participants: 15 were on ART, and 8 were viremic and not receiving ART. The treatment reduced viremia significantly only in the viremic subjects. In 4 of these subjects, the reduction in viremia was accompanied by outgrowth of viruses that were less neutralization-sensitive.
Lynch2015
(immunotherapy)
-
VRC01: CD4-binding site Abs are reviewed. New insights from donor-serum responses, atomic-level structures of antibody-Env complexes, and next-generation sequencing of B-cell transcripts are invigorating vaccine-design efforts to elicit effective CD4-binding site Abs. Analysis of the epitopes recognized by CD4-binding Abs reveals substantial similarity in the recognized region of gp120. VRC01 targets the outer domain of gp120.
Georgiev2013a
(review)
-
VRC01: The human Ab gene repertoires of uninfected and HIV-1-infected individuals were studied at genomic DNA (gDNA) and cDNA levels to determine the frequencies of putative germline Ab genes of known HIV-1 bnAbs. All libraries were deep sequenced and analysed using IMGT/HighV-QUEST software (http://imgt.org/HighV-QUEST/index. The human gDNA Ab libraries were more diverse in heavy and light chain V-gene lineage usage than the cDNA libraries. This implied that the human gDNA Ab gene repertoires may have more potential than the cDNA repertoires to develop HIV-1 bnmAbs. Relatively high frequencies of the VH and VKs and VLs that used the same V-genes and had the same CDR3 lengths as known HIV-1 bnmAbs regardless of (D)J-gene usage. The putative germline genes were determined for a set of mAbs (b12, VRC01, VRC03, NIH45-46, 3BNC60, PG9, PGT127, and X5).
Zhang2013
(antibody lineage, germline)
-
VRC01: A previous study demonstrated the presence of VRC01-resistant strains in an HIV-1 infected patient during antiretroviral therapy. This study report follow-up of two subsequent samples, CRF08-BC env clones,CNE47 and CNE48 from the same patient. With genetic and phenotypic analysis it showed that VRC01-resistant HIV-1 continued to exist and the resistant phenotype was associated with a single asparagine residue at position 460 (N460), a potential N-linked glycosylation site in the V5 region.
Guo2014
-
VRC01: A subset of bNAbs that inhibit both cell-free and cell-mediated infection in primary CD4+ lymphocytes have been identified. These antibodies target either the CD4-binding site or the glycan/V3 loop on HIV-1 gp120 and act at low concentrations by inhibiting multiple steps of viral cell to cell transmission. This property of blocking viral transmission to plasmacytoid DCs and interfering with type-I IFN production should be considered an important characteristic defining the potency for therapeutic or prophylactic antiviral strategies. VRC01 was only partially effective in blocking cell to cell transmission.
Malbec2013
-
VRC01: The effect of PNGS on viral infectivity and antibody neutralization (2F5, 4E10, b12, VRC01, VRC03, PG9, PG16, 3869) was evaluated through systemic mutations of each PNGS on CRF07_BC strain. Mutations at N197 (C2), N301 (V3), N442 (C4), and N625 (gp41) rendered the virus more susceptible to neutralization by MAbs that recognize the CD4 binding site or gp41. Generally, mutations on V4/V5 loops, C2/C3/C4 regions, and gp41 reduced the neutralization sensitivity to PG16. However, mutation of N289 (C2) made the virus more sensitive to both PG9 and PG16. Mutations at N142 (V1), N355 (C3) and N463 (V5) conferred resistance to neutralization by anti-gp41 MAbs. Available structural information of HIV Env and homology modeling was used to provide a structural basis for the observed biological effects of these mutations.
Wang2013
(neutralization, structure)
-
VRC01: This review surveyed the Vectored Immuno Prophylaxis (VIP) strategy, which involves passive immunization by viral vector-mediated delivery of genes encoding bnAbs for in vivo expression. Recently published studies in humanized mice and macaques were discussed as well as the pros and cons of VIP towards clinical applications to control HIV endemics. A single injection of AAV8 vector achieved peak Ab production in serum at week 6.VRC01 could provide full protection against HIV challenge (10 ng) at a titer of 8.3 μg/mL conforming the superiority over b12.
Yang2014
(immunoprophylaxis, review, antibody gene transfer)
-
VRC01: Engineered nanoparticle immunogens eOD-GT8 in 60mer and 3mer form bound VRC01 bNAb precursors and induced VRC01-class bNAbs with classic short CDRL3 in a VRC01 gH (approximated germline-reverted heavy chain precursor) knock-in mouse. Induced antibodies had mutations favoring binding to near-native gp120 constructs.
Jardine2015
(antibody generation, enhancing activity, broad neutralizer)
-
VRC01: The ability of bNAbs to inhibit the HIV cell entry was tested for b12, VRC01,VRC03, PG9, PG16, PGT121, 2F5, 10E8, 2G12. Among them, PGT121, VRC01, and VRC03 potently inhibited HIV entry into CD4+ T cells of infected individuals whose viremia was suppressed by ART.
Chun2014
(immunotherapy)
-
VRC01: The heavy and light chains of VRC01 were stably expressed in tobacco plant cells. The resulting antibody had neutralization breadth and potency similar to that produced in HEK cells. The results demonstrate a method for low-cost production of anti-HIV antibodies.
Teh2014
(antibody gene transfer)
-
VRC01: A gp140 trimer mosaic construct (MosM) was produced based on M group sequences. MosM bound to CD4 as well as multiple bNAbs, including VRC01, 3BNC117, PGT121, PGT126, PGT145, PG9 and PG16. The immunogenicity of this construct, both alone and mixed together with a clade C Env protein vaccine, suggest a promising approach for improving NAb responses.
Nkolola2014
(vaccine antigen design)
-
VRC01: Cross-group neutralization of HIV-1 isolates from groups M, N, O, and P was tested with diverse patient sera and bNAbs PG9, PG16, 4E10, b12, 2F5, 2G12, VRC01, VRC03, and HJ16. The primary isolates displayed a wide spectrum of sensitivity to neutralization by the human sera, with some cross-group neutralization clearly observed. Among the bNAbs, only PG9 and PG16 showed any cross-group neutralization. The group N prototype strain YBF30 was highly sensitive to neutralization by PG9, and the interaction between their key residues was confirmed by molecular modeling. The conservation of the PG9/PG16 epitope within groups M and N suggests its relevance as a vaccine immunogen.
Braibant2013
(neutralization, variant cross-reactivity)
-
VRC01: VRC01 was one of 10 MAbs used to study chronic vs. consensus vs. transmitted/founder (T/F) gp41 Envs for immunogenicity. Consensus Envs were the most potent eliciters of response but could only neutralize tier 1 and some tier 2 viruses. T/F Envs elicited the greatest breadth of NAb response; and chronic Envs elicited the lowest level and narrowest response. This CD4BS binding Nab bound well at <10 nM to 3/5 chronic Envs, 4/6 Consensus Envs and 6/7 T/F Envs.
Liao2013c
(antibody interactions, binding affinity)
-
VRC01: Study evaluated 4 gp140 Env protein vaccine immunogens derived from an elite neutralizer donor VC10042, an HIV+ African American male from Vanderbilt cohort. Env immunogens, VC10042.05, VC10042.05RM, VC10042.08 and VC10042.ela, elicited high titers of cross-reactive Abs recognizing V1/V2 regions. All the Env protein except VC10042.05 bound to VRC01, although weak binding was detected with VC10042.05 monomer. Parental Env of VC10042.ela was highly neutralized by VRC01.
Carbonetti2014
(elite controllers and/or long-term non-progressors, vaccine-induced immune responses)
-
VRC01: The effect of low pH and HIV-1 Abs which increased the transcytosis of the virus by 20 fold, has been reported. This enhanced transcytosis was due to the Fc neonatal receptor (FcRn), which facilitates HIV-1's own transmission by usurping Ab responses directed against itself. Both infectious and noninfectious viruses were transcytosed by VRC01.
Gupta2013
-
VRC01: A set of potent VRC01-like (PVL) MAbs were generated from VRC01-derivatve NIH45-46G54W and they were more potent than even NIH45-46 or NIH45-46G54W, cross-recognizing viruses across clades. The novel antibodies designed based on crystal structure were NIH45-46m2, NIH45-46m7, NIH45-46m25 and NIH45-46m28, with NIH45-46m2 being the single most broad and potent antibody till date. 45-46m2 and 45-46m7 in combination with each other and a third antibody were able to thwart viral escape routes.
Diskin2013
-
VRC01: Clade A Env sequence, BG505, was identified to bind to bNAbs representative of most of the known NAb classes. This sequence is the best natural sequence match (73%) to the MRCA sequence from 19 Env sequences derived from PG9 and PG16 MAbs' donor. A point mutation at position L111A of BG505 enabled more efficient production of a stable gp120 monomer, preserving the major neutralization epitopes. The antisera produced by this adjuvanted formulation of gp120 competed with bnAbs from 3 classes of non-overlapping epitopes. VRC01 showed very high neutralization titer against BG505 pseudovirus in a competitive binding assay as shown in Table 1.
Hoffenberg2013
(antibody interactions, neutralization)
-
VRC01: This study evaluated the frequency of anti-gp120 B cells in follicular (FO) and marginal zone (MZ) B cells compartments of naive WT mice and human populations. Mouse MZ B cells use IGHV1-53, closely related to human IGHV1-2*02 that encodes VRC01, to generate gp120-specific Abs. VRC01 bound very well to RSC3, but IGHV1-53 didn't. These MZ B cell derived germline Abs showed similarity to purported VRC01 germline and are not protective against HIV.
Pujanauski2013
(antibody lineage)
-
VRC01: 4 new variants of VRC07, a MAb from the VRC01 class of neutralizing antibodies were generated using structure-guided optimization and were between 4 and 5.7 times more potent than VRC01.
Rudicell2014
-
VRC01: The neutralization profile of 1F7, a human CD4bs mAb, is reported and compared to other bnNAbs. 1F7 exhibited extreme potency against primary HIV-1, but limited breadth across clades.VRC01 neutralized 92% of a cross-clade panel of 157 HIV-1 isolates (Fig. S1) while 1F7 neutralized only 20% of the isolates.
Gach2013
(neutralization)
-
VRC01: This study reports the development of a new cell-line (A3R5)-based highly sensitive Ab detection assay. This T-lymphoblastoid cell-line stably expreses CCR5 and recognizes CCR5-tropic circulating strains of HIV-1. A3R5 cells showed greater neutralization potency compared to the current cell-line of choice TZM-bl. VRC01 was used as a reference Ab in neutralization assay comparing A3R5 and TZM-bl.
McLinden2013
(assay or method development)
-
VRC01: This is a review of identified bNAbs, including the ontogeny of B cells that give rise to these antibodies. Breadth and magnitude of neutralization, unique features and similar bNAbs are listed. VRC01 is a CD4bs Ab, with breadth 87%, IC50 0.98 μg per ml, and its unique feature is CD4 mimicry by its VH1-2-derived heavy chain. Similar MAbs include VRC02, VRC03, NIH45-46, 3BNC60, BNC62, 3BNC117, 12A12, 12A21, 12A30, VRC-PG04, VRC-CH31.
Kwong2013
(review)
-
VRC01: A highly conserved mechanism of exposure of ADCC epitopes on Env is reported, showing that binding of Env and CD4 within the same HIV-1 infected cell effectively exposes these epitopes. The mechanism might explain the evolutionary advantage of downregulation of cell surface CD4v by the Vpu and Nef proteins. VRC01 was used in CD4 coexpression and competitive binding assay.
Veillette2014
(effector function)
-
VRC01: The ability of MAb A32 to recognize HIV-1 Env expressed on the surface of infected CD4(+) T cells as well as its ability to mediate antibody-dependent cellular cytotoxicity (ADCC) activity was investigated. This study demonstrates that the epitope defined by MAb A32 is a major target on gp120 for plasma ADCC activity. VRC01 was used as a control and A32 showed >3 fold higher ADCC activity than VRC01.
Ferrari2011a
(effector function)
-
VRC01d45: The ontogeny of VRC01 class Abs was determined by enumerating VRC01-class characteristics in many donors by next-gen sequencing and X-ray crystallography. Analysis included VRC01 (donor NIH 45), VRC-PG04 (donor IAVI 74), VRC-CH31 (donor 0219), 3BNC117 (donor RU3), 12A21 (donor IAVI 57), and somatically related VRC-PG19,19b, 20, 20b MAbs from donor IAVI 23. Despite the sequence differences of VRC01-class Abs, exceeding 50%, Ab-gp120 cocrystal structures showed VRC01-class recognition to be remarkably similar. It is reported that glutamic acid to glutamine mutation at residue 96 decreased the binding affinity to 10 fold in VRC01.
Zhou2013a
(antibody sequence, structure, antibody lineage)
-
VRC01: Next generation sequencing was applied to a new donor C38 (different from donor NIH45) to identify VRC01 class bNAbs. VRC01 class heavy chains were selected through a cross-donor phylogenetic analysis. VRC01 class light chains were identified through a five-amino-acid sequence motif. (CDR L3 length of 5 amino acids and Q or E at position 96 (Kabat numbering) or position 4 within the CDR L3 sequence.)
Zhu2013a
(antibody sequence)
-
VRC01: Series of VRC01 and 10E8 variants with partial framework reversions to germline in both H and L chains were created and their neutralization activity was compared to that of the mature antibody. Some of these Abs retained broad and potent neutralization activity even when their framework regions were substantially reverted back to germline, suggesting the promise of partial framework reversion for Ab optimization.
Georgiev2014
(neutralization, antibody lineage)
-
VRC01: A statistical model selection method was used to identify a global panel of 12 reference Env clones among 219 Env-pseudotyped viruses that represent the spectrum of neutralizing activity seen with sera from 205 chronically HIV-1-infected individuals. This small final panel was also highly sensitive for detection of many of the known bNAbs, including this one. The small panel of 12 Env clones should facilitate assessments of vacine-elicited NAbs.
Decamp2014
(assay or method development)
-
VRC01: N276D was determined as the critical binding site of MAb HJ16 by resistance induction in a sensitive primary CRF02_AG strain. N-linked glycosylation site removing N276D mutation was responsible for resistance to HJ16 by site-directed mutagenesis in envs of the homologous CRF02_AG, as well as of a subtype A and a subtype C primary isolate. Sensitivity to the CD4bs VRC01 and VRC03 mAbs was increased in the N276D mutated viruses.
Balla-Jhagjhoorsingh2013
(glycosylation)
-
VRC01:X-ray crystallography, surface plasmon resonance and pseudovirus neutralization were used to characterize a heavy chain only llama antibody, named JM4. The full-length IgG2b version of JM4 neutralizes over 95% of circulating HIV-1 isolates. JM4 targets a hybrid epitope on gp120 that combines elements from both the CD4 binding region and the coreceptor binding surface. JM4 epitope overlaps very little with the VRC01 although the binding sites are in close proximity. JM4 IgG2b was able to potently neutralize the HIV-1 isolates that were resistant to VRC01.
Acharya2013
(neutralization)
-
VRC01: This is a review of a satellite symposium at the AIDS Vaccine 2012 conference, focusing on antibody gene transfer. Dennis Burton showed that PGT121 provides protection in lower in vivo concentrations than b12.
Balazs2013
(immunoprophylaxis)
-
VRC01: A computational method to predict Ab epitopes at the residue level, based on structure and neutralization panels of diverse viral strains has been described. This method was evaluated using 19 Env-Abs, including VRC01, against 181 diverse HIV-1 strains with available Ab-Ag complex structures.
Chuang2013
(computational prediction)
-
VRC01: The complexity of the epitopes recognized by ADCC responses in HIV-1 infected individuals and candidate vaccine recipients is discussed in this review. VRC01 is discussed as the CD4bs-targeting, neutralizing anti-gp120 mAb exhibiting ADCC activity and having a discontinuous epitope. Both VRC01 and b12 recognize the outer domain of gp120. b12 recognizes using Ab heavy chain, where as VRC01 uses both heavy and light chains. This differences is crucial for their neutralization breadth.
Pollara2013
(effector function, review)
-
VRC01: "Neutralization fingerprints" for 30 neutralizing antibodies were determined using a panel of 34 diverse HIV-1 strains. 10 antibody clusters were defined: VRC01-like, PG9-like, PGT128-like, 2F5-like, 10E8-like and separate clusters for b12, CD4, 2G12, HJ16, 8ANC195. This mAb belongs to PG9-like cluster.
Georgiev2013
(neutralization)
-
VRC01: Cryoelectron tomography was used to determine structures of A12, m36, or m36/CD4 complexed to trimeric Env displayed on intact HIV-1 BaL virus. The steric interactions at the distal ends of the bound Ab moieties are likely to play a role in determining the rotation of gp120 as in A12 and b12 or without any quaternary structure change as in VRC01.
Meyerson2013
(antibody binding site, structure)
-
VRC01: Systematic computational analyses of gp120 plasticity and conformational transition in complexes with CD4 binding fragments, mimetic proteins and Ab fragments is described to explain the molecular mechanisms by which gp120 interacts with the CD4bs at local and subdomain levels. An isotopic elastic network analysis, a full atomic normal mode analysis and simulation of conformational transitions were used to compare the gp120 structures in CD4 bound and Ab-bound states. VRC01 was mentioned in the context of CD4 binding sites.
Korkut2012
(structure)
-
VRC01: This study describes an ˜11 Angstrom cryo-EM structure of the trimeric HIV-1 Env precursor in its unliganded state. The three gp120 and gp41 subunits form a cage like structure with an interior void surrounding the trimer axis which restricts Ab access. VRC01 was used in ELISA to asses the recognition of the purified Env glycoproteins and recognized conformation dependent epitopes near CD4 binding site of gp120.
Mao2012
(structure)
-
VRC01: The sera of 20 HIV-1 patients were screened for ADCC in a novel assay measuring granzyme B (GrB) and T cell elimination and reported that complex sera mediated greater levels of ADCC than anti-HIV mAbs. The data suggested that total amount of IgG bound is an important determinant of robust ADCC which improves the vaccine potency. VRC01 was used as an anti CD4 binding Ab to study effects of Ab specificity and affinity on ADCC against HIV-1 infected targets.
Smalls-Mantey2012
(assay or method development, effector function)
-
VRC01: Neutralizing antibody response was studied in elite controller. Subject VC10042 is an African American male, infected with clade B for 2 decades (since 1984) without any signs of disease and no antiretroviral treatment. The neutralizing activity of autologous CD4bs NAbs was very similar to that of NIH45-46W, but very different from other anti-CD4bs MAbs tested. The viral autologous variants that were resistant to neutralization by autologous and most bnMAbs tested had an extremely rare R272/N368 combination. This mutation was shown in the study to impart a fitness cost to the virus.
Sather2012
(autologous responses, elite controllers and/or long-term non-progressors, neutralization, escape, polyclonal antibodies)
-
VRC01: Isolation of VRC06 and VRC06b MAbs from a slow progressor donor 45 is reported. This is the same donor from whom bnMAbs VRC01, VRC03 and NIH 45-46 were isolated and the new MAbs are clonal variants of VRC03. VRC01 was used as a broadly reactive CD4bs MAb to compare neutralizing specificity of VRC06.
Li2012
-
VRC01: This is a comment on Tan2012. It is noted that Tran and colleagues used high-resolution 3D cryoelectron tomography to define the conformation of Env when bound to soluble CD4 and to a series of monoclonal antibodies. It was demonstrated that antibodies binding to the CD4 binding site or coreceptor binding site of Env may lead to significantly different conformations of the trimeric Env complex. VRC01 locks the complex in a closed conformation, while binding to soluble CD4 or the monoclonal antibody 17b fixed the trimer in an open conformation.
Wright2012
(novel epitope)
-
VRC01: Previous cryo-electron tomographic studies were extended. A more complete picture of the HIV entry process was presented by showing that HIV-1 Env binding to either soluble CD4 (sCD4) or the co-receptor mimic 17b leads to the same structural opening, or activation, of the Env spike. Atudy also demonstrated structurally that the broadly neutralizing antibodies VRC01, VRC02, VRC03 are able to block this activation, locking Env in a state that resembles closed, native Env. The cryo-electron microscopic structure of soluble trimeric Env in the 17b-bound state is presented at ˜9 Å resolution, revealing it as a novel, activated intermediate conformation of trimeric Env that could serve as a new template for immunogen design.
Tran2012
(structure)
-
VRC01: Efficacy of VRC01 as a topically administered microbicide to prevent sexual transmission was evaluated in a RAG-hu humanized mouse model of vaginal HIV-1 transmission. A combination of MAbs b12, 2F5, 4E10 and 2G12, was used as a positive efficacy control. 7/9 VRC01 antibody administered mice and all of the mice receiving the four bNAb antibody combination were protected against HIV-1 challenge.
Veselinovic2012
(immunoprophylaxis)
-
VRC01: Two genetically related and two unrelated envelope clones, derived from CRF08_BC-infected patients, with distinct VRC01 neutralization profiles were studied, and 22 chimeric envelope clones were generated by interchanging the loop D and/or V5 regions between the original envelopes or by single alanine substitutions within each region. Interchanging the V5 region between the genetically related or unrelated clones completely swapped their VRC01 sensitivity profiles. Asn-460, a potential N-linked glycosylation site in the V5 region, was a key factor for observed resistance. The long side chain of Asn-460, and potential glycosylation, may create steric hindrance that lowers binding affinity, thereby increasing resistance to VRC01 neutralization
Guo2012
(neutralization, structure)
-
VRC01: Neutralization profiles of 7 bnAbs were analyzed against 45 Envs (A, C, D clades), obtained soon after infection (median 59 days). The transmitted variants have distinct characteristics compared to variants from chronic patients, such as shorter variable loops and fewer potential N-linked glycosylation sites (PNGS). VRC01 neutralized 71% of these viruses.
Goo2012
(neutralization, rate of progression)
-
VRC01: A computational tool (Antibody Database) identifying Env residues affecting antibody activity was developed. As input, the tool incorporates antibody neutralization data from large published pseudovirus panels, corresponding viral sequence data and available structural information. The model consists of a set of rules that provide an estimated IC50 based on Env sequence data, and important residues are found by minimizing the difference between logarithms of actual and estimated IC50. The program was validated by analysis of MAb 8ANC195, which had unknown specificity. Predicted critical N-glycosylation for 8ANC195 were confirmed in vitro and in humanized mice. The key associated residues for each MAb are summarized in the Table 1 of the paper and also in the Neutralizing Antibody Contexts & Features tool at Los Alamos Immunology Database.
West2013
(glycosylation, computational prediction)
-
VRC01: Identification of broadly neutralizing antibodies, their epitopes on the HIV-1 spike, the molecular basis for their remarkable breadth, and the B cell ontogenies of their generation and maturation are reviewed. Ontogeny and structure-based classification is presented, based on MAb binding site, type (structural mode of recognition), class (related ontogenies in separate donors) and family (clonal lineage). This MAb's classification: gp120 CD4-binding site, CD4-mimicry by heavy chain, VRC01 class, VRC01 family.
Kwong2012
(review, structure, broad neutralizer)
-
VRC01: This review discusses the new research developments in bnAbs for HIV-1, Influenza, HCV. Models of the HIV-1 Env spike and of Influenza visrus spike with select bnAbs bound are shown.
Burton2012
(review)
-
VRC01: This review summarizes challenges to the development of an HIV-1 vaccine, lessons learned from scientific investigation and completed vaccine trials, and promising developments in HIV-1 vaccine design. VRC01 identification and characterization is discussed in detail.
Kwong2012a
(review)
-
VRC01: This review discusses how analysis of infection and vaccine candidate-induced antibodies and their genes may guide vaccine design. This MAb is listed as CD4 binding site bnAb, isolated after 2009 by fluorescence-activated cell sorting (FACS) using a resurfaced core gp120 molecule (RSC3).
Bonsignori2012b
(vaccine antigen design, vaccine-induced immune responses, review)
-
VRC01: Different adjuvants, including Freund's adjuvant (FCA/FIA), MF59, Carbopol-971P and 974P were compared on their ability to elicit antibody responses in rabbits. Combination of Carbopol-971P and MF59 induced potent adjuvant activity with significantly higher titer nAbs than FCA/FIA. There was no difference in binding of this MAb to gp140 SF162 with FIA, MF59, C974 and C974+MF59 adjuvants, but there was 3-fold decrease of antigenicity with C971 and C971+MF59 as compared to the unadjuvanted sample.
Lai2012
(adjuvant comparison)
-
VRC01: Somatic hypermutations are preferably found in CDR loops, which alter the Ab combining sites, but not the overall structure of the variable domain. FWR of CDR are usually resistant to and less tolerant of mutations. This study reports that most bnAbs require somatic mutations in the FWRs which provide flexibility, increasing Ab breadth and potency. To determine the consequence of FWR mutations the framework residues were reverted to the Ab's germline counterpart (FWR-GL) and binding and neutralizing properties were then evaluated. VRC01, a CD4Bs Ab, was among the 17 bnAbs which were used in studying the mutations in FWR. Fig S4C described the comparison of Ab framework amino acid replacement vs. interactive surface area on VRC01.
Klein2013
(neutralization, structure, antibody lineage)
-
VRC01: This study shows that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target CD4BS. However, the elimination of a conserved NLGS at Asn276 in Loop D and the NLGS at positions 460 and 463, located in variable region 5 of Env increased the binding and activation of VRC01 and NIH45-46. This study showed that elimination of NLGS from these regions from Clade C Env 426c increases VRC01 binding.
McGuire2013
(neutralization, antibody lineage)
-
VRC01: Antigenic properties of 2 biochemically stable and homogeneous gp140 trimers (A clade 92UG037 and C clade CZA97012) were compared with the corresponding gp120 monomers derived from the same percursor sequences. The trimers had nearly all the antigenic properties expected for native viral spikes and were markedly different from monomeric gp120. All gp120 and gp140 trimers bound tightly to VRC01 Fab, with the higher affinity for VRC01-gp140 interactions. the trimers also resisted conformational changes induced by VRC01, as demonstrated by 17b binding.
Kovacs2012
(antibody binding site, neutralization, binding affinity)
-
VRC01: Glycan shield of HIV Env protein helps to escape the Ab recognition. Several of the PGT BnAbs interact directly with the HIV glycan coat. Crystal structures of Fabs PGT127 and PGT128 showed that the high neutralizing potency was mediated by cross-linking Env trimers on the viral surface. PGT128 was compared and referred as an order of magnitude more potent than VRC01.
Pejchal2011
(glycosylation, structure, broad neutralizer)
-
VRC01: Intrinsic reactivity of HIV-1, a new property regulating the level of both entry and sensitivity to Abs has been reported. This activity dictates the level of responsiveness of Env protein to co-receptor, CD4 engagement and Abs. VRC01 has been used as a control CD4BS binding Ab in immuno-precipitation assay.
Haim2011
(antibody interactions)
-
VRC01: Computational and crystallographic analysis and in vitro screening were employed to design a gp120 outer domain immunogen (eOD-GT6) that could bind to VRC01-class bNAbs and to their germline precursors. When multimerized on nanoparticles, eOD-GT6 activated germline and mature VRC01-class B cells and thus can be a promising vaccine prime. eOD-GT6 had 10 mutations relative to HXB2. Removal of glycans at positions 276 and 463 was necessary for GL affinity and removal of glycans at positions 386 and 403 also improved affinity. T278R, I371F, N460V are involved in the binding interface. L260F, K357R, G471S stabilize loops involved in the interface. eOD-GT6 bound both VRC01 mature and germline antibodies.
Jardine2013
(glycosylation, vaccine antigen design, structure, antibody lineage)
-
VRC01: The study used the swarm of quasispecies representing Env protein variants to identify mutants conferring sensitivity and resistance to BnAbs. Libraries of Env proteins were cloned and in vitro mutagenesis was used to identify the specific AA responsible for altered neutralization/resistance, which appeared to be associated with conformational changes and exposed epitopes in different regions of gp160. The result showed that sequences in gp41, the CD4bs, and V2 domain act as global regulator of neutralization sensitivity. VRC01 was used as BnAb to screen Env clones and no significant change was observed with VRC01 neutralization.
ORourke2012
(neutralization)
-
VRC01: Concomitant virus evolution and antibody maturation, leading to induction of a lineage of broadly neutralizing antibodies CH103-CH106, were followed in an African patient CH505 for 34 months from the time of infection. Compared to 30-36% VRC01, CH31 and NIH45-46 mutation frequencies of the published CD4 binding sites, CH103-CH106 exhibited 13-17% mutations.
Liao2013
(broad neutralizer)
-
VRC01: This study reports the isolation of a panel of Env vaccine elicited CD4bs-directed macaque mAbs and genetic and functional features that distinguish these Abs from CD4bs MAbs produced during chronic HIV-1 infection. VRC01 was used as a control bNAb.
Sundling2012
(vaccine-induced immune responses)
-
VRC01: Existing structural and sequence data was analyzed. A set of signature features for potent VRC01-like (PVL) and almost PVL abs was proposed and verified by mutagenesis. Sequences of VRC01, NIH45-46 and VRC-PG04 revealed a striking correlation for the length of CDRL3 (5 residues).
West2012a
(antibody lineage)
-
VRC01: Synthesis of an engineered soluble heterotrimeric gp140 is described. These gp140 protomers were designed against clade A and clade B viruses. The heterotrimer gp140s exhibited broader anti-tier1 isolate neutralizing antibody responses than homotrimer gp140. VRC01 was used to determine and compare the immunogenicity of homo and heterotrimers gp140s.
Sellhorn2012
(vaccine antigen design)
-
VRC01: The use of computationally derived B cell clonal lineages as templates for HIV-1 immunogen design is discussed. VRC01 has been discussed in terms of immunogenic and functional characteristics of representative HIV-1 BnAbs and their reactions to antigens.
Haynes2012
(antibody interactions, memory cells, vaccine antigen design, review, antibody polyreactivity, broad neutralizer)
-
VRC01: Crystal structures of unliganded core gp120 from HIV-1 clade B, C, and E were determined to understand the mechanism of CD4 binding capacity of unliganded HIV-1. The results suggest that the CD4 bound conformation represents "a ground state" for the gp120 core with variable loop. VRC01 was used as a control to prove whether the purified and crystallized gp120 is in the CD4 bound conformational state or not.
Kwon2012
(structure)
-
VRC01: Polyclonal B cell responses to conserved neutralization epitopes are reported. Cross-reactive plasma samples were identified and evaluated from 308 subjects tested. VRC01 was used as a control mAb in the comprehensive set of assays performed.
Tomaras2011
(neutralization, polyclonal antibodies)
-
VRC01: Several antibodies including 10-1074 were isolated from B-cell clone encoding PGT121, from a clade A-infected African donor using YU-2 gp140 trimers as bait. These antibodies were segregated into PGT121-like (PGT121-123 and 9 members) and 10-1074-like (20 members) groups distinguished by sequence, binding affinity, carbohydrate recognition, neutralizing activity, the V3 loop binding and the role of glycans in epitope formation. VRC01 was used as a control in virus neutralization assay. Detail information on the binding and neutralization assays are described in the figures S2-S11.
Mouquet2012a
(glycosylation, neutralization, binding affinity)
-
VRC01: YU2 gp140 bait was used to characterize 189 new MAbs representing 51 independent IgG memory B cell clones from 3 clade A or B HIV infected patients exhibiting broad neutralizing activity. The neutralizing potency of the antibodies was compared and none of these antibodies were as broad as VRC01. It has also been referred in discussing the efficiency of YU-2 gp140 trimer as a bait for Ab capture.
Mouquet2011
(neutralization)
-
VRC01: The rational design of vaccines to elicit broadly neutralizing antibodies to HIV-1 is discussed in relation to understanding of vaccine recognition sites, the structural basis of interaction with HIV-1 env and vaccine developmental pathways. Role of VRC01 has been described regarding the sites of HIV-1 vulnerability to neutralizing antibodies and relating to humoral immune response during infection. VRC01 appears to target the site very effectively resulting in neutralization of ˜90% of circulating isolates.
Kwong2011
(antibody binding site, neutralization, vaccine antigen design, review)
-
VRC01: A panel of glycan deletion mutants was created by point mutation into HIV gp160, showing that glycans are important targets on HIV-1 glycoproteins for broad neutralizing responses in vivo. Enrichment of high mannose N-linked glycan(HM-glycan) of HIV-1 glycoprotein enhanced neutralizing activity of sera from 8/9 patients. VRC01 was used as a control to compare the neutralizing activity of patients' sera.
Lavine2012
(neutralization)
-
VRC01: Ab-driven escape and Ab role in infection control and prevention are reviewed. Main focus is on NAbs, but Ab acting through effector mechanisms are also discussed. Highly potent VRC01 (anti-CD4b) is discussed in the context of developing broadly cross-neutralizing antibodies.
Overbaugh2012
(escape, review)
-
VRC01: Neutralization activity was compared against MAb 10E8 and other broad and potent neutralizers in a 181-isolate Env-pseudovirus panel. 2F5 neutralized 89% of viruses at IC50<50 μg/ml and 75% of viruses at IC50<1 μg/ml, compared with 98% and 72% of MAb 10E8, respectively.
Huang2012a
(neutralization)
-
VRC01: Antigenic properties of undigested VLPs and endo H-digested WT trimer VLPs were compared. Binding to E168K+ N189A WT VLPs was stronger than binding to the parent WT VLPs, uncleaved VLPs. There was no significant correlation between E168K+N189A WT VLP binding and VRC01 neutralization, while trimer VLP ELISA binding and neutralization exhibited a significant correlation. BN-PAGE shifts using digested E168K + N189A WT trimer VLPs exhibited prominence compared to WT VLPs.
Tong2012
(neutralization, binding affinity)
-
VRC01: The role of V1V2 in the resistance of HIV-1 to neutralizing Abs was studied using a panel of neutralization-sensitive and -resistant HIV-1 variants and through exchanging regions of Env between neutralization-sensitive and -resistant viruses. An increase in the length of the V1V2 loop and/or the number of potential N-linked glycosylation sites (PNGS) in that same region of Env was directly involved in the neutralization resistance. The introduction of a longer V1V2 loop with more PNGS of HIV-1 from contemporary seroconverters into the background of Env of HIV-1 from historical seroconverters resulted in a 2-fold increase in neutralization resistance to MAb VRC01 for 10/18 viruses.
vanGils2011
(glycosylation, neutralization, escape)
-
VRC01: To improve the immunogenicity of HIV-1 Env vaccines, a chimeric gp140 trimer in which V1V2 region was replaced by the GM-CSF cytokine was constructed. We selected GM-CSF was selected because of its defined adjuvant activity. Chimeric EnvGM-CSF protein enhanced Env-specific Ab and T cell responses in mice compared with wild-type Env. Probing with neutralizing antibodies showed that both the Env and GM-CSF components of the chimeric protein were folded correctly. 3 proteins were studied: Env-wild-type, Env-ΔV1V2, Env-hGM-CSF. MAb VRC01 against discontinuous epitope associated with the CD4bs recognized Env-hGM-CSF, but the binding was subtly (2-fold) less efficient compared with that to Env-wild-type, suggesting that the CD4bs on Env-hGM-CSF is intact, but the accessibility and/or conformation of the VRC01 epitope is subtly altered by the replacement of the V1V2 domain by GM-CSF.
vanMontfort2011
(vaccine antigen design)
-
VRC01: Broadly neutralizing antibodies circulating in plasma were studied by affinity chromatography and isoelectric focusing. The Abs fell in 2 groups. One group consisted of antibodies with restricted neutralization breadth that had neutral isoelectric points. These Abs bound to envelope monomers and trimers versus core antigens from which variable loops and other domains have been deleted. Another minor group consisted of broadly neutralizing antibodies consistently distinguished by more basic isoelectric points and specificity for epitopes shared by monomeric gp120, gp120 core, or CD4-induced structures. The pI values estimated for neutralizing plasma IgGs were compared to those of human anti-gp120 MAbs, including 5 bnMAbs (PG9, PG16, VRC01, b12, and 2G12), 2 narrowly neutralizing MAbs (17b and E51), and 3 nonneutralizing MAbs (A32, C11, and 19e). bnMAbs VRC01, 2G12 and b12 had basic pIs (8.1 to >9).
Sajadi2012
(polyclonal antibodies)
-
VRC01: Sensitivity to neutralization was studied in 107 full-length Env molecular clones from multiple risk groups in various locations in China. Neutralization sensitivity to plasma pools and bNAbs was not correlated. IgG1b12 and VRC01 had different neutralization potency and breadth, despite both of them recognizing the critical CD4-binding domain. IgG1b12 neutralized 45% (14/31) while VRC01 neutralized about 81% (25/31) of the viruses tested.
Shang2011
(glycosylation, neutralization, subtype comparisons)
-
VRC01: Given the potential importance of cell-associated virus during mucosal HIV-1 transmission, sensitivity of bNAbs targeting HIV-1 envelope surface unit gp120 (VRCO1, PG16, b12, and 2G12) and transmembrane domain gp41 (4E10 and 2F5) was examined for both cell-free and mDC-mediated infections of TZM-bl and CD4+ T cells. It was reported that higher gp120-bNAb concentrations, but not gp41-directed bNAb concentrations, are required to inhibit mDC-mediated virus spread, compared with cell-free transmission. In all cases except for 89.6, the VRC01 concentration required to inhibit infection by 50% (IC50) was significantly lower for cell-free infection as compared with mDC-associated trans-infection. For 89.6, VRC01 did not demonstrate <50% inhibition of either cell-free or mDC-associated HIV-1 at the highest tested doses. 4E10 and 2F5 bound a significantly greater percentage of mDCs, compared with VRC01.
Sagar2012
(neutralization, binding affinity)
-
VRC01: To overcome the many limitations of current systems for HIV-1 virus-like particle (VLP) production, a novel strategy was developed to produce HIV-1 VLP using stably transfected Drosophila S2 cells by cotransfecting S2 cells with plasmids encoding an envelope glycoprotein (consensus B or consensus C), a Rev-independent Gag (Pr55) protein, and a Rev protein, along with a pCoBlast selection marker. Except for antigenic epitope PG16, all other broadly neutralizing antigenic epitopes 2G12, b12, VRC01, and 4E10 tested are preserved on spikes of HIV-1 VLP produced by S2 clones.
Yang2012
(assay or method development, neutralization)
-
VRC01: In order to increase recognition of CD4 by Env and to elicit stronger neutralizing antibodies against it, two Env probes were produced and tested - monomeric Env was stabilized by pocket filling mutations in the CD4bs (PF2) and trimeric Env was formed by appending trimerization motifs to soluble gp120/gp14. PF2-containing proteins were better recognized by bNMAb against CD4bs and more rapidly elicited neutralizing antibodies against the CD4bs. Trimeric Env, however, elicited a higher neutralization potency that mapped to the V3 region of gp120.
Feng2012
(neutralization)
-
VRC01: The sera of 113 HIV-1 seroconverters from three cohorts were analyzed for binding to a set of well-characterized gp120 core and resurfaced stabilized core (RSC3) protein probes, and their cognate CD4bs knockout mutants. VRC01 bound very strongly to the gp120 core and RSC3, strongly bound to RSC3/G367R, weakly bound to gp120 core D368R and RSC3 Δ3711, and very weakly bound to RSC3 Δ3711/P363N.
Lynch2012
(binding affinity)
-
VRC01: The interaction of CD4bs-binding MAbs (VRC01, VRC-PG04) and V1V2 glycan-dependent MAbs (PG9, PG16) was analyzed. MAb binding and neutralization studies showed that these two Env targets to not cross-compete and that their combination can mediate additive neutralization. The combination of MAbs VRC01 and PG9 provides a predicted coverage of 97% of 208 isolates at IC50 < 50 μg/ml and of 91% at IC50 < 50 μg/ml. In contrast, the combination of PG9 and PG16 (or the combination of VRC01 and VRC-PG04) was only marginally better than either MAb alone.
Doria-Rose2012
(antibody interactions)
-
VRC01: The strategy of incorporating extra glycans onto gp120 was explored, with the goal to occlude the epitopes of non-neutralizing MAbs while maintaining exposure of the b12 site. The focus was on the head-to-head comparison of the ability of 2 adjuvants, monophosphoryl lipid A (MPL) and Quil A, to promote CD4-specific Ab responses in mice immunized with the engineered mutant Q105N compared to gp120wt. Neutralizing and non-neutralizing antibodies targeting three areas on gp120 – the CD4bs (F105, b6, b12, b13, VRC01, VRC03 and CD4- IgG2), the glycosylated ‘silent face’ (2G12) and the V3 loop (B4e8) – were assessed for binding. The antibodies b6, b12, b13, VRC01 and 2G12 bound best to mutant Q105N, albeit with lower affinities than to gp120wt. Retention of b6 and b13 binding was not expected, but can be explained by their very similar mode of interaction with the CD4bs compared to b12. Abs F105 and VRC03 did not bind Q105N at all. The V3-specific antibody B4e8 did not bind to Q105N.
Ahmed2012
(adjuvant comparison, antibody binding site, glycosylation, neutralization, escape)
-
VRC01: The neutralization activities of IA versus IgG and Fab versions of three broadly neutralizing antibodies: PG9, PG16, and VRC01 was compared to more fully understand the potential trade-offs in vector and construct design. The potential to combine VCR01 and PG9/PG16 activities to produce a single reagent with two gp120 specificities was also explored. In an Env-pseudotyped HIV-1 neutralization assay against a panel of 30 strains, VRC01 neutralized 25 strains in IgG form, 24 strains in IgG-2A form, 21 stains in Fab form, 18 strains in IA form and 27 strains in VRC01scFv-PG16 form. It was found that the PG9, PG16, and VRC01 IAs were severalfold less potent than their IgG forms.
West2012
(neutralization)
-
VRC01: The role of envelope expression context and producer cell type was characterized for nine novel replication-competent chimeric HIV-1 isolates from the dominant circulating HIV-1 subtypes in Africa, where most new HIV-1 infections are occurring. Pseudoviruses generated in 293T cells were the most sensitive to antibody neutralization. Replicating viruses generated in primary lymphocytes were most resistant to neutralization by most monoclonal antibodies including VRC01. PBMC-derived chimeras displayed increased neutralization resistance compared to 293T-derived chimeras for VRC01.
Provine2012
(neutralization)
-
VRC01: Phenotypic activities of a single transmitted/founder (T/F) virus from 24 acute individuals were compared to that of 17 viruses from chronics. T/F Envs were more sensitive than chronic Envs to MAbs b12 and VRC01. The binding of b12 and VRC01 to the trimeric Envs was strongly correlated to their sensitivity to inhibition for both T/F and chronic viruses. Binding of VRC01 to the T/F was increased relative to a subgroup of 11 chronics.
Wilen2011
(neutralization, binding affinity)
-
VRC01: HIV-1 adaptation to neutralization by MAbs VRC01, PG9, PG16 was studied using HIV-1 variants from historic (1985-1989) and contemporary (2003-2006) seroconverters. VRC01 neutralized 33% of contemporary viruses at IC50 < 1 μ g/ml and 76% at IC50 < 4 μ g/ml. Viruses from contemporary seroconverters were significantly more resistant to neutralization by VRC01 and tended to be more resistant to neutralization by PG16. Despite that, all recently transmitted viruses were sensitive to at least one broadly neutralizing Ab at concentration < 5 μg/ml. There was no clear correlation between the sensitivity to VRC01 and presence or absence of certain amino acids.
Euler2011
(neutralization, escape)
-
VRC01: VRC01 selection pressure was studied using viral quasispecies from 3 time points (2001, 2006, 2009) in donor 45, from whom VRC01 was initially isolated, and from several time points in 5 additional donors with broadly serum neutralizing Abs. 473 Envs were assessed in total. While VRC01 neutralizes 90% of genetically diverse heterologous HIV-1 strains, most plasma derived autologous Env variants from donor 45 were highly resistant to VRC01. Isolation of HIV-1 env sequences from proviral DNA allowed to identify archival ENV clones highly sensitive to VRC01, suggesting that donor 45 was infected with a VRC01 sensitive virus that evolved to escape from VRC01.
Wu2012
(neutralization, escape)
-
VRC01: MAb VRC01 neutralization is further characterized in the context of full-length gp120, its impact on the architecture of the viral Env functional spike upon binding, and viral factors associated with the relatively few cases of HIV-1 neutralization resistance. It was confirmed that mutations of structurally defined contact residues in loop D (N terminal to the V3 region), the CD4 binding loop, and the V5-β24-α5 region diminished VRC01-mediated binding or neutralization.
Li2011
(acute/early infection)
-
VRC01: The neutralization potency of PG9, PG16, VRC01 and PGV04 was approximately 10-fold greater than that of MAbs b12, 2G12, 2F5 and 4E10. Alanine substitutions D279A, I420A and I423A abrogated PGV04 neutralization, and decreased neutralization by VRC01. In contrast to VRC01, PGV04 did not enhance 17b or X5 binding to their epitopes in the co-receptor region on the gp120 monomer, and in contrast to CD4, none of the CD4bs MAbs tested induced the 17b site on trimeric cleaved Env, suggesting that a degree of mimicry of CD4 by anti-CD4bs bnMAbs may be a consequence of binding to the CD4 epitope on monomeric gp120 rather than a neutralization mechanism.
Falkowska2012
(neutralization)
-
VRC01: Neutralizing antibody repertoires of 4 HIV-infected donors with remarkably broad and potent neutralizing responses were probed. 17 new monoclonal antibodies that neutralize broadly across clades were rescued. All MAbs exhibited broad cross-clade neutralizing activity, but several showed exceptional potency. Although VRC01 neutralized 93% of 162 isolates at IC50<50 μg/ml, it was almost 10-fold less potent than several new antibodies PGT 121-123 and 125-128, for which the median antibody concentration required to inhibit HIV activity by 50% or 90% (IC50 and IC90 values) was almost 10-fold lower than that of PG9, VRC01 and PGV04.
Walker2011
(neutralization, broad neutralizer)
-
VRC01: 576 new HIV antibodies were cloned from 4 unrelated individuals producing expanded clones of potent broadly neutralizing CD4bs antibodies that bind to the 2CC core. In order to amplify highly somatically mutated immunoglobulin genes, a new primer set with the 5' primer set further upstream from the potentially mutated region was used. Despite extensive hypermutation, the new antibodies shared a consensus sequence of 68 IgH chain amino acids and arose independently from two related IgH genes. With the exception of 8ANC195 MAb, all of the antibodies tested resemble CD4 and VRC01 in that they facilitate CD4i-antibody binding to one or both viral spikes. Comparison of the crystal structure of 3BNC60 MAb to VRC01 revealed conservation of the contacts to the HIV spike. In this study, VRC01 neutralized 100% of 118 isolates representing major HIV-1 clades, with IC50<50μg/ml, but only 17 of the viruses tested were more sensitive to VRC01 than to 3BNC117. NIH45-46, a new variant of VRC01, was more potent than VRC01 on 62 of the viruses tested but still less potent than 3BNC117. VRC01 was not polyreactive - reacted with LPS, but not with dsDNA, ssDNA or insulin.
Scheid2011
(neutralization, antibody sequence, broad neutralizer)
-
VRC01: Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies was studied by isolation of VRC01-like neutralizers with CD4bs probe; structural definition of gp120 recognition by RSC3-identified antibodies from different donors; functional complementation of heavy and light chains among VRC01-like antibodies; identification of VRC01 antibodies by 454 pyrosequencing; and cross-donor phylogenetic analysis of sequences derived from the same precursor germline gene. VRC01 strongly bound to YU2 gp120 wild type and mutated proteins, HXB2 gp120 and antigenically resurfaced protein RSC3. All 10 antibodies isolated by RSC3 binding use the IGHV1-2*02 germline and accrue 70 to 90 nucleotide changes. The structure of VRC-PG04 in complex with gp120 showed striking similarity with the previously determined complex with VRC01, despite low sequence identity and different donors. Heavy- and light-chain cross-pairing chimeras of VRC01, VRC03, VRC-PG04, VRC-CH31 could neutralize up to 90% of 20 clade A, B and C viruses. Thousands of heavy and light chain sequences were found by 454 pyrosequencing, with the sequence identity to VRC01 and VRC02 heavy chains below 75%. Dozens chimeric antibodies obtained by pairing heavy-chain sequences with VRC03 and PG04 light chains and light-chain sequences with VRC01, VRC03,PG04 heavy chains displayed potent neutralization (up to 90%) of A, B and C clade viruses. Cross-donor phylogenetic analysis suggested that common maturation intermediates with 20 to 30 affinity maturation changes from IGHV1-2*02 genomic precursor are found in different individuals. These intermediates give rise to potent broadly neutralizing antibodies with 70-90 changes from IGHV1-2*02. Analysis presented in this study suggests stimulation the elicitation of these intermediates with modified gp120 can be employed for vaccine induced elicitation of VRC01-like antibodies.
Wu2011
(neutralization, antibody sequence, structure)
-
VRC01: One Env clone (4–2.J45) obtained from a recently infected Indian patient (NARI-IVC4) had exceptional neutralization sensitivity compared to other Envs obtained at the same time point from the same patient. Both Envs expressing M424 and I424 showed comparable sensitivity to VRC01, possibly due to the fact that I424M did not impact conformational masking of VRC01 epitope.
Ringe2011
(neutralization)
-
VRC01: Two SHIV-C mutants were designed: SHIV-1157ipEL-pΔ3N, a mutant of the early SHIV-1157ipEL-p which lacked the 3N residues in the V2 stem, and SHIV-1157ipd3N4+3N, a mutant of the late SHIV-1157ipd3N4 where 3N residues was added in the V2 stem. VRC01 neutralized and bound to all four SHIV-Cs with no significant differences. For VRC01, the movement of the V2 loop resulting from the deletion in the V2 stem does not mask the cognate epitope, implying that VRC01 is less sensitive than b12 to conformational masking by the V2 loop.
Watkins2011
(neutralization, binding affinity)
-
VRC01: The characteristics of HIV-1-specific NAbs were evaluated in 100 breast-fed infants of HIV-1-positive mothers who were HIV-1 negative at birth and they were monitored until age 2. A panel of eight viruses that included variants representative of those in the study region as well as more diverse strains was used to determine the breadth of the infant NAbs. VRC01 had low neutralization potency for 1 (THRO4156.18) out of 8 pseudoviruses in the panel but high for the rest of them. For maternal variants, VRC01 had low neutralization potency for 1 (MK184.E4) out of 12 variants and high for the rest of them.
Lynch2011
(neutralization, variant cross-reactivity, mother-to-infant transmission)
-
VRC01: The impact of specific changes at distal sites on antibody binding and neutralization was examined on Q461 variants. The changes at position 675 in conjunction with Thr to Ala at position 569 resulted in a dramatic increase in the neutralization sensitivity to some gp41 and gp120 MAbs and plasma but had less effect on the more potent MAb VRC01. There was an increase in VRC01 neutralization sensitivity to viruses with both mutations with intermediate effect for the individual mutants.
Lovelace2011
(neutralization, variant cross-reactivity)
-
VRC01: This review discusses recent rational structure-based approaches in HIV vaccine design that helped in understanding the link between Env antigenicity and immunogenicity. This MAb was mentioned in the context of immunogens based on the epitopes recognized by bNAbs. VRC01 displayed greater breadth and potency compared to b12.
Walker2010a
(neutralization, review)
-
VRC01: This review discusses current understanding of Env neutralization by antibodies in relation to epitope exposure and how this insight might benefit vaccine design strategies. This MAb is in the list of current MAbs with notable cross-neutralizing activity.
Pantophlet2010
(neutralization, variant cross-reactivity, review)
-
VRC01: This review outlines the general structure of the gp160 viral envelope, the dynamics of viral entry, the evolution of humoral response, the mechanisms of viral escape and the characterization of broadly neutralizing Abs. It is noted that mAbs VRC01 and VRC02 are somatic variants of the same IgG1 clone and neutralize over 90 percent of circulating HIV-1 isolates.
Gonzalez2010
(neutralization, variant cross-reactivity, escape, review)
-
VRC01: This review discusses strategies for design of neutralizing antibody-based vaccines against HIV-1 and recent major advances in the field regarding isolation of potent broadly neutralizing Abs.
Sattentau2010
(review)
-
VRC01: Novel techniques for generation of broadly neutralizing Abs and how these Ab can aid in development of an effective vaccine are discussed.
Joyce2010
(review)
-
VRC01: The review describes several different methods that have been used to isolate and characterize HIV MAbs within the human Ab repertoire. Relative advantages and limitations of methods such as EBV transformation, human hybridoma, non-immortalized B cell culture, combinatorial libraries from B cells and clonal sorting are discussed.
Hammond2010
(review)
-
VRC01: This review summarizes novel techniques recently developed for isolation of broadly neutralizing monoclonal Abs from HIV-infected donors. Future challenges and importance of these techniques for development of HIV vaccines is also discussed.
Burton2010
(review)
-
VRC01: The crystal structure for VRC01 in complex with an HIV-1 gp120 core from a clade A/E recombinant strain was analyzed to understand the structural basis for its neutralization breadth and potency. Crystal structure of Fab VRC01 in complex with gp120 was determined. VRC01 was shown to partially mimic CD4 interaction with gp120, with 73% of the CD4 N-terminal domain overlapping with VRC01 and 98% of the site of initial CD4 attachment covered by this Ab. VRC01 showed high affinity for both CD4-bound and non-CD4-bound conformations of gp120. Th source of most natural resistance to VRC01 was found to be variation in the V5 region and alternations in gp120 D-loop. Genomic precursors of VRC01 did not bind or neutralize virus. Thus, neutralization of HIV-1 by VRC01 was mediated through partial receptor mimicry and extensive affinity maturation. VRC01 was also shown to recognize N-linked glycan at position 276.
Zhou2010
(antibody binding site, glycosylation, neutralization, binding affinity, structure)
-
VRC01: This broadly neutralizing Ab was derived from B-cells from a donor that was screened for CD4bs mAbs with resurfaced stabilized core 3 (RSC3) protein. The protein was designed to preserve the antigenic structure of the gp120 CD4bs neutralizing surface but eliminate other antigenic regions of HIV-1. VRC01 neutralized 91% of 190 virus strains of different HIV-1 clades. VRC01 bound strongly to RSC3 and was highly somatically mutated. Binding of VRC01 to gp120 was competed by b12 and F105. Binding of 17b was markedly enhanced by the addition of VRC01.
Wu2010
(antibody binding site, antibody generation, antibody interactions, enhancing activity, neutralization, variant cross-reactivity, kinetics, binding affinity, antibody sequence)
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Mattia Bonsignori, Tongqing Zhou, Zizhang Sheng, Lei Chen, Feng Gao, M. Gordon Joyce, Gabriel Ozorowski, Gwo-Yu Chuang, Chaim A. Schramm, Kevin Wiehe, S. Munir Alam, Todd Bradley, Morgan A. Gladden, Kwan-Ki Hwang, Sheelah Iyengar, Amit Kumar, Xiaozhi Lu, Kan Luo, Michael C. Mangiapani, Robert J. Parks, Hongshuo Song, Priyamvada Acharya, Robert T. Bailer, Allen Cao, Aliaksandr Druz, Ivelin S. Georgiev, Young D. Kwon, Mark K. Louder, Baoshan Zhang, Anqi Zheng, Brenna J. Hill, Rui Kong, Cinque Soto, NISC Comparative Sequencing Program, James C. Mullikin, Daniel C. Douek, David C. Montefiori, Michael A. Moody, George M. Shaw, Beatrice H. Hahn, Garnett Kelsoe, Peter T. Hraber, Bette T. Korber, Scott D. Boyd, Andrew Z. Fire, Thomas B. Kepler, Lawrence Shapiro, Andrew B. Ward, John R. Mascola, Hua-Xin Liao, Peter D. Kwong, and Barton F. Haynes. Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody. Cell, 165(2):449-463, 7 Apr 2016. PubMed ID: 26949186.
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Bonsignori2018
Mattia Bonsignori, Eric Scott, Kevin Wiehe, David Easterhoff, S. Munir Alam, Kwan-Ki Hwang, Melissa Cooper, Shi-Mao Xia, Ruijun Zhang, David C. Montefiori, Rory Henderson, Xiaoyan Nie, Garnett Kelsoe, M. Anthony Moody, Xuejun Chen, M. Gordon Joyce, Peter D. Kwong, Mark Connors, John R. Mascola, Andrew T. McGuire, Leonidas Stamatatos, Max Medina-Ramirez, Rogier W. Sanders, Kevin O. Saunders, Thomas B. Kepler, and Barton F. Haynes. Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier. Immunity, 49(6):1162-1174.e8, 18 Dec 2018. PubMed ID: 30552024.
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Borst2018
Andrew J. Borst, Connor E. Weidle, Matthew D. Gray, Brandon Frenz, Joost Snijder, M. Gordon Joyce, Ivelin S. Georgiev, Guillaume B. E. Stewart-Jones, Peter D. Kwong, Andrew T. McGuire, Frank DiMaio, Leonidas Stamatatos, Marie Pancera, and David Veesler. Germline VRC01 Antibody Recognition of a Modified Clade C HIV-1 Envelope Trimer and a Glycosylated HIV-1 Gp120 Core. eLife, 7, 7 Nov 2018. PubMed ID: 30403372.
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Bradley2016a
Todd Bradley, Ashley Trama, Nancy Tumba, Elin Gray, Xiaozhi Lu, Navid Madani, Fatemeh Jahanbakhsh, Amanda Eaton, Shi-Mao Xia, Robert Parks, Krissey E. Lloyd, Laura L. Sutherland, Richard M. Scearce, Cindy M. Bowman, Susan Barnett, Salim S. Abdool-Karim, Scott D. Boyd, Bruno Melillo, Amos B. Smith, 3rd., Joseph Sodroski, Thomas B. Kepler, S. Munir Alam, Feng Gao, Mattia Bonsignori, Hua-Xin Liao, M Anthony Moody, David Montefiori, Sampa Santra, Lynn Morris, and Barton F. Haynes. Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity. EBioMedicine, 12:196-207, Oct 2016. PubMed ID: 27612593.
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Braibant2013
Martine Braibant, Eun-Yeung Gong, Jean-Christophe Plantier, Thierry Moreau, Elodie Alessandri, François Simon, and Francis Barin. Cross-Group Neutralization of HIV-1 and Evidence for Conservation of the PG9/PG16 Epitopes within Divergent Groups. AIDS, 27(8):1239-1244, 15 May 2013. PubMed ID: 23343910.
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Bricault2019
Christine A. Bricault, Karina Yusim, Michael S. Seaman, Hyejin Yoon, James Theiler, Elena E. Giorgi, Kshitij Wagh, Maxwell Theiler, Peter Hraber, Jennifer P. Macke, Edward F. Kreider, Gerald H. Learn, Beatrice H. Hahn, Johannes F. Scheid, James M. Kovacs, Jennifer L. Shields, Christy L. Lavine, Fadi Ghantous, Michael Rist, Madeleine G. Bayne, George H. Neubauer, Katherine McMahan, Hanqin Peng, Coraline Chéneau, Jennifer J. Jones, Jie Zeng, Christina Ochsenbauer, Joseph P. Nkolola, Kathryn E. Stephenson, Bing Chen, S. Gnanakaran, Mattia Bonsignori, LaTonya D. Williams, Barton F. Haynes, Nicole Doria-Rose, John R. Mascola, David C. Montefiori, Dan H. Barouch, and Bette Korber. HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design. Cell Host Microbe, 25(1):59-72.e8, 9 Jan 2019. PubMed ID: 30629920.
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Briney2016
Bryan Briney, Devin Sok, Joseph G. Jardine, Daniel W. Kulp, Patrick Skog, Sergey Menis, Ronald Jacak, Oleksandr Kalyuzhniy, Natalia de Val, Fabian Sesterhenn, Khoa M. Le, Alejandra Ramos, Meaghan Jones, Karen L. Saye-Francisco, Tanya R. Blane, Skye Spencer, Erik Georgeson, Xiaozhen Hu, Gabriel Ozorowski, Yumiko Adachi, Michael Kubitz, Anita Sarkar, Ian A. Wilson, Andrew B. Ward, David Nemazee, Dennis R. Burton, and William R. Schief. Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies. Cell, 166(6):1459-1470.e11, 8 Sep 2016. PubMed ID: 27610570.
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Bruel2016
Timothée Bruel, Florence Guivel-Benhassine, Sonia Amraoui, Marine Malbec, Léa Richard, Katia Bourdic, Daniel Aaron Donahue, Valérie Lorin, Nicoletta Casartelli, Nicolas Noël, Olivier Lambotte, Hugo Mouquet, and Olivier Schwartz. Elimination of HIV-1-Infected Cells by Broadly Neutralizing Antibodies. Nat. Commun., 7:10844, 3 Mar 2016. PubMed ID: 26936020.
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Burton2010
Dennis R. Burton and Robin A. Weiss. A Boost for HIV Vaccine Design. Science, 329(5993):770-773, 13 Aug 2010. PubMed ID: 20705840.
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Burton2012
Dennis R. Burton, Pascal Poignard, Robyn L. Stanfield, and Ian A. Wilson. Broadly Neutralizing Antibodies Present New Prospects to Counter Highly Antigenically Diverse Viruses. Science, 337(6091):183-186, 13 Jul 2012. PubMed ID: 22798606.
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Burton2016
Dennis R. Burton and Lars Hangartner. Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design. Annu. Rev. Immunol., 34:635-659, 20 May 2016. PubMed ID: 27168247.
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Cai2017
Yongfei Cai, Selen Karaca-Griffin, Jia Chen, Sai Tian, Nicholas Fredette, Christine E. Linton, Sophia Rits-Volloch, Jianming Lu, Kshitij Wagh, James Theiler, Bette Korber, Michael S. Seaman, Stephen C. Harrison, Andrea Carfi, and Bing Chen. Antigenicity-Defined Conformations of an Extremely Neutralization-Resistant HIV-1 Envelope Spike. Proc. Natl. Acad. Sci. U.S.A., 114(17):4477-4482, 25 Apr 2017. PubMed ID: 28396421.
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Carbonetti2014
Sara Carbonetti, Brian G. Oliver, Jolene Glenn, Leonidas Stamatatos, and D. Noah Sather. Soluble HIV-1 Envelope Immunogens Derived from an Elite Neutralizer Elicit Cross-Reactive V1V2 Antibodies and Low Potency Neutralizing Antibodies. PLoS One, 9(1):e86905, 2014. PubMed ID: 24466285.
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Caskey2017
Marina Caskey, Till Schoofs, Henning Gruell, Allison Settler, Theodora Karagounis, Edward F. Kreider, Ben Murrell, Nico Pfeifer, Lilian Nogueira, Thiago Y. Oliveira, Gerald H. Learn, Yehuda Z. Cohen, Clara Lehmann, Daniel Gillor, Irina Shimeliovich, Cecilia Unson-O'Brien, Daniela Weiland, Alexander Robles, Tim Kummerle, Christoph Wyen, Rebeka Levin, Maggi Witmer-Pack, Kemal Eren, Caroline Ignacio, Szilard Kiss, Anthony P. West, Jr., Hugo Mouquet, Barry S. Zingman, Roy M. Gulick, Tibor Keler, Pamela J. Bjorkman, Michael S. Seaman, Beatrice H. Hahn, Gerd Fätkenheuer, Sarah J. Schlesinger, Michel C. Nussenzweig, and Florian Klein. Antibody 10-1074 Suppresses Viremia in HIV-1-Infected Individuals. Nat. Med., 23(2):185-191, Feb 2017. PubMed ID: 28092665.
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Castillo-Menendez2019
Luis R. Castillo-Menendez, Hanh T. Nguyen, and Joseph Sodroski. Conformational Differences between Functional Human Immunodeficiency Virus Envelope Glycoprotein Trimers and Stabilized Soluble Trimers. J. Virol., 93(3), 1 Feb 2019. PubMed ID: 30429345.
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Cheeseman2017
Hannah M. Cheeseman, Natalia J. Olejniczak, Paul M. Rogers, Abbey B. Evans, Deborah F. L. King, Paul Ziprin, Hua-Xin Liao, Barton F. Haynes, and Robin J. Shattock. Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies. J. Virol., 91(1), 1 Jan 2017. PubMed ID: 27795431.
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Chen2015
Jia Chen, James M. Kovacs, Hanqin Peng, Sophia Rits-Volloch, Jianming Lu, Donghyun Park, Elise Zablowsky, Michael S. Seaman, and Bing Chen. Effect of the Cytoplasmic Domain on Antigenic Characteristics of HIV-1 Envelope Glycoprotein. Science, 349(6244):191-195, 10 Jul 2015. PubMed ID: 26113642.
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Chen2016
Danying Chen, Xiaozhou He, Jingrong Ye, Pengxiang Zhao, Yi Zeng, and Xia Feng. Genetic and Phenotypic Analysis of CRF01\_AE HIV-1 env Clones from Patients Residing in Beijing, China. AIDS Res. Hum. Retroviruses, 32(10-11):1113-1124, Nov 2016. PubMed ID: 27066910.
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Chen2016b
Yajing Chen, Richard Wilson, Sijy O'Dell, Javier Guenaga, Yu Feng, Karen Tran, Chi-I Chiang, Heather E. Arendt, Joanne DeStefano, John R. Mascola, Richard T. Wyatt, and Yuxing Li. An HIV-1 Env-Antibody Complex Focuses Antibody Responses to Conserved Neutralizing Epitopes. J. Immunol., 197(10):3982-3998, 15 Nov 2016. PubMed ID: 27815444.
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Chuang2013
Gwo-Yu Chuang, Priyamvada Acharya, Stephen D. Schmidt, Yongping Yang, Mark K. Louder, Tongqing Zhou, Young Do Kwon, Marie Pancera, Robert T. Bailer, Nicole A. Doria-Rose, Michel C. Nussenzweig, John R. Mascola, Peter D. Kwong, and Ivelin S. Georgiev. Residue-Level Prediction of HIV-1 Antibody Epitopes Based on Neutralization of Diverse Viral Strains. J. Virol., 87(18):10047-10058, Sep 2013. PubMed ID: 23843642.
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Chuang2017
Gwo-Yu Chuang, Hui Geng, Marie Pancera, Kai Xu, Cheng Cheng, Priyamvada Acharya, Michael Chambers, Aliaksandr Druz, Yaroslav Tsybovsky, Timothy G. Wanninger, Yongping Yang, Nicole A. Doria-Rose, Ivelin S. Georgiev, Jason Gorman, M. Gordon Joyce, Sijy O'Dell, Tongqing Zhou, Adrian B. McDermott, John R. Mascola, and Peter D. Kwong. Structure-Based Design of a Soluble Prefusion-Closed HIV-1 Env Trimer with Reduced CD4 Affinity and Improved Immunogenicity. J. Virol., 91(10), 15 May 2017. PubMed ID: 28275193.
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Chuang2019
Gwo-Yu Chuang, Jing Zhou, Priyamvada Acharya, Reda Rawi, Chen-Hsiang Shen, Zizhang Sheng, Baoshan Zhang, Tongqing Zhou, Robert T. Bailer, Venkata P. Dandey, Nicole A. Doria-Rose, Mark K. Louder, Krisha McKee, John R. Mascola, Lawrence Shapiro, and Peter D. Kwong. Structural Survey of Broadly Neutralizing Antibodies Targeting the HIV-1 Env Trimer Delineates Epitope Categories and Characteristics of Recognition. Structure, 27(1):196-206.e6, 2 Jan 2019. PubMed ID: 30471922.
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Chuang2020
Gwo-Yu Chuang, Mangaiarkarasi Asokan, Vera B. Ivleva, Amarendra Pegu, Eun Sung Yang, Baoshan Zhang, Rajoshi Chaudhuri, Hui Geng, Bob C. Lin, Mark K. Louder, Krisha McKee, Sijy O'Dell, Hairong Wang, Tongqing Zhou, Nicole A. Doria-Rose, Lisa A. Kueltzo, Q. Paula Lei, John R. Mascola, and Peter D. Kwong. Removal of Variable Domain N-Linked Glycosylation as a Means To Improve the Homogeneity of HIV-1 Broadly Neutralizing Antibodies. mAbs, 12(1):1836719, 2020. PubMed ID: 33121334.
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Chun2014
Tae-Wook Chun, Danielle Murray, Jesse S. Justement, Jana Blazkova, Claire W. Hallahan, Olivia Fankuchen, Kathleen Gittens, Erika Benko, Colin Kovacs, Susan Moir, and Anthony S. Fauci. Broadly Neutralizing Antibodies Suppress HIV in the Persistent Viral Reservoir. Proc. Natl. Acad. Sci. U.S.A., 111(36):13151-13156, 9 Sep 2014. PubMed ID: 25157148.
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Clark2017
Anthony J. Clark, Tatyana Gindin, Baoshan Zhang, Lingle Wang, Robert Abel, Colleen S. Murret, Fang Xu, Amy Bao, Nina J. Lu, Tongqing Zhou, Peter D. Kwong, Lawrence Shapiro, Barry Honig, and Richard A. Friesner. Free Energy Perturbation Calculation of Relative Binding Free Energy between Broadly Neutralizing Antibodies and the gp120 Glycoprotein of HIV-1. J. Mol. Biol., 429(7):930-947, 7 Apr 2017. PubMed ID: 27908641.
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Corey2021
Lawrence Corey, Peter B. Gilbert, Michal Juraska, David C. Montefiori, Lynn Morris, Shelly T. Karuna, Srilatha Edupuganti, Nyaradzo M. Mgodi, Allan C. deCamp, Erika Rudnicki, Yunda Huang, Pedro Gonzales, Robinson Cabello, Catherine Orrell, Javier R. Lama, Fatima Laher, Erica M. Lazarus, Jorge Sanchez, Ian Frank, Juan Hinojosa, Magdalena E. Sobieszczyk, Kyle E. Marshall, Pamela G. Mukwekwerere, Joseph Makhema, Lindsey R. Baden, James I. Mullins, Carolyn Williamson, John Hural, M. Juliana McElrath, Carter Bentley, Simbarashe Takuva, Margarita M. Gomez Lorenzo, David N. Burns, Nicole Espy, April K. Randhawa, Nidhi Kochar, Estelle Piwowar-Manning, Deborah J. Donnell, Nirupama Sista, Philip Andrew, James G. Kublin, Glenda Gray, Julie E. Ledgerwood, John R. Mascola, Myron S. Cohen, and HVTN 704/HPTN 085 and HVTN 703/HPTN 081 Study Teams. Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition. N. Engl. J. Med., 384(11):1003-1014, 18 Mar 2021. PubMed ID: 33730454.
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Crooks2015
Ema T. Crooks, Tommy Tong, Bimal Chakrabarti, Kristin Narayan, Ivelin S. Georgiev, Sergey Menis, Xiaoxing Huang, Daniel Kulp, Keiko Osawa, Janelle Muranaka, Guillaume Stewart-Jones, Joanne Destefano, Sijy O'Dell, Celia LaBranche, James E. Robinson, David C. Montefiori, Krisha McKee, Sean X. Du, Nicole Doria-Rose, Peter D. Kwong, John R. Mascola, Ping Zhu, William R. Schief, Richard T. Wyatt, Robert G. Whalen, and James M. Binley. Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site. PLoS Pathog, 11(5):e1004932, May 2015. PubMed ID: 26023780.
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Danesh2020
Ali Danesh, Yanqin Ren, and R. Brad Jones. Roles of Fragment Crystallizable-Mediated Effector Functions in Broadly Neutralizing Antibody Activity against HIV. Curr. Opin. HIV AIDS, 15(5):316-323, Sep 2020. PubMed ID: 32732552.
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Decamp2014
Allan deCamp, Peter Hraber, Robert T. Bailer, Michael S. Seaman, Christina Ochsenbauer, John Kappes, Raphael Gottardo, Paul Edlefsen, Steve Self, Haili Tang, Kelli Greene, Hongmei Gao, Xiaoju Daniell, Marcella Sarzotti-Kelsoe, Miroslaw K. Gorny, Susan Zolla-Pazner, Celia C. LaBranche, John R. Mascola, Bette T. Korber, and David C. Montefiori. Global Panel of HIV-1 Env Reference Strains for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies. J. Virol., 88(5):2489-2507, Mar 2014. PubMed ID: 24352443.
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Derking2015
Ronald Derking, Gabriel Ozorowski, Kwinten Sliepen, Anila Yasmeen, Albert Cupo, Jonathan L. Torres, Jean-Philippe Julien, Jeong Hyun Lee, Thijs van Montfort, Steven W. de Taeye, Mark Connors, Dennis R. Burton, Ian A. Wilson, Per-Johan Klasse, Andrew B. Ward, John P. Moore, and Rogier W. Sanders. Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer. PLoS Pathog, 11(3):e1004767, Mar 2015. PubMed ID: 25807248.
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deTaeye2015
Steven W. de Taeye, Gabriel Ozorowski, Alba Torrents de la Peña, Miklos Guttman, Jean-Philippe Julien, Tom L. G. M. van den Kerkhof, Judith A. Burger, Laura K. Pritchard, Pavel Pugach, Anila Yasmeen, Jordan Crampton, Joyce Hu, Ilja Bontjer, Jonathan L. Torres, Heather Arendt, Joanne DeStefano, Wayne C. Koff, Hanneke Schuitemaker, Dirk Eggink, Ben Berkhout, Hansi Dean, Celia LaBranche, Shane Crotty, Max Crispin, David C. Montefiori, P. J. Klasse, Kelly K. Lee, John P. Moore, Ian A. Wilson, Andrew B. Ward, and Rogier W. Sanders. Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-Neutralizing Epitopes. Cell, 163(7):1702-1715, 17 Dec 2015. PubMed ID: 26687358.
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deTaeye2018
Steven W. de Taeye, Alba Torrents de la Peña, Andrea Vecchione, Enzo Scutigliani, Kwinten Sliepen, Judith A. Burger, Patricia van der Woude, Anna Schorcht, Edith E. Schermer, Marit J. van Gils, Celia C. LaBranche, David C. Montefiori, Ian A. Wilson, John P. Moore, Andrew B. Ward, and Rogier W. Sanders. Stabilization of the gp120 V3 Loop through Hydrophobic Interactions Reduces the Immunodominant V3-Directed Non-Neutralizing Response to HIV-1 Envelope Trimers. J. Biol. Chem., 293(5):1688-1701, 2 Feb 2018. PubMed ID: 29222332.
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deTaeye2019
Steven W. de Taeye, Eden P. Go, Kwinten Sliepen, Alba Torrents de la Peña, Kimberly Badal, Max Medina-Ramírez, Wen-Hsin Lee, Heather Desaire, Ian A. Wilson, John P. Moore, Andrew B. Ward, and Rogier W. Sanders. Stabilization of the V2 Loop Improves the Presentation of V2 Loop-Associated Broadly Neutralizing Antibody Epitopes on HIV-1 Envelope Trimers. J. Biol. Chem., 294(14):5616-5631, 5 Apr 2019. PubMed ID: 30728245.
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Ding2015
Shilei Ding, Maxime Veillette, Mathieu Coutu, Jérémie Prévost, Louise Scharf, Pamela J. Bjorkman, Guido Ferrari, James E. Robinson, Christina Stürzel, Beatrice H. Hahn, Daniel Sauter, Frank Kirchhoff, George K. Lewis, Marzena Pazgier, and Andrés Finzi. A Highly Conserved Residue of the HIV-1 gp120 Inner Domain Is Important for Antibody-Dependent Cellular Cytotoxicity Responses Mediated by Anti-cluster A Antibodies. J. Virol., 90(4):2127-2134, Feb 2016. PubMed ID: 26637462.
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Dingens2019
Adam S. Dingens, Dana Arenz, Haidyn Weight, Julie Overbaugh, and Jesse D. Bloom. An Antigenic Atlas of HIV-1 Escape from Broadly Neutralizing Antibodies Distinguishes Functional and Structural Epitopes. Immunity, 50(2):520-532.e3, 19 Feb 2019. PubMed ID: 30709739.
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Diskin2013
Ron Diskin, Florian Klein, Joshua A. Horwitz, Ariel Halper-Stromberg, D. Noah Sather, Paola M. Marcovecchio, Terri Lee, Anthony P. West, Jr., Han Gao, Michael S. Seaman, Leonidas Stamatatos, Michel C. Nussenzweig, and Pamela J. Bjorkman. Restricting HIV-1 Pathways for Escape Using Rationally Designed Anti-HIV-1 Antibodies. J. Exp. Med., 210(6):1235-1249, 3 Jun 2013. PubMed ID: 23712429.
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Doria-Rose2012
Nicole A. Doria-Rose, Mark K. Louder, Zhongjia Yang, Sijy O'Dell, Martha Nason, Stephen D. Schmidt, Krisha McKee, Michael S. Seaman, Robert T. Bailer, and John R. Mascola. HIV-1 Neutralization Coverage Is Improved by Combining Monoclonal Antibodies That Target Independent Epitopes. J. Virol., 86(6):3393-3397, Mar 2012. PubMed ID: 22258252.
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Doria-Rose2017
Nicole A. Doria-Rose, Han R. Altae-Tran, Ryan S. Roark, Stephen D. Schmidt, Matthew S. Sutton, Mark K. Louder, Gwo-Yu Chuang, Robert T. Bailer, Valerie Cortez, Rui Kong, Krisha McKee, Sijy O'Dell, Felicia Wang, Salim S. Abdool Karim, James M. Binley, Mark Connors, Barton F. Haynes, Malcolm A. Martin, David C. Montefiori, Lynn Morris, Julie Overbaugh, Peter D. Kwong, John R. Mascola, and Ivelin S. Georgiev. Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting. PLoS Pathog., 13(1):e1006148, Jan 2017. PubMed ID: 28052137.
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Duan2018
Hongying Duan, Xuejun Chen, Jeffrey C. Boyington, Cheng Cheng, Yi Zhang, Alexander J. Jafari, Tyler Stephens, Yaroslav Tsybovsky, Oleksandr Kalyuzhniy, Peng Zhao, Sergey Menis, Martha C. Nason, Erica Normandin, Maryam Mukhamedova, Brandon J. DeKosky, Lance Wells, William R. Schief, Ming Tian, Frederick W. Alt, Peter D. Kwong, and John R. Mascola. Glycan Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies. Immunity, 49(2):301-311.e5, 21 Aug 2018. PubMed ID: 30076101.
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Dubrovskaya2019
Viktoriya Dubrovskaya, Karen Tran, Gabriel Ozorowski, Javier Guenaga, Richard Wilson, Shridhar Bale, Christopher A. Cottrell, Hannah L. Turner, Gemma Seabright, Sijy O'Dell, Jonathan L. Torres, Lifei Yang, Yu Feng, Daniel P. Leaman, Néstor Vázquez Bernat, Tyler Liban, Mark Louder, Krisha McKee, Robert T. Bailer, Arlette Movsesyan, Nicole A . Doria-Rose, Marie Pancera, Gunilla B. Karlsson Hedestam, Michael B. Zwick, Max Crispin, John R. Mascola, Andrew B. Ward, and Richard T. Wyatt. Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability. Immunity, 51(5):915-929.e7, 19 Nov 2019. PubMed ID: 31732167.
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Dufloo2022
Jérémy Dufloo, Cyril Planchais, Stéphane Frémont, Valérie Lorin, Florence Guivel-Benhassine, Karl Stefic, Nicoletta Casartelli, Arnaud Echard, Philippe Roingeard, Hugo Mouquet, Olivier Schwartz, and Timothée Bruel. Broadly Neutralizing Anti-HIV-1 Antibodies Tether Viral Particles at the Surface of Infected Cells. Nat. Commun., 13(1):630, 2 Feb 2022. PubMed ID: 35110562.
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Easterhoff2017
David Easterhoff, M. Anthony Moody, Daniela Fera, Hao Cheng, Margaret Ackerman, Kevin Wiehe, Kevin O. Saunders, Justin Pollara, Nathan Vandergrift, Rob Parks, Jerome Kim, Nelson L. Michael, Robert J. O'Connell, Jean-Louis Excler, Merlin L. Robb, Sandhya Vasan, Supachai Rerks-Ngarm, Jaranit Kaewkungwal, Punnee Pitisuttithum, Sorachai Nitayaphan, Faruk Sinangil, James Tartaglia, Sanjay Phogat, Thomas B. Kepler, S. Munir Alam, Hua-Xin Liao, Guido Ferrari, Michael S. Seaman, David C. Montefiori, Georgia D. Tomaras, Stephen C. Harrison, and Barton F. Haynes. Boosting of HIV Envelope CD4 Binding Site Antibodies with Long Variable Heavy Third Complementarity Determining Region in the Randomized Double Blind RV305 HIV-1 Vaccine Trial. PLoS Pathog., 13(2):e1006182, Feb 2017. PubMed ID: 28235027.
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Euler2011
Zelda Euler, Evelien M. Bunnik, Judith A. Burger, Brigitte D. M. Boeser-Nunnink, Marlous L. Grijsen, Jan M. Prins, and Hanneke Schuitemaker. Activity of Broadly Neutralizing Antibodies, Including PG9, PG16, and VRC01, against Recently Transmitted Subtype B HIV-1 Variants from Early and Late in the Epidemic. J. Virol., 85(14):7236-7245, Jul 2011. PubMed ID: 21561918.
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Falkowska2012
Emilia Falkowska, Alejandra Ramos, Yu Feng, Tongqing Zhou, Stephanie Moquin, Laura M. Walker, Xueling Wu, Michael S. Seaman, Terri Wrin, Peter D. Kwong, Richard T. Wyatt, John R. Mascola, Pascal Poignard, and Dennis R. Burton. PGV04, an HIV-1 gp120 CD4 Binding Site Antibody, Is Broad and Potent in Neutralization but Does Not Induce Conformational Changes Characteristic of CD4. J. Virol., 86(8):4394-4403, Apr 2012. PubMed ID: 22345481.
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Feng2012
Yu Feng, Krisha McKee, Karen Tran, Sijy O'Dell, Stephen D. Schmidt, Adhuna Phogat, Mattias N. Forsell, Gunilla B. Karlsson Hedestam, John R. Mascola, and Richard T. Wyatt. Biochemically Defined HIV-1 Envelope Glycoprotein Variant Immunogens Display Differential Binding and Neutralizing Specificities to the CD4-Binding Site. J. Biol. Chem., 287(8):5673-5686, 17 Feb 2012. PubMed ID: 22167180.
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Ferrari2011a
Guido Ferrari, Justin Pollara, Daniel Kozink, Tiara Harms, Mark Drinker, Stephanie Freel, M. Anthony Moody, S. Munir Alam, Georgia D. Tomaras, Christina Ochsenbauer, John C. Kappes, George M. Shaw, James A. Hoxie, James E. Robinson, and Barton F. Haynes. An HIV-1 gp120 Envelope Human Monoclonal Antibody That Recognizes a C1 Conformational Epitope Mediates Potent Antibody-Dependent Cellular Cytotoxicity (ADCC) Activity and Defines a Common ADCC Epitope in Human HIV-1 Serum. J. Virol., 85(14):7029-7036, Jul 2011. PubMed ID: 21543485.
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Freund2015
Natalia T. Freund, Joshua A. Horwitz, Lilian Nogueira, Stuart A. Sievers, Louise Scharf, Johannes F. Scheid, Anna Gazumyan, Cassie Liu, Klara Velinzon, Ariel Goldenthal, Rogier W. Sanders, John P. Moore, Pamela J. Bjorkman, Michael S. Seaman, Bruce D. Walker, Florian Klein, and Michel C. Nussenzweig. A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo. PLoS Pathog, 11(10):e1005238, Oct 2015. PubMed ID: 26516768.
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Fu2018
Qingshan Fu, Md Munan Shaik, Yongfei Cai, Fadi Ghantous, Alessandro Piai, Hanqin Peng, Sophia Rits-Volloch, Zhijun Liu, Stephen C. Harrison, Michael S. Seaman, Bing Chen, and James J. Chou. Structure of the Membrane Proximal External Region of HIV-1 Envelope Glycoprotein. Proc. Natl. Acad. Sci. U.S.A., 115(38):E8892-E8899, 18 Sep 2018. PubMed ID: 30185554.
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Gach2013
Johannes S. Gach, Heribert Quendler, Tommy Tong, Kristin M. Narayan, Sean X. Du, Robert G. Whalen, James M. Binley, Donald N. Forthal, Pascal Poignard, and Michael B. Zwick. A Human Antibody to the CD4 Binding Site of gp120 Capable of Highly Potent but Sporadic Cross Clade Neutralization of Primary HIV-1. PLoS One, 8(8):e72054, 2013. PubMed ID: 23991039.
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Gardner2016
Matthew R. Gardner, Christoph H. Fellinger, Neha R. Prasad, Amber S. Zhou, Hema R. Kondur, Vinita R. Joshi, Brian D. Quinlan, and Michael Farzan. CD4-Induced Antibodies Promote Association of the HIV-1 Envelope Glycoprotein with CD4-Binding Site Antibodies. J. Virol., 90(17):7822-7832, 1 Sep 2016. PubMed ID: 27334589.
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Gartner2023
Matthew J. Gartner, Carolin Tumpach, Ashanti Dantanarayana, Jared Stern, Jennifer M. Zerbato, J. Judy Chang, Thomas A. Angelovich, Jenny L. Anderson, Jori Symons, Steve G. Deeks, Jacqueline K. Flynn, Sharon R. Lewin, Melissa J. Churchill, Paul R. Gorry, and Michael Roche. Persistence of Envelopes in Different CD4+ T-Cell Subsets in Antiretroviral Therapy-Suppressed People with HIV. AIDS, 37(2):247-257, 1 Feb 2023. PubMed ID: 36541637.
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Gaudinski2018
Martin R. Gaudinski, Emily E. Coates, Katherine V. Houser, Grace L. Chen, Galina Yamshchikov, Jamie G. Saunders, LaSonji A. Holman, Ingelise Gordon, Sarah Plummer, Cynthia S. Hendel, Michelle Conan-Cibotti, Margarita Gomez Lorenzo, Sandra Sitar, Kevin Carlton, Carolyn Laurencot, Robert T. Bailer, Sandeep Narpala, Adrian B. McDermott, Aryan M. Namboodiri, Janardan P. Pandey, Richard M. Schwartz, Zonghui Hu, Richard A. Koup, Edmund Capparelli, Barney S. Graham, John R. Mascola, Julie E. Ledgerwood, and VRC 606 Study Team. Safety and Pharmacokinetics of the Fc-Modified HIV-1 Human Monoclonal Antibody VRC01LS: A Phase 1 Open-Label Clinical Trial in Healthy Adults. PLoS Med., 15(1):e1002493, Jan 2018. PubMed ID: 29364886.
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Gautam2016
Rajeev Gautam, Yoshiaki Nishimura, Amarendra Pegu, Martha C. Nason, Florian Klein, Anna Gazumyan, Jovana Golijanin, Alicia Buckler-White, Reza Sadjadpour, Keyun Wang, Zachary Mankoff, Stephen D. Schmidt, Jeffrey D. Lifson, John R. Mascola, Michel C. Nussenzweig, and Malcolm A. Martin. A Single Injection of Anti-HIV-1 Antibodies Protects against Repeated SHIV Challenges. Nature, 533(7601):105-109, 5 May 2016. PubMed ID: 27120156.
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Georgiev2013
Ivelin S. Georgiev, Nicole A. Doria-Rose, Tongqing Zhou, Young Do Kwon, Ryan P. Staupe, Stephanie Moquin, Gwo-Yu Chuang, Mark K. Louder, Stephen D. Schmidt, Han R. Altae-Tran, Robert T. Bailer, Krisha McKee, Martha Nason, Sijy O'Dell, Gilad Ofek, Marie Pancera, Sanjay Srivatsan, Lawrence Shapiro, Mark Connors, Stephen A. Migueles, Lynn Morris, Yoshiaki Nishimura, Malcolm A. Martin, John R. Mascola, and Peter D. Kwong. Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization. Science, 340(6133):751-756, 10 May 2013. PubMed ID: 23661761.
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Georgiev2013a
Ivelin S. Georgiev, M. Gordon Joyce, Tongqing Zhou, and Peter D. Kwong. Elicitation of HIV-1-Neutralizing Antibodies against the CD4-Binding Site. Curr. Opin. HIV AIDS, 8(5):382-392, Sep 2013. PubMed ID: 23924998.
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Georgiev2014
Ivelin S. Georgiev, Rebecca S. Rudicell, Kevin O. Saunders, Wei Shi, Tatsiana Kirys, Krisha McKee, Sijy O'Dell, Gwo-Yu Chuang, Zhi-Yong Yang, Gilad Ofek, Mark Connors, John R. Mascola, Gary J. Nabel, and Peter D. Kwong. Antibodies VRC01 and 10E8 Neutralize HIV-1 with High Breadth and Potency Even with Ig-Framework Regions Substantially Reverted to Germline. J. Immunol., 192(3):1100-1106, 1 Feb 2014. PubMed ID: 24391217.
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Gilbert2017
Peter B. Gilbert, Michal Juraska, Allan C. deCamp, Shelly Karuna, Srilatha Edupuganti, Nyaradzo Mgodi, Deborah J. Donnell, Carter Bentley, Nirupama Sista, Philip Andrew, Abby Isaacs, Yunda Huang, Lily Zhang, Edmund Capparelli, Nidhi Kochar, Jing Wang, Susan H. Eshleman, Kenneth H. Mayer, Craig A. Magaret, John Hural, James G. Kublin, Glenda Gray, David C. Montefiori, Margarita M. Gomez, David N. Burns, Julie McElrath, Julie Ledgerwood, Barney S. Graham, John R. Mascola, Myron Cohen, and Lawrence Corey. Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials. Stat. Commun. Infect. Dis., 9(1), Jan 2017. PubMed ID: 29218117.
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Gilbert2022
Peter B. Gilbert, Yunda Huang, Allan C. deCamp, Shelly Karuna, Yuanyuan Zhang, Craig A. Magaret, Elena E. Giorgi, Bette Korber, Paul T. Edlefsen, Raabya Rossenkhan, Michal Juraska, Erika Rudnicki, Nidhi Kochar, Ying Huang, Lindsay N. Carpp, Dan H. Barouch, Nonhlanhla N. Mkhize, Tandile Hermanus, Prudence Kgagudi, Valerie Bekker, Haajira Kaldine, Rutendo E. Mapengo, Amanda Eaton, Elize Domin, Carley West, Wenhong Feng, Haili Tang, Kelly E. Seaton, Jack Heptinstall, Caroline Brackett, Kelvin Chiong, Georgia D. Tomaras, Philip Andrew, Bryan T. Mayer, Daniel B. Reeves, Magdalena E. Sobieszczyk, Nigel Garrett, Jorge Sanchez, Cynthia Gay, Joseph Makhema, Carolyn Williamson, James I. Mullins, John Hural, Myron S. Cohen, Lawrence Corey, David C. Montefiori, and Lynn Morris. Neutralization Titer Biomarker for Antibody-Mediated Prevention of HIV-1 Acquisition. Nat. Med., 28(9):1924-1932, Sep 2022. PubMed ID: 35995954.
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Gonzalez2010
Nuria Gonzalez, Amparo Alvarez, and Jose Alcami. Broadly Neutralizing Antibodies and their Significance for HIV-1 Vaccines. Curr. HIV Res., 8(8):602-612, Dec 2010. PubMed ID: 21054253.
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Goo2012
Leslie Goo, Zahra Jalalian-Lechak, Barbra A. Richardson, and Julie Overbaugh. A Combination of Broadly Neutralizing HIV-1 Monoclonal Antibodies Targeting Distinct Epitopes Effectively Neutralizes Variants Found in Early Infection. J. Virol., 86(19):10857-10861, Oct 2012. PubMed ID: 22837204.
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Gray2016
Glenda E. Gray, Fatima Laher, Erica Lazarus, Barbara Ensoli, and Lawrence Corey. Approaches to Preventative and Therapeutic HIV Vaccines. Curr. Opin. Virol., 17:104-109, Apr 2016. PubMed ID: 26985884.
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Gristick2016
Harry B. Gristick, Lotta von Boehmer, Anthony P. West, Jr., Michael Schamber, Anna Gazumyan, Jovana Golijanin, Michael S. Seaman, Gerd Fätkenheuer, Florian Klein, Michel C. Nussenzweig, and Pamela J. Bjorkman. Natively Glycosylated HIV-1 Env Structure Reveals New Mode for Antibody Recognition of the CD4-Binding Site. Nat. Struct. Mol. Biol., 23(10):906-915, Oct 2016. PubMed ID: 27617431.
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Guenaga2015
Javier Guenaga, Natalia de Val, Karen Tran, Yu Feng, Karen Satchwell, Andrew B. Ward, and Richard T. Wyatt. Well-Ordered Trimeric HIV-1 Subtype B and C Soluble Spike Mimetics Generated by Negative Selection Display Native-Like Properties. PLoS Pathog., 11(1):e1004570, Jan 2015. PubMed ID: 25569572.
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Guenaga2015a
Javier Guenaga, Viktoriya Dubrovskaya, Natalia de Val, Shailendra K. Sharma, Barbara Carrette, Andrew B. Ward, and Richard T. Wyatt. Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers. J. Virol., 90(6):2806-2817, 30 Dec 2015. PubMed ID: 26719252.
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Gunn2016
B. M. Gunn, J. R. Schneider, M. Shansab, A. R. Bastian, K. M. Fahrbach, A. D. Smith, A. E. Mahan, M. M. Karim, A. F. Licht, I. Zvonar, J. Tedesco, M. R. Anderson, A. Chapel, T. J. Suscovich, D. C. Malaspina, H. Streeck, B. D. Walker, A. Kim, G. Lauer, M. Altfeld, S. Pillai, I. Szleifer, N. L. Kelleher, P. F. Kiser, T. J. Hope, and G. Alter. Enhanced Binding of Antibodies Generated During Chronic HIV Infection to Mucus Component MUC16. Mucosal. Immunol., 9(6):1549-1558, Nov 2016. PubMed ID: 26960182.
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Guo2012
Dongxing Guo, Xuanling Shi, Kelly C. Arledge, Dingka Song, Liwei Jiang, Lili Fu, Xinqi Gong, Senyan Zhang, Xinquan Wang, and Linqi Zhang. A Single Residue within the V5 Region of HIV-1 Envelope Facilitates Viral Escape from the Broadly Neutralizing Monoclonal Antibody VRC01. J. Biol. Chem., 287(51):43170-43179, 14 Dec 2012. PubMed ID: 23100255.
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Guo2014
Dongxing Guo, Xuanling Shi, Dingka Song, and Linqi Zhang. Persistence of VRC01-Resistant HIV-1 during Antiretroviral Therapy. Sci. China Life Sci., 57(1):88-96, Jan 2014. PubMed ID: 24369354.
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Gupta2013
Sandeep Gupta, Johannes S. Gach, Juan C. Becerra, Tran B. Phan, Jeffrey Pudney, Zina Moldoveanu, Sarah B. Joseph, Gary Landucci, Medalyn Jude Supnet, Li-Hua Ping, Davide Corti, Brian Moldt, Zdenek Hel, Antonio Lanzavecchia, Ruth M. Ruprecht, Dennis R. Burton, Jiri Mestecky, Deborah J. Anderson, and Donald N. Forthal. The Neonatal Fc Receptor (FcRn) Enhances Human Immunodeficiency Virus Type 1 (HIV-1) Transcytosis across Epithelial Cells. PLoS Pathog., 9(11):e1003776, Nov 2013. PubMed ID: 24278022.
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Guzzo2018
Christina Guzzo, Peng Zhang, Qingbo Liu, Alice L. Kwon, Ferzan Uddin, Alexandra I. Wells, Hana Schmeisser, Raffaello Cimbro, Jinghe Huang, Nicole Doria-Rose, Stephen D. Schmidt, Michael A. Dolan, Mark Connors, John R. Mascola, and Paolo Lusso. Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation. mBio, 9(6), 11 Dec 2018. PubMed ID: 30538178.
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Haim2011
Hillel Haim, Bettina Strack, Aemro Kassa, Navid Madani, Liping Wang, Joel R. Courter, Amy Princiotto, Kathleen McGee, Beatriz Pacheco, Michael S. Seaman, Amos B. Smith, 3rd., and Joseph Sodroski. Contribution of Intrinsic Reactivity of the HIV-1 Envelope Glycoproteins to CD4-Independent Infection and Global Inhibitor Sensitivity. PLoS Pathog., 7(6):e1002101, Jun 2011. PubMed ID: 21731494.
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Hammond2010
Philip W. Hammond. Accessing the Human Repertoire for Broadly Neutralizing HIV Antibodies. MAbs, 2(2):157-164, Mar-Apr 2010. PubMed ID: 20168075.
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Haynes2012
Barton F. Haynes, Garnett Kelsoe, Stephen C. Harrison, and Thomas B. Kepler. B-Cell-Lineage Immunogen Design in Vaccine Development with HIV-1 as a Case Study. Nat. Biotechnol., 30(5):423-433, May 2012. PubMed ID: 22565972.
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Haynes2016
Barton F. Haynes, George M. Shaw, Bette Korber, Garnett Kelsoe, Joseph Sodroski, Beatrice H. Hahn, Persephone Borrow, and Andrew J. McMichael. HIV-Host Interactions: Implications for Vaccine Design. Cell Host Microbe, 19(3):292-303, 9 Mar 2016. PubMed ID: 26922989.
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He2018
Linling He, Sonu Kumar, Joel D. Allen, Deli Huang, Xiaohe Lin, Colin J. Mann, Karen L. Saye-Francisco, Jeffrey Copps, Anita Sarkar, Gabrielle S. Blizard, Gabriel Ozorowski, Devin Sok, Max Crispin, Andrew B. Ward, David Nemazee, Dennis R. Burton, Ian A. Wilson, and Jiang Zhu. HIV-1 Vaccine Design through Minimizing Envelope Metastability. Sci. Adv., 4(11):eaau6769, Nov 2018. PubMed ID: 30474059.
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Henderson2019
Rory Henderson, Brian E. Watts, Hieu N. Ergin, Kara Anasti, Robert Parks, Shi-Mao Xia, Ashley Trama, Hua-Xin Liao, Kevin O. Saunders, Mattia Bonsignori, Kevin Wiehe, Barton F. Haynes, and S. Munir Alam. Selection of Immunoglobulin Elbow Region Mutations Impacts Interdomain Conformational Flexibility in HIV-1 Broadly Neutralizing Antibodies. Nat. Commun., 10(1):654, 8 Feb 2019. PubMed ID: 30737386.
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Hessell2016
Ann J. Hessell, J. Pablo Jaworski, Erin Epson, Kenta Matsuda, Shilpi Pandey, Christoph Kahl, Jason Reed, William F. Sutton, Katherine B. Hammond, Tracy A. Cheever, Philip T. Barnette, Alfred W. Legasse, Shannon Planer, Jeffrey J. Stanton, Amarendra Pegu, Xuejun Chen, Keyun Wang, Don Siess, David Burke, Byung S. Park, Michael K. Axthelm, Anne Lewis, Vanessa M. Hirsch, Barney S. Graham, John R. Mascola, Jonah B. Sacha, and Nancy L. Haigwood. Early Short-Term Treatment with Neutralizing Human Monoclonal Antibodies Halts SHIV Infection in Infant Macaques. Nat. Med., 22(4):362-368, Apr 2016. PubMed ID: 26998834.
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Hoffenberg2013
Simon Hoffenberg, Rebecca Powell, Alexei Carpov, Denise Wagner, Aaron Wilson, Sergei Kosakovsky Pond, Ross Lindsay, Heather Arendt, Joanne DeStefano, Sanjay Phogat, Pascal Poignard, Steven P. Fling, Melissa Simek, Celia LaBranche, David Montefiori, Terri Wrin, Pham Phung, Dennis Burton, Wayne Koff, C. Richter King, Christopher L. Parks, and Michael J. Caulfield. Identification of an HIV-1 Clade A Envelope That Exhibits Broad Antigenicity and Neutralization Sensitivity and Elicits Antibodies Targeting Three Distinct Epitopes. J. Virol., 87(10):5372-5383, May 2013. PubMed ID: 23468492.
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Hogan2018
Michael J. Hogan, Angela Conde-Motter, Andrea P. O. Jordan, Lifei Yang, Brad Cleveland, Wenjin Guo, Josephine Romano, Houping Ni, Norbert Pardi, Celia C. LaBranche, David C. Montefiori, Shiu-Lok Hu, James A. Hoxie, and Drew Weissman. Increased Surface Expression of HIV-1 Envelope Is Associated with Improved Antibody Response in Vaccinia Prime/Protein Boost Immunization. Virology, 514:106-117, 15 Jan 2018. PubMed ID: 29175625.
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Hraber2014
Peter Hraber, Michael S. Seaman, Robert T. Bailer, John R. Mascola, David C. Montefiori, and Bette T. Korber. Prevalence of Broadly Neutralizing Antibody Responses during Chronic HIV-1 Infection. AIDS, 28(2):163-169, 14 Jan 2014. PubMed ID: 24361678.
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Hraber2017
Peter Hraber, Cecilia Rademeyer, Carolyn Williamson, Michael S. Seaman, Raphael Gottardo, Haili Tang, Kelli Greene, Hongmei Gao, Celia LaBranche, John R. Mascola, Lynn Morris, David C. Montefiori, and Bette Korber. Panels of HIV-1 Subtype C Env Reference Strains for Standardized Neutralization Assessments. J. Virol., 91(19), 1 Oct 2017. PubMed ID: 28747500.
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Hsu2021
Denise C. Hsu, John W. Mellors, and Sandhya Vasan. Can Broadly Neutralizing HIV-1 Antibodies Help Achieve an ART-Free Remission? Front. Immunol., 12:710044, 2021. PubMed ID: 34322136.
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Joyce K. Hu, Jordan C. Crampton, Albert Cupo, Thomas Ketas, Marit J. van Gils, Kwinten Sliepen, Steven W. de Taeye, Devin Sok, Gabriel Ozorowski, Isaiah Deresa, Robyn Stanfield, Andrew B. Ward, Dennis R. Burton, Per Johan Klasse, Rogier W. Sanders, John P. Moore, and Shane Crotty. Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity. J. Virol., 89(20):10383-10398, Oct 2015. PubMed ID: 26246566.
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Xintao Hu, Yuanyuan Hu, Chunhong Zhao, Hongmei Gao, Kelli M. Greene, Li Ren, Liying Ma, Yuhua Ruan, Marcella Sarzotti-Kelsoe, David C. Montefiori, Kunxue Hong, and Yiming Shao. Profiling the Neutralizing Antibody Response in Chronically HIV-1 CRF07\_BC-Infected Intravenous Drug Users Naive to Antiretroviral Therapy. Sci. Rep., 7:46308, 7 Apr 2017. PubMed ID: 28387330.
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Hu2021
Yuanyuan Hu, Sen Zou, Zheng Wang, Ying Liu, Li Ren, Yanling Hao, Shasha Sun, Xintao Hu, Yuhua Ruan, Liying Ma, Yiming Shao, and Kunxue Hong. Virus Evolution and Neutralization Sensitivity in an HIV-1 Subtype B' Infected Plasma Donor with Broadly Neutralizing Activity. Vaccines (Basel), 9(4), 25 Mar 2021. PubMed ID: 33805985.
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Hu2023
Yuanyuan Hu, Dan Li, Zhenzhen Yuan, Yi Feng, Li Ren, Yanling Hao, Shuo Wang, Xintao Hu, Ying Liu, Kunxue Hong, Yiming Shao, and Zheng Wang. Characterization of a VRC01-Like Antibody Lineage with Immature V(L) from an HIV-1 Infected Chinese Donor. Mol. Immunol., 154:11-23, Feb 2023. PubMed ID: 36577292.
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Yunda Huang, Lily Zhang, Julie Ledgerwood, Nicole Grunenberg, Robert Bailer, Abby Isaacs, Kelly Seaton, Kenneth H. Mayer, Edmund Capparelli, Larry Corey, and Peter B. Gilbert. Population Pharmacokinetics Analysis of VRC01, an HIV-1 Broadly Neutralizing Monoclonal Antibody, in Healthy Adults. MAbs, 9(5):792-800, Jul 2017. PubMed ID: 28368743.
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Xun Huang, Qianqian Zhu, Xiaoxing Huang, Lifei Yang, Yufeng Song, Ping Zhu, and Paul Zhou. In Vivo Electroporation in DNA-VLP Prime-Boost Preferentially Enhances HIV-1 Envelope-Specific IgG2a, Neutralizing Antibody and CD8 T Cell Responses. Vaccine, 35(16):2042-2051, 11 Apr 2017. PubMed ID: 28318765.
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Yunda Huang, Shelly Karuna, Lindsay N. Carpp, Daniel Reeves, Amarendra Pegu, Kelly Seaton, Kenneth Mayer, Joshua Schiffer, John Mascola, and Peter B. Gilbert. Modeling Cumulative Overall Prevention Efficacy for the VRC01 Phase 2b Efficacy Trials. Hum. Vaccin. Immunother., :1-12, 23 Apr 2018. PubMed ID: 29683765.
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Hutchinson2019
Jennie M. Hutchinson, Kathryn A. Mesa, David L. Alexander, Bin Yu, Sara M. O'Rourke, Kay L. Limoli, Terri Wrin, Steven G. Deeks, and Phillip W. Berman. Unusual Cysteine Content in V1 Region of gp120 from an Elite Suppressor That Produces Broadly Neutralizing Antibodies. Front. Immunol., 10:1021, 2019. PubMed ID: 31156622.
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Joseph Jardine, Jean-Philippe Julien, Sergey Menis, Takayuki Ota, Oleksandr Kalyuzhniy, Andrew McGuire, Devin Sok, Po-Ssu Huang, Skye MacPherson, Meaghan Jones, Travis Nieusma, John Mathison, David Baker, Andrew B. Ward, Dennis R. Burton, Leonidas Stamatatos, David Nemazee, Ian A. Wilson, and William R. Schief. Rational HIV Immunogen Design to Target Specific Germline B Cell Receptors. Science, 340(6133):711-716, 10 May 2013. PubMed ID: 23539181.
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Joseph G. Jardine, Takayuki Ota, Devin Sok, Matthias Pauthner, Daniel W. Kulp, Oleksandr Kalyuzhniy, Patrick D. Skog, Theresa C. Thinnes, Deepika Bhullar, Bryan Briney, Sergey Menis, Meaghan Jones, Mike Kubitz, Skye Spencer, Yumiko Adachi, Dennis R. Burton, William R. Schief, and David Nemazee. Priming a Broadly Neutralizing Antibody Response to HIV-1 Using a Germline-Targeting Immunogen. Science, 349(6244):156-161, 10 Jul 2015. PubMed ID: 26089355.
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Joseph G. Jardine, Devin Sok, Jean-Philippe Julien, Bryan Briney, Anita Sarkar, Chi-Hui Liang, Erin A. Scherer, Carole J. Henry Dunand, Yumiko Adachi, Devan Diwanji, Jessica Hsueh, Meaghan Jones, Oleksandr Kalyuzhniy, Michael Kubitz, Skye Spencer, Matthias Pauthner, Karen L. Saye-Francisco, Fabian Sesterhenn, Patrick C. Wilson, Denise M. Galloway, Robyn L. Stanfield, Ian A. Wilson, Dennis R. Burton, and William R. Schief. Minimally Mutated HIV-1 Broadly Neutralizing Antibodies to Guide Reductionist Vaccine Design. PLoS Pathog, 12(8):e1005815, 25 Aug 2016. PubMed ID: 27560183.
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T. L. Jeffries, Jr., C. R. Sacha, J. Pollara, J. Himes, F. H. Jaeger, S. M. Dennison, E. McGuire, E. Kunz, J. A. Eudailey, A. M. Trama, C. LaBranche, G. G. Fouda, K. Wiehe, D. C. Montefiori, B. F. Haynes, H.-X. Liao, G. Ferrari, S. M. Alam, M. A. Moody, and S. R. Permar. The Function and Affinity Maturation of HIV-1 gp120-Specific Monoclonal Antibodies Derived from Colostral B Cells. Mucosal. Immunol., 9(2):414-427, Mar 2016. PubMed ID: 26242599.
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Joyce2010
Joseph G. Joyce and Jan ter Meulen. Pushing the Envelope on HIV-1 Neutralization. Nat. Biotechnol., 28(9):929-931, Sep 2010. PubMed ID: 20829830.
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Jean-Philippe Julien, Jeong Hyun Lee, Gabriel Ozorowski, Yuanzi Hua, Alba Torrents de la Peña, Steven W. de Taeye, Travis Nieusma, Albert Cupo, Anila Yasmeen, Michael Golabek, Pavel Pugach, P. J. Klasse, John P. Moore, Rogier W. Sanders, Andrew B. Ward, and Ian A. Wilson. Design and Structure of Two HIV-1 Clade C SOSIP.664 Trimers That Increase the Arsenal of Native-Like Env Immunogens. Proc. Natl. Acad. Sci. U.S.A., 112(38):11947-11952, 22 Sep 2015. PubMed ID: 26372963.
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Garnett Kelsoe and Barton F. Haynes. Host Controls of HIV Broadly Neutralizing Antibody Development. Immunol. Rev., 275(1):79-88, Jan 2017. PubMed ID: 28133807.
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Sannula Kesavardhana, Raksha Das, Michael Citron, Rohini Datta, Linda Ecto, Nonavinakere Seetharam Srilatha, Daniel DiStefano, Ryan Swoyer, Joseph G. Joyce, Somnath Dutta, Celia C. LaBranche, David C. Montefiori, Jessica A. Flynn, and Raghavan Varadarajan. Structure-Based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies. J. Biol. Chem., 292(1):278-291, 6 Jan 2017. PubMed ID: 27879316.
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Florian Klein, Ron Diskin, Johannes F. Scheid, Christian Gaebler, Hugo Mouquet, Ivelin S. Georgiev, Marie Pancera, Tongqing Zhou, Reha-Baris Incesu, Brooks Zhongzheng Fu, Priyanthi N. P. Gnanapragasam, Thiago Y. Oliveira, Michael S. Seaman, Peter D. Kwong, Pamela J. Bjorkman, and Michel C. Nussenzweig. Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization. Cell, 153(1):126-138, 28 Mar 2013. PubMed ID: 23540694.
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Bette Korber, Peter Hraber, Kshitij Wagh, and Beatrice H. Hahn. Polyvalent Vaccine Approaches to Combat HIV-1 Diversity. Immunol. Rev., 275(1):230-244, Jan 2017. PubMed ID: 28133800.
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Anil Korkut and Wayne A. Hendrickson. Structural Plasticity and Conformational Transitions of HIV Envelope Glycoprotein gp120. PLoS One, 7(12):e52170, 2012. PubMed ID: 23300605.
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James M. Kovacs, Joseph P. Nkolola, Hanqin Peng, Ann Cheung, James Perry, Caroline A. Miller, Michael S. Seaman, Dan H. Barouch, and Bing Chen. HIV-1 Envelope Trimer Elicits More Potent Neutralizing Antibody Responses than Monomeric gp120. Proc. Natl. Acad. Sci. U.S.A., 109(30):12111-12116, 24 Jul 2012. PubMed ID: 22773820.
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Kreer2020
Christoph Kreer, Henning Gruell, Thierry Mora, Aleksandra M. Walczak, and Florian Klein. Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies. Vaccines (Basel), 8(1):13 doi, Jan 2020. PubMed ID: 31906351
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Kulp2017
Daniel W. Kulp, Jon M. Steichen, Matthias Pauthner, Xiaozhen Hu, Torben Schiffner, Alessia Liguori, Christopher A. Cottrell, Colin Havenar-Daughton, Gabriel Ozorowski, Erik Georgeson, Oleksandr Kalyuzhniy, Jordan R. Willis, Michael Kubitz, Yumiko Adachi, Samantha M. Reiss, Mia Shin, Natalia de Val, Andrew B. Ward, Shane Crotty, Dennis R. Burton, and William R. Schief. Structure-Based Design of Native-Like HIV-1 Envelope Trimers to Silence Non-Neutralizing Epitopes and Eliminate CD4 Binding. Nat. Commun., 8(1):1655, 21 Nov 2017. PubMed ID: 29162799.
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Kumar2018
Amit Kumar, Claire E. P. Smith, Elena E. Giorgi, Joshua Eudailey, David R. Martinez, Karina Yusim, Ayooluwa O. Douglas, Lisa Stamper, Erin McGuire, Celia C. LaBranche, David C. Montefiori, Genevieve G. Fouda, Feng Gao, and Sallie R. Permar. Infant Transmitted/Founder HIV-1 Viruses from Peripartum Transmission Are Neutralization Resistant to Paired Maternal Plasma. PLoS Pathog., 14(4):e1006944, Apr 2018. PubMed ID: 29672607.
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Young Do Kwon, Marie Pancera, Priyamvada Acharya, Ivelin S. Georgiev, Emma T. Crooks, Jason Gorman, M. Gordon Joyce, Miklos Guttman, Xiaochu Ma, Sandeep Narpala, Cinque Soto, Daniel S. Terry, Yongping Yang, Tongqing Zhou, Goran Ahlsen, Robert T. Bailer, Michael Chambers, Gwo-Yu Chuang, Nicole A. Doria-Rose, Aliaksandr Druz, Mark A. Hallen, Adam Harned, Tatsiana Kirys, Mark K. Louder, Sijy O'Dell, Gilad Ofek, Keiko Osawa, Madhu Prabhakaran, Mallika Sastry, Guillaume B. E. Stewart-Jones, Jonathan Stuckey, Paul V. Thomas, Tishina Tittley, Constance Williams, Baoshan Zhang, Hong Zhao, Zhou Zhou, Bruce R. Donald, Lawrence K. Lee, Susan Zolla-Pazner, Ulrich Baxa, Arne Schön, Ernesto Freire, Lawrence Shapiro, Kelly K. Lee, James Arthos, James B. Munro, Scott C. Blanchard, Walther Mothes, James M. Binley, Adrian B. McDermott, John R. Mascola, and Peter D. Kwong. Crystal Structure, Conformational Fixation and Entry-Related Interactions of Mature Ligand-Free HIV-1 Env. Nat. Struct. Mol. Biol., 22(7):522-531, Jul 2015. PubMed ID: 26098315.
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Kwon2021
Young D. Kwon, Mangaiarkarasi Asokan, Jason Gorman, Baoshan Zhang, Qingbo Liu, Mark K. Louder, Bob C. Lin, Krisha McKee, Amarendra Pegu, Raffaello Verardi, Eun Sung Yang, VRC Production Program, Kevin Carlton, Nicole A. Doria-Rose, Paolo Lusso, John R. Mascola, and Peter D. Kwong. A Matrix of Structure-Based Designs Yields Improved VRC01-Class Antibodies for HIV-1 Therapy and Prevention. MAbs, 13(1):1946918, Jan-Dec 2021. PubMed ID: 34328065.
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Peter D. Kwong and John R. Mascola. Human Antibodies that Neutralize HIV-1: Identification, Structures, and B Cell Ontogenies. Immunity, 37(3):412-425, 21 Sep 2012. PubMed ID: 22999947.
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Peter D. Kwong, John R. Mascola, and Gary J. Nabel. Broadly Neutralizing Antibodies and the Search for an HIV-1 Vaccine: The End of the Beginning. Nat. Rev. Immunol., 13(9):693-701, Sep 2013. PubMed ID: 23969737.
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Peter D. Kwong and John R. Mascola. HIV-1 Vaccines Based on Antibody Identification, B Cell Ontogeny, and Epitope Structure. Immunity, 48(5):855-871, 15 May 2018. PubMed ID: 29768174.
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Celia C. LaBranche, Andrew T. McGuire, Matthew D. Gray, Shay Behrens, Xuejun Chen, Tongqing Zhou, Quentin J. Sattentau, James Peacock, Amanda Eaton, Kelli Greene, Hongmei Gao, Haili Tang, Lautaro G. Perez, Kevin O. Saunders, Peter D. Kwong, John R. Mascola, Barton F. Haynes, Leonidas Stamatatos, and David C. Montefiori. HIV-1 Envelope Glycan Modifications That Permit Neutralization by Germline-Reverted VRC01-Class Broadly Neutralizing Antibodies. PLoS Pathog., 14(11):e1007431, Nov 2018. PubMed ID: 30395637.
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Lai2012
Rachel P. J. Lai, Michael S. Seaman, Paul Tonks, Frank Wegmann, David J. Seilly, Simon D. W. Frost, Celia C. LaBranche, David C. Montefiori, Antu K. Dey, Indresh K. Srivastava, Quentin Sattentau, Susan W. Barnett, and Jonathan L. Heeney. Mixed Adjuvant Formulations Reveal a New Combination That Elicit Antibody Response Comparable to Freund's Adjuvants. PLoS One, 7(4):e35083, 2012. PubMed ID: 22509385.
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Christy L. Lavine, Socheata Lao, David C. Montefiori, Barton F. Haynes, Joseph G. Sodroski, Xinzhen Yang, and NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI). High-Mannose Glycan-Dependent Epitopes Are Frequently Targeted in Broad Neutralizing Antibody Responses during Human Immunodeficiency Virus Type 1 Infection. J. Virol., 86(4):2153-2164, Feb 2012. PubMed ID: 22156525.
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Jeong Hyun Lee, Raiees Andrabi, Ching-Yao Su, Anila Yasmeen, Jean-Philippe Julien, Leopold Kong, Nicholas C. Wu, Ryan McBride, Devin Sok, Matthias Pauthner, Christopher A. Cottrell, Travis Nieusma, Claudia Blattner, James C. Paulson, Per Johan Klasse, Ian A. Wilson, Dennis R. Burton, and Andrew B. Ward. A Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope Trimer Apex via a Long, Rigidified, and Anionic beta-Hairpin Structure. Immunity, 46(4):690-702, 18 Apr 2017. PubMed ID: 28423342.
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Yuxing Li, Sijy O'Dell, Laura M. Walker, Xueling Wu, Javier Guenaga, Yu Feng, Stephen D. Schmidt, Krisha McKee, Mark K. Louder, Julie E. Ledgerwood, Barney S. Graham, Barton F. Haynes, Dennis R. Burton, Richard T. Wyatt, and John R. Mascola. Mechanism of Neutralization by the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01. J. Virol., 85(17):8954-8967, Sep 2011. PubMed ID: 21715490.
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Yuxing Li, Sijy O'Dell, Richard Wilson, Xueling Wu, Stephen D. Schmidt, Carl-Magnus Hogerkorp, Mark K. Louder, Nancy S. Longo, Christian Poulsen, Javier Guenaga, Bimal K. Chakrabarti, Nicole Doria-Rose, Mario Roederer, Mark Connors, John R. Mascola, and Richard T. Wyatt. HIV-1 Neutralizing Antibodies Display Dual Recognition of the Primary and Coreceptor Binding Sites and Preferential Binding to Fully Cleaved Envelope Glycoproteins. J. Virol., 86(20):11231-11241, Oct 2012. PubMed ID: 22875963.
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Hongru Li, Chati Zony, Ping Chen, and Benjamin K. Chen. Reduced Potency and Incomplete Neutralization of Broadly Neutralizing Antibodies against Cell-to-Cell Transmission of HIV-1 with Transmitted Founder Envs. J. Virol., 91(9), 1 May 2017. PubMed ID: 28148796.
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Yu Liang, Miklos Guttman, James A. Williams, Hans Verkerke, Daniel Alvarado, Shiu-Lok Hu, and Kelly K. Lee. Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan. J. Virol., 90(20):9224-9236, 15 Oct 2016. PubMed ID: 27489265.
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Hua-Xin Liao, Rebecca Lynch, Tongqing Zhou, Feng Gao, S. Munir Alam, Scott D. Boyd, Andrew Z. Fire, Krishna M. Roskin, Chaim A. Schramm, Zhenhai Zhang, Jiang Zhu, Lawrence Shapiro, NISC Comparative Sequencing Program, James C. Mullikin, S. Gnanakaran, Peter Hraber, Kevin Wiehe, Garnett Kelsoe, Guang Yang, Shi-Mao Xia, David C. Montefiori, Robert Parks, Krissey E. Lloyd, Richard M. Scearce, Kelly A. Soderberg, Myron Cohen, Gift Kamanga, Mark K. Louder, Lillian M. Tran, Yue Chen, Fangping Cai, Sheri Chen, Stephanie Moquin, Xiulian Du, M. Gordon Joyce, Sanjay Srivatsan, Baoshan Zhang, Anqi Zheng, George M. Shaw, Beatrice H. Hahn, Thomas B. Kepler, Bette T. M. Korber, Peter D. Kwong, John R. Mascola, and Barton F. Haynes. Co-Evolution of a Broadly Neutralizing HIV-1 Antibody and Founder Virus. Nature, 496(7446):469-476, 25 Apr 2013. PubMed ID: 23552890.
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Liao2013c
Hua-Xin Liao, Chun-Yen Tsao, S. Munir Alam, Mark Muldoon, Nathan Vandergrift, Ben-Jiang Ma, Xiaozhi Lu, Laura L. Sutherland, Richard M. Scearce, Cindy Bowman, Robert Parks, Haiyan Chen, Julie H. Blinn, Alan Lapedes, Sydeaka Watson, Shi-Mao Xia, Andrew Foulger, Beatrice H. Hahn, George M. Shaw, Ron Swanstrom, David C. Montefiori, Feng Gao, Barton F. Haynes, and Bette Korber. Antigenicity and Immunogenicity of Transmitted/Founder, Consensus, and Chronic Envelope Glycoproteins of Human Immunodeficiency Virus Type 1. J. Virol., 87(8):4185-4201, Apr 2013. PubMed ID: 23365441.
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Liu2015a
Mengfei Liu, Guang Yang, Kevin Wiehe, Nathan I. Nicely, Nathan A. Vandergrift, Wes Rountree, Mattia Bonsignori, S. Munir Alam, Jingyun Gao, Barton F. Haynes, and Garnett Kelsoe. Polyreactivity and Autoreactivity among HIV-1 Antibodies. J. Virol., 89(1):784-798, Jan 2015. PubMed ID: 25355869.
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Bingfeng Liu, Fan Zou, Lijuan Lu, Cancan Chen, Dalian He, Xu Zhang, Xiaoping Tang, Chao Liu, Linghua Li, and Hui Zhang. Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4+ T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy. J. Virol., 90(21):9712-9724, 1 Nov 2016. PubMed ID: 27535056.
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Liu2019
Qingbo Liu, Yen-Ting Lai, Peng Zhang, Mark K. Louder, Amarendra Pegu, Reda Rawi, Mangaiarkarasi Asokan, Xuejun Chen, Chen-Hsiang Shen, Gwo-Yu Chuang, Eun Sung Yang, Huiyi Miao, Yuge Wang, Anthony S. Fauci, Peter D. Kwong, John R. Mascola, and Paolo Lusso. Improvement of Antibody Functionality by Structure-Guided Paratope Engraftment. Nat. Commun., 10(1):721, 13 Feb 2019. PubMed ID: 30760721.
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John B. Lynch, Ruth Nduati, Catherine A. Blish, Barbra A. Richardson, Jennifer M. Mabuka, Zahra Jalalian-Lechak, Grace John-Stewart, and Julie Overbaugh. The Breadth and Potency of Passively Acquired Human Immunodeficiency Virus Type 1-Specific Neutralizing Antibodies Do Not Correlate with the Risk of Infant Infection. J. Virol., 85(11):5252-5261, Jun 2011. PubMed ID: 21411521.
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Lyumkis2013
Dmitry Lyumkis, Jean-Philippe Julien, Natalia de Val, Albert Cupo, Clinton S. Potter, Per-Johan Klasse, Dennis R. Burton, Rogier W. Sanders, John P. Moore, Bridget Carragher, Ian A. Wilson, and Andrew B. Ward. Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV-1 Envelope Trimer. Science, 342(6165):1484-1490, 20 Dec 2013. PubMed ID: 24179160.
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Marine Malbec, Françoise Porrot, Rejane Rua, Joshua Horwitz, Florian Klein, Ari Halper-Stromberg, Johannes F. Scheid, Caroline Eden, Hugo Mouquet, Michel C. Nussenzweig, and Olivier Schwartz. Broadly Neutralizing Antibodies That Inhibit HIV-1 Cell to Cell Transmission. J. Exp. Med., 210(13):2813-2821, 16 Dec 2013. PubMed ID: 24277152.
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Malherbe2014
Delphine C. Malherbe, Franco Pissani, D. Noah Sather, Biwei Guo, Shilpi Pandey, William F. Sutton, Andrew B. Stuart, Harlan Robins, Byung Park, Shelly J. Krebs, Jason T. Schuman, Spyros Kalams, Ann J. Hessell, and Nancy L. Haigwood. Envelope variants circulating as initial neutralization breadth developed in two HIV-infected subjects stimulate multiclade neutralizing antibodies in rabbits. J Virol, 88(22):12949-67 doi, Nov 2014. PubMed ID: 25210191
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Mandizvo2022
Tawanda Mandizvo, Nombali Gumede, Bongiwe Ndlovu, Siphiwe Ndlovu, Jaclyn K. Mann, Denis R. Chopera, Lanish Singh, Krista L. Dong, Bruce D. Walker, Zaza M. Ndhlovu, Christy L. Lavine, Michael S. Seaman, Kamini Gounder, and Thumbi Ndung'u. Subtle Longitudinal Alterations in Env Sequence Potentiate Differences in Sensitivity to Broadly Neutralizing Antibodies following Acute HIV-1 Subtype C Infection. J. Virol., 96(24):e0127022, 21 Dec 2022. PubMed ID: 36453881.
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Mannar2021
Dhiraj Mannar, Karoline Leopold, and Sriram Subramaniam. Glycan Reactive Anti-HIV-1 Antibodies bind the SARS-CoV-2 Spike Protein But Do Not Block Viral Entry. Sci. Rep., 11(1):12448, 14 Jun 2021. PubMed ID: 34127709.
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Mao2012
Youdong Mao, Liping Wang, Christopher Gu, Alon Herschhorn, Shi-Hua Xiang, Hillel Haim, Xinzhen Yang, and Joseph Sodroski. Subunit Organization of the Membrane-Bound HIV-1 Envelope Glycoprotein Trimer. Nat. Struct. Mol. Biol., 19(9):893-899, Sep 2012. PubMed ID: 22864288.
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Mayer2017
Kenneth H. Mayer, Kelly E. Seaton, Yunda Huang, Nicole Grunenberg, Abby Isaacs, Mary Allen, Julie E. Ledgerwood, Ian Frank, Magdalena E. Sobieszczyk, Lindsey R. Baden, Benigno Rodriguez, Hong Van Tieu, Georgia D. Tomaras, Aaron Deal, Derrick Goodman, Robert T. Bailer, Guido Ferrari, Ryan Jensen, John Hural, Barney S. Graham, John R. Mascola, Lawrence Corey, David C. Montefiori, HVTN 104 Protocol Team, and NIAID HIV Vaccine Trials Network. Safety, Pharmacokinetics, and Immunological Activities of Multiple Intravenous or Subcutaneous Doses of an Anti-HIV Monoclonal Antibody, VRC01, Administered to HIV-Uninfected Adults: Results of a Phase 1 Randomized Trial. PLoS Med, 14(11):e1002435, Nov 2017. PubMed ID: 29136037.
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McGuire2013
Andrew T. McGuire, Sam Hoot, Anita M. Dreyer, Adriana Lippy, Andrew Stuart, Kristen W. Cohen, Joseph Jardine, Sergey Menis, Johannes F. Scheid, Anthony P. West, William R. Schief, and Leonidas Stamatatos. Engineering HIV Envelope Protein To Activate Germline B Cell Receptors of Broadly Neutralizing Anti-CD4 Binding Site Antibodies. J. Exp. Med., 210(4):655-663, 8 Apr 2013. PubMed ID: 23530120.
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McGuire2016
Andrew T. McGuire, Matthew D. Gray, Pia Dosenovic, Alexander D. Gitlin, Natalia T. Freund, John Petersen, Colin Correnti, William Johnsen, Robert Kegel, Andrew B. Stuart, Jolene Glenn, Michael S. Seaman, William R. Schief, Roland K. Strong, Michel C. Nussenzweig, and Leonidas Stamatatos. Specifically Modified Env Immunogens Activate B-Cell Precursors of Broadly Neutralizing HIV-1 Antibodies in Transgenic Mice. Nat. Commun., 7:10618, 24 Feb 2016. PubMed ID: 26907590.
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McLinden2013
Robert J. McLinden, Celia C. LaBranche, Agnès-Laurence Chenine, Victoria R. Polonis, Michael A. Eller, Lindsay Wieczorek, Christina Ochsenbauer, John C. Kappes, Stephen Perfetto, David C. Montefiori, Nelson L. Michael, and Jerome H. Kim. Detection of HIV-1 Neutralizing Antibodies in a Human CD4+/CXCR4+/CCR5+ T-Lymphoblastoid Cell Assay System. PLoS One, 8(11):e77756, 2013. PubMed ID: 24312168.
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Meyerson2013
Joel R. Meyerson, Erin E. H. Tran, Oleg Kuybeda, Weizao Chen, Dimiter S. Dimitrov, Andrea Gorlani, Theo Verrips, Jeffrey D. Lifson, and Sriram Subramaniam. Molecular Structures of Trimeric HIV-1 Env in Complex with Small Antibody Derivatives. Proc. Natl. Acad. Sci. U.S.A., 110(2):513-518, 8 Jan 2013. PubMed ID: 23267106.
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Mishra2020
Nitesh Mishra, Shaifali Sharma, Ayushman Dobhal, Sanjeev Kumar, Himanshi Chawla, Ravinder Singh, Bimal Kumar Das, Sushil Kumar Kabra, Rakesh Lodha, and Kalpana Luthra. A Rare Mutation in an Infant-Derived HIV-1 Envelope Glycoprotein Alters Interprotomer Stability and Susceptibility to Broadly Neutralizing Antibodies Targeting the Trimer Apex. J. Virol., 94(19), 15 Sep 2020. PubMed ID: 32669335.
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Mishra2020a
Nitesh Mishra, Shaifali Sharma, Ayushman Dobhal, Sanjeev Kumar, Himanshi Chawla, Ravinder Singh, Muzamil Ashraf Makhdoomi, Bimal Kumar Das, Rakesh Lodha, Sushil Kumar Kabra, and Kalpana Luthra. Broadly Neutralizing Plasma Antibodies Effective against Autologous Circulating Viruses in Infants with Multivariant HIV-1 Infection. Nat. Commun., 11(1):4409, 2 Sep 2020. PubMed ID: 32879304.
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Mkhize2023
Nonhlanhla N. Mkhize, Anna E. J. Yssel, Haajira Kaldine, Rebecca T. van Dorsten, Amanda S. Woodward Davis, Nicolas Beaume, David Matten, Bronwen Lambson, Tandile Modise, Prudence Kgagudi, Talita York, Dylan H. Westfall, Elena E. Giorgi, Bette Korber, Colin Anthony, Rutendo E. Mapengo, Valerie Bekker, Elizabeth Domin, Amanda Eaton, Wenjie Deng, Allan DeCamp, Yunda Huang, Peter B . Gilbert, Asanda Gwashu-Nyangiwe, Ruwayhida Thebus, Nonkululeko Ndabambi, Dieter Mielke, Nyaradzo Mgodi, Shelly Karuna, Srilatha Edupuganti, Michael S. Seaman, Lawrence Corey, Myron S. Cohen, John Hural, M. Juliana McElrath, James I. Mullins, David Montefiori, Penny L. Moore, Carolyn Williamson, and Lynn Morris. Neutralization Profiles of HIV-1 Viruses from the VRC01 Antibody Mediated Prevention (AMP) Trials. PLoS Pathog., 19(6):e1011469, Jun 2023. PubMed ID: 37384759.
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Molinos-Albert2023
Luis M. Molinos-Albert, Eduard Baquero, Melanie Bouvin-Pley, Valerie Lorin, Caroline Charre, Cyril Planchais, Jordan D. Dimitrov, Valerie Monceaux, Matthijn Vos, Laurent Hocqueloux, Jean-Luc Berger, Michael S. Seaman, Martine Braibant, Veronique Avettand-Fenoel, Asier Saez-Cirion, and Hugo Mouquet. Anti-V1/V3-glycan broadly HIV-1 neutralizing antibodies in a post-treatment controller. Cell Host Microbe, 31(8):1275-1287e8 doi, Aug 2023. PubMed ID: 37433296
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Morgand2015
Marion Morgand, Mélanie Bouvin-Pley, Jean-Christophe Plantier, Alain Moreau, Elodie Alessandri, François Simon, Craig S. Pace, Marie Pancera, David D. Ho, Pascal Poignard, Pamela J. Bjorkman, Hugo Mouquet, Michel C. Nussenzweig, Peter D. Kwong, Daniel Baty, Patrick Chames, Martine Braibant, and Francis Barin. A V1V2 Neutralizing Epitope Is Conserved in Divergent Non-M Groups of HIV-1. J. Acquir. Immune Defic. Syndr., 21 Sep 2015. PubMed ID: 26413851.
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Mouquet2011
Hugo Mouquet, Florian Klein, Johannes F. Scheid, Malte Warncke, John Pietzsch, Thiago Y. K. Oliveira, Klara Velinzon, Michael S. Seaman, and Michel C. Nussenzweig. Memory B Cell Antibodies to HIV-1 gp140 Cloned from Individuals Infected with Clade A and B Viruses. PLoS One, 6(9):e24078, 2011. PubMed ID: 21931643.
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Mouquet2012a
Hugo Mouquet, Louise Scharf, Zelda Euler, Yan Liu, Caroline Eden, Johannes F. Scheid, Ariel Halper-Stromberg, Priyanthi N. P. Gnanapragasam, Daniel I. R. Spencer, Michael S. Seaman, Hanneke Schuitemaker, Ten Feizi, Michel C. Nussenzweig, and Pamela J. Bjorkman. Complex-Type N-Glycan Recognition by Potent Broadly Neutralizing HIV Antibodies. Proc. Natl. Acad. Sci. U.S.A, 109(47):E3268-E3277, 20 Nov 2012. PubMed ID: 23115339.
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Moyo2018
Thandeka Moyo, June Ereño-Orbea, Rajesh Abraham Jacob, Clara E. Pavillet, Samuel Mundia Kariuki, Emily N. Tangie, Jean-Philippe Julien, and Jeffrey R. Dorfman. Molecular Basis of Unusually High Neutralization Resistance in Tier 3 HIV-1 Strain 253-11. J. Virol., 92(14), 15 Jul 2018. PubMed ID: 29618644.
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Mullick2021
Ranajoy Mullick, Jyoti Sutar, Nitin Hingankar, Suprit Deshpande, Madhuri Thakar, Seema Sahay, Rajesh P. Ringe, Sampurna Mukhopadhyay, Ajit Patil, Shubhangi Bichare, Kailapuri G. Murugavel, Aylur K. Srikrishnan, Rajat Goyal, Devin Sok, and Jayanta Bhattacharya. Neutralization Diversity of HIV-1 Indian Subtype C Envelopes Obtained from Cross Sectional and Followed up Individuals against Broadly Neutralizing Monoclonal Antibodies Having Distinct gp120 Specificities. Retrovirology, 18(1):12, 14 May 2021. PubMed ID: 33990195.
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Narayan2013
Kristin M. Narayan, Nitish Agrawal, Sean X. Du, Janelle E. Muranaka, Katherine Bauer, Daniel P. Leaman, Pham Phung, Kay Limoli, Helen Chen, Rebecca I. Boenig, Terri Wrin, Michael B. Zwick, and Robert G. Whalen. Prime-Boost Immunization of Rabbits with HIV-1 gp120 Elicits Potent Neutralization Activity against a Primary Viral Isolate. PLoS One, 8(1):e52732, 9 Jan 2013. PubMed ID: 23326351.
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Nie2020
Jianhui Nie, Weijin Huang, Qiang Liu, and Youchun Wang. HIV-1 Pseudoviruses Constructed in China Regulatory Laboratory. Emerg. Microbes Infect., 9(1):32-41, 2020. PubMed ID: 31859609.
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Nkolola2014
Joseph P. Nkolola, Christine A. Bricault, Ann Cheung, Jennifer Shields, James Perry, James M. Kovacs, Elena Giorgi, Margot van Winsen, Adrian Apetri, Els C. M. Brinkman-van der Linden, Bing Chen, Bette Korber, Michael S. Seaman, and Dan H. Barouch. Characterization and Immunogenicity of a Novel Mosaic M HIV-1 gp140 Trimer. J. Virol., 88(17):9538-9552, 1 Sep 2014. PubMed ID: 24965452.
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ORourke2012
Sara M. O'Rourke, Becky Schweighardt, Pham Phung, Kathryn A. Mesa, Aaron L. Vollrath, Gwen P. Tatsuno, Briana To, Faruk Sinangil, Kay Limoli, Terri Wrin, and Phillip W. Berman. Sequences in Glycoprotein gp41, the CD4 Binding Site, and the V2 Domain Regulate Sensitivity and Resistance of HIV-1 to Broadly Neutralizing Antibodies. J. Virol., 86(22):12105-12114, Nov 2012. PubMed ID: 22933284.
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Overbaugh2012
Julie Overbaugh and Lynn Morris. The Antibody Response against HIV-1. Cold Spring Harb. Perspect. Med., 2(1):a007039, Jan 2012. PubMed ID: 22315717.
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Pantophlet2010
Ralph Pantophlet. Antibody Epitope Exposure and Neutralization of HIV-1. Curr. Pharm. Des., 16(33):3729-3743, 2010. PubMed ID: 21128886.
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Pegu2017
Amarendra Pegu, Ann J. Hessell, John R. Mascola, and Nancy L. Haigwood. Use of Broadly Neutralizing Antibodies for HIV-1 Prevention. Immunol. Rev., 275(1):296-312, Jan 2017. PubMed ID: 28133803.
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Pejchal2011
Robert Pejchal, Katie J. Doores, Laura M. Walker, Reza Khayat, Po-Ssu Huang, Sheng-Kai Wang, Robyn L. Stanfield, Jean-Philippe Julien, Alejandra Ramos, Max Crispin, Rafael Depetris, Umesh Katpally, Andre Marozsan, Albert Cupo, Sebastien Maloveste, Yan Liu, Ryan McBride, Yukishige Ito, Rogier W. Sanders, Cassandra Ogohara, James C. Paulson, Ten Feizi, Christopher N. Scanlan, Chi-Huey Wong, John P. Moore, William C. Olson, Andrew B. Ward, Pascal Poignard, William R. Schief, Dennis R. Burton, and Ian A. Wilson. A Potent and Broad Neutralizing Antibody Recognizes and Penetrates the HIV Glycan Shield. Science, 334(6059):1097-1103, 25 Nov 2011. PubMed ID: 21998254.
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Pilewski2023
Kelsey A. Pilewski, Steven Wall, Simone I. Richardson, Nelia P. Manamela, Kaitlyn Clark, Tandile Hermanus, Elad Binshtein, Rohit Venkat, Giuseppe A. Sautto, Kevin J. Kramer, Andrea R. Shiakolas, Ian Setliff, Jordan Salas, Rutendo E. Mapengo, Naveen Suryadevara, John R. Brannon, Connor J. Beebout, Rob Parks, Nagarajan Raju, Nicole Frumento, Lauren M. Walker, Emilee Friedman Fechter, Juliana S. Qin, Amyn A. Murji, Katarzyna Janowska, Bhishem Thakur, Jared Lindenberger, Aaron J. May, Xiao Huang, Salam Sammour, Priyamvada Acharya, Robert H. Carnahan, Ted M. Ross, Barton F. Haynes, Maria Hadjifrangiskou, James E. Crowe, Jr., Justin R. Bailey, Spyros Kalams, Lynn Morris, and Ivelin S. Georgiev. Functional HIV-1/HCV Cross-Reactive Antibodies Isolated from a Chronically Co-Infected Donor. Cell Rep., 42(2):112044, 27 Jan 2023. PubMed ID: 36708513.
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Pollara2013
Justin Pollara, Mattia Bonsignori, M. Anthony Moody, Marzena Pazgier, Barton F. Haynes, and Guido Ferrari. Epitope Specificity of Human Immunodeficiency Virus-1 Antibody Dependent Cellular Cytotoxicity (ADCC) Responses. Curr. HIV Res., 11(5):378-387, Jul 2013. PubMed ID: 24191939.
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Prigent2018
Julie Prigent, Annaëlle Jarossay, Cyril Planchais, Caroline Eden, Jérémy Dufloo, Ayrin Kök, Valérie Lorin, Oxana Vratskikh, Thérèse Couderc, Timothée Bruel, Olivier Schwartz, Michael S. Seaman, Ohlenschläger, Jordan D. Dimitrov, and Hugo Mouquet. Conformational Plasticity in Broadly Neutralizing HIV-1 Antibodies Triggers Polyreactivity. Cell Rep., 23(9):2568-2581, 29 May 2018. PubMed ID: 29847789.
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Provine2012
Nicholas M. Provine, Valerie Cortez, Vrasha Chohan, and Julie Overbaugh. The Neutralization Sensitivity of Viruses Representing Human Immunodeficiency Virus Type 1 Variants of Diverse Subtypes from Early in Infection Is Dependent on Producer Cell, as Well as Characteristics of the Specific Antibody and Envelope Variant. Virology, 427(1):25-33, 25 May 2012. PubMed ID: 22369748.
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Pugach2015
Pavel Pugach, Gabriel Ozorowski, Albert Cupo, Rajesh Ringe, Anila Yasmeen, Natalia de Val, Ronald Derking, Helen J. Kim, Jacob Korzun, Michael Golabek, Kevin de Los Reyes, Thomas J. Ketas, Jean-Philippe Julien, Dennis R. Burton, Ian A. Wilson, Rogier W. Sanders, P. J. Klasse, Andrew B. Ward, and John P. Moore. A Native-Like SOSIP.664 Trimer Based on an HIV-1 Subtype B env Gene. J. Virol., 89(6):3380-3395, Mar 2015. PubMed ID: 25589637.
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Lindsey M. Pujanauski, Edward N. Janoff, Martin D. McCarter, Roberta Pelanda, and Raul M. Torres. Mouse Marginal Zone B Cells Harbor Specificities Similar to Human Broadly Neutralizing HIV Antibodies. Proc. Natl. Acad. Sci. U.S.A., 110(4):1422-1427, 22 Jan 2013. PubMed ID: 23288906.
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Rademeyer2016
Cecilia Rademeyer, Bette Korber, Michael S. Seaman, Elena E. Giorgi, Ruwayhida Thebus, Alexander Robles, Daniel J. Sheward, Kshitij Wagh, Jetta Garrity, Brittany R. Carey, Hongmei Gao, Kelli M. Greene, Haili Tang, Gama P. Bandawe, Jinny C. Marais, Thabo E. Diphoko, Peter Hraber, Nancy Tumba, Penny L. Moore, Glenda E. Gray, James Kublin, M. Juliana McElrath, Marion Vermeulen, Keren Middelkoop, Linda-Gail Bekker, Michael Hoelscher, Leonard Maboko, Joseph Makhema, Merlin L. Robb, Salim Abdool Karim, Quarraisha Abdool Karim, Jerome H. Kim, Beatrice H. Hahn, Feng Gao, Ronald Swanstrom, Lynn Morris, David C. Montefiori, and Carolyn Williamson. Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization. PLoS Pathog., 12(7):e1005742, Jul 2016. PubMed ID: 27434311.
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Rathore2017
Ujjwal Rathore, Piyali Saha, Sannula Kesavardhana, Aditya Arun Kumar, Rohini Datta, Sivasankar Devanarayanan, Raksha Das, John R. Mascola, and Raghavan Varadarajan. Glycosylation of the Core of the HIV-1 Envelope Subunit Protein gp120 Is Not Required for Native Trimer Formation or Viral Infectivity. J. Biol. Chem., 292(24):10197-10219, 16 Jun 2017. PubMed ID: 28446609.
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Ren2018
Yanqin Ren, Maria Korom, Ronald Truong, Dora Chan, Szu-Han Huang, Colin C. Kovacs, Erika Benko, Jeffrey T. Safrit, John Lee, Hermes Garbán, Richard Apps, Harris Goldstein, Rebecca M. Lynch, and R. Brad Jones. Susceptibility to Neutralization by Broadly Neutralizing Antibodies Generally Correlates with Infected Cell Binding for a Panel of Clade B HIV Reactivated from Latent Reservoirs. J. Virol., 92(23), 1 Dec 2018. PubMed ID: 30209173.
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Ringe2011
Rajesh Ringe, Deepak Sharma, Susan Zolla-Pazner, Sanjay Phogat, Arun Risbud, Madhuri Thakar, Ramesh Paranjape, and Jayanta Bhattacharya. A Single Amino Acid Substitution in the C4 Region in gp120 Confers Enhanced Neutralization of HIV-1 by Modulating CD4 Binding Sites and V3 Loop. Virology, 418(2):123-132, 30 Sep 2011. PubMed ID: 21851958.
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Roark2021
Ryan S. Roark, Hui Li, Wilton B. Williams, Hema Chug, Rosemarie D. Mason, Jason Gorman, Shuyi Wang, Fang-Hua Lee, Juliette Rando, Mattia Bonsignori, Kwan-Ki Hwang, Kevin O. Saunders, Kevin Wiehe, M. Anthony Moody, Peter T. Hraber, Kshitij Wagh, Elena E. Giorgi, Ronnie M. Russell, Frederic Bibollet-Ruche, Weimin Liu, Jesse Connell, Andrew G. Smith, Julia DeVoto, Alexander I. Murphy, Jessica Smith, Wenge Ding, Chengyan Zhao, Neha Chohan, Maho Okumura, Christina Rosario, Yu Ding, Emily Lindemuth, Anya M. Bauer, Katharine J. Bar, David Ambrozak, Cara W. Chao, Gwo-Yu Chuang, Hui Geng, Bob C. Lin, Mark K. Louder, Richard Nguyen, Baoshan Zhang, Mark G. Lewis, Donald D. Raymond, Nicole A. Doria-Rose, Chaim A. Schramm, Daniel C. Douek, Mario Roederer, Thomas B. Kepler, Garnett Kelsoe, John R. Mascola, Peter D. Kwong, Bette T. Korber, Stephen C. Harrison, Barton F. Haynes, Beatrice H. Hahn, and George M. Shaw. Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth. Science, 371(6525), 8 Jan 2021. PubMed ID: 33214287.
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Rosenberg2015
Yvonne Rosenberg, Markus Sack, David Montefiori, Celia Labranche, Mark Lewis, Lori Urban, Lingjun Mao, Rainer Fischer, and Xiaoming Jiang. Pharmacokinetics and Immunogenicity of Broadly Neutralizing HIV Monoclonal Antibodies in Macaques. PLoS One, 10(3):e0120451, 25 Mar 2015. PubMed ID: 25807114.
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Rebecca S. Rudicell, Young Do Kwon, Sung-Youl Ko, Amarendra Pegu, Mark K. Louder, Ivelin S. Georgiev, Xueling Wu, Jiang Zhu, Jeffrey C. Boyington, Xuejun Chen, Wei Shi, Zhi-Yong Yang, Nicole A. Doria-Rose, Krisha McKee, Sijy O'Dell, Stephen D. Schmidt, Gwo-Yu Chuang, Aliaksandr Druz, Cinque Soto, Yongping Yang, Baoshan Zhang, Tongqing Zhou, John-Paul Todd, Krissey E. Lloyd, Joshua Eudailey, Kyle E. Roberts, Bruce R. Donald, Robert T. Bailer, Julie Ledgerwood, NISC Comparative Sequencing Program, James C. Mullikin, Lawrence Shapiro, Richard A. Koup, Barney S. Graham, Martha C. Nason, Mark Connors, Barton F. Haynes, Srinivas S. Rao, Mario Roederer, Peter D. Kwong, John R. Mascola, and Gary J. Nabel. Enhanced Potency of a Broadly Neutralizing HIV-1 Antibody In Vitro Improves Protection against Lentiviral Infection In Vivo. J. Virol., 88(21):12669-12682, 1 Nov 2014. PubMed ID: 25142607.
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Rudometova2022
N. B. Rudometova, N. S. Shcherbakova, D. N. Shcherbakov, O. S. Taranov, B. N. Zaitsev, and L. I. Karpenko. Construction and Characterization of HIV-1 env-Pseudoviruses of the Recombinant Form CRF63_02A and Subtype A6. Bull Exp Biol Med, 172(6):729-733 doi, Apr 2022. PubMed ID: 35501651
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Rusert2016
Peter Rusert, Roger D. Kouyos, Claus Kadelka, Hanna Ebner, Merle Schanz, Michael Huber, Dominique L. Braun, Nathanael Hozé, Alexandra Scherrer, Carsten Magnus, Jacqueline Weber, Therese Uhr, Valentina Cippa, Christian W. Thorball, Herbert Kuster, Matthias Cavassini, Enos Bernasconi, Matthias Hoffmann, Alexandra Calmy, Manuel Battegay, Andri Rauch, Sabine Yerly, Vincent Aubert, Thomas Klimkait, Jürg Böni, Jacques Fellay, Roland R. Regoes, Huldrych F. Günthard, Alexandra Trkola, and Swiss HIV Cohort Study. Determinants of HIV-1 Broadly Neutralizing Antibody Induction. Nat. Med., 22(11):1260-1267, Nov 2016. PubMed ID: 27668936.
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Sadanand2016
Saheli Sadanand, Todd J. Suscovich, and Galit Alter. Broadly Neutralizing Antibodies Against HIV: New Insights to Inform Vaccine Design. Annu. Rev. Med., 67:185-200, 2016. PubMed ID: 26565674.
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Sagar2012
Manish Sagar, Hisashi Akiyama, Behzad Etemad, Nora Ramirez, Ines Freitas, and Suryaram Gummuluru. Transmembrane Domain Membrane Proximal External Region but Not Surface Unit-Directed Broadly Neutralizing HIV-1 Antibodies Can Restrict Dendritic Cell-Mediated HIV-1 Trans-Infection. J. Infect. Dis., 205(8):1248-1257, 15 Apr 2012. PubMed ID: 22396600.
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Sajadi2012
Mohammad M. Sajadi, George K. Lewis, Michael S. Seaman, Yongjun Guan, Robert R. Redfield, and Anthony L. DeVico. Signature Biochemical Properties of Broadly Cross-Reactive HIV-1 Neutralizing Antibodies in Human Plasma. J. Virol., 86(9):5014-5025, May 2012. PubMed ID: 22379105.
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V. Sanchez-Merino, A. Fabra-Garcia, N. Gonzalez, D. Nicolas, A. Merino-Mansilla, C. Manzardo, J. Ambrosioni, A. Schultz, A. Meyerhans, J. R. Mascola, J. M. Gatell, J. Alcami, J. M. Miro, and E. Yuste. Detection of Broadly Neutralizing Activity within the First Months of HIV-1 Infection. J. Virol., 90(11):5231-5245, 1 Jun 2016. PubMed ID: 26984721.
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Sanders2013
Rogier W. Sanders, Ronald Derking, Albert Cupo, Jean-Philippe Julien, Anila Yasmeen, Natalia de Val, Helen J. Kim, Claudia Blattner, Alba Torrents de la Peña, Jacob Korzun, Michael Golabek, Kevin de los Reyes, Thomas J. Ketas, Marit J. van Gils, C. Richter King, Ian A. Wilson, Andrew B. Ward, P. J. Klasse, and John P. Moore. A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but not Non-Neutralizing Antibodies. PLoS Pathog., 9(9):e1003618, Sep 2013. PubMed ID: 24068931.
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D. Noah Sather, Sara Carbonetti, Jenny Kehayia, Zane Kraft, Iliyana Mikell, Johannes F. Scheid, Florian Klein, and Leonidas Stamatatos. Broadly Neutralizing Antibodies Developed by an HIV-Positive Elite Neutralizer Exact a Replication Fitness Cost on the Contemporaneous Virus. J. Virol., 86(23):12676-12685, Dec 2012. PubMed ID: 22973035.
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D. Noah Sather, Sara Carbonetti, Delphine C. Malherbe, Franco Pissani, Andrew B. Stuart, Ann J. Hessell, Mathew D. Gray, Iliyana Mikell, Spyros A. Kalams, Nancy L. Haigwood, and Leonidas Stamatatos. Emergence of Broadly Neutralizing Antibodies and Viral Coevolution in Two Subjects during the Early Stages of Infection with Human Immunodeficiency Virus Type 1. J. Virol., 88(22):12968-12981, Nov 2014. PubMed ID: 25122781.
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Louise Scharf, Anthony P. West, Jr., Stuart A. Sievers, Courtney Chen, Siduo Jiang, Han Gao, Matthew D. Gray, Andrew T. McGuire, Johannes F. Scheid, Michel C. Nussenzweig, Leonidas Stamatatos, and Pamela J. Bjorkman. Structural Basis for Germline Antibody Recognition of HIV-1 Immunogens. Elife, 5, 21 Mar 2016. PubMed ID: 26997349.
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Scheid2011
Johannes F. Scheid, Hugo Mouquet, Beatrix Ueberheide, Ron Diskin, Florian Klein, Thiago Y. K. Oliveira, John Pietzsch, David Fenyo, Alexander Abadir, Klara Velinzon, Arlene Hurley, Sunnie Myung, Farid Boulad, Pascal Poignard, Dennis R. Burton, Florencia Pereyra, David D. Ho, Bruce D. Walker, Michael S. Seaman, Pamela J. Bjorkman, Brian T. Chait, and Michel C. Nussenzweig. Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding. Science, 333(6049):1633-1637, 16 Sep 2011. PubMed ID: 21764753.
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Schiffner2016
Torben Schiffner, Natalia de Val, Rebecca A. Russell, Steven W. de Taeye, Alba Torrents de la Peña, Gabriel Ozorowski, Helen J. Kim, Travis Nieusma, Florian Brod, Albert Cupo, Rogier W. Sanders, John P. Moore, Andrew B. Ward, and Quentin J. Sattentau. Chemical Cross-Linking Stabilizes Native-Like HIV-1 Envelope Glycoprotein Trimer Antigens. J. Virol., 90(2):813-828, 28 Oct 2015. PubMed ID: 26512083.
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Schiffner2018
Torben Schiffner, Jesper Pallesen, Rebecca A. Russell, Jonathan Dodd, Natalia de Val, Celia C. LaBranche, David Montefiori, Georgia D. Tomaras, Xiaoying Shen, Scarlett L. Harris, Amin E. Moghaddam, Oleksandr Kalyuzhniy, Rogier W. Sanders, Laura E. McCoy, John P. Moore, Andrew B. Ward, and Quentin J. Sattentau. Structural and Immunologic Correlates of Chemically Stabilized HIV-1 Envelope Glycoproteins. PLoS Pathog., 14(5):e1006986, May 2018. PubMed ID: 29746590.
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Schommers2020
Philipp Schommers, Henning Gruell, Morgan E. Abernathy, My-Kim Tran, Adam S. Dingens, Harry B. Gristick, Christopher O. Barnes, Till Schoofs, Maike Schlotz, Kanika Vanshylla, Christoph Kreer, Daniela Weiland, Udo Holtick, Christof Scheid, Markus M. Valter, Marit J. van Gils, Rogier W. Sanders, Jörg J. Vehreschild, Oliver A. Cornely, Clara Lehmann, Gerd Fätkenheuer, Michael S. Seaman, Jesse D. Bloom, Pamela J. Bjorkman, and Florian Klein. Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody. Cell, 180(3):471-489.e22, 6 Feb 2020. PubMed ID: 32004464.
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Schorcht2020
Anna Schorcht, Tom L. G. M. van den Kerkhof, Christopher A. Cottrell, Joel D. Allen, Jonathan L. Torres, Anna-Janina Behrens, Edith E. Schermer, Judith A. Burger, Steven W. de Taeye, Alba Torrents de la Peña, Ilja Bontjer, Stephanie Gumbs, Gabriel Ozorowski, Celia C. LaBranche, Natalia de Val, Anila Yasmeen, Per Johan Klasse, David C. Montefiori, John P. Moore, Hanneke Schuitemaker, Max Crispin, Marit J. van Gils, Andrew B. Ward, and Rogier W. Sanders. Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers. J. Virol., 94(24), 23 Nov 2020. PubMed ID: 32999024.
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Scott2015
Yanille M. Scott, Seo Young Park, and Charlene S. Dezzutti. Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo. Antimicrob. Agents Chemother., 60(2):904-912, Feb 2016. PubMed ID: 26596954.
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Seaton2023
Kelly E. Seaton, Yunda Huang, Shelly Karuna, Jack R. Heptinstall, Caroline Brackett, Kelvin Chiong, Lily Zhang, Nicole L Yates, Mark Sampson, Erika Rudnicki, Michal Juraska, Allan C. deCamp, Paul T. Edlefsen, James I. Mullins, Carolyn Williamson, Raabya Rossenkhan, Elena E. Giorgi, Avi Kenny, Heather Angier, April Randhawa, Joshua A. Weiner, Michelle Rojas, Marcella Sarzotti-Kelsoe, Lu Zhang, Sheetal Sawant, Margaret E. Ackerman, Adrian B. McDermott, John R. Mascola, John Hural, M. Julianna McElrath, Philip Andrew, Jose A. Hidalgo, Jesse Clark, Fatima Laher, Catherine Orrell, Ian Frank, Pedro Gonzales, Srilatha Edupuganti, Nyaradzo Mgodi, Lawrence Corey, Lynn Morris, David Montefiori, Myron S. Cohen, Peter B. Gilbert, and Georgia D. Tomaras. Pharmacokinetic Serum Concentrations of VRC01 Correlate with Prevention of HIV-1 Acquisition. EBioMedicine, 93:104590, Jul 2023. PubMed ID: 37300931.
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Sellhorn2012
George Sellhorn, Zane Kraft, Zachary Caldwell, Katharine Ellingson, Christine Mineart, Michael S. Seaman, David C. Montefiori, Eliza Lagerquist, and Leonidas Stamatatos. Engineering, Expression, Purification, and Characterization of Stable Clade A/B Recombinant Soluble Heterotrimeric gp140 Proteins. J. Virol., 86(1):128-142, Jan 2012. PubMed ID: 22031951.
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Sengupta2023
Srona Sengupta, Josephine Zhang, Madison C. Reed, Jeanna Yu, Aeryon Kim, Tatiana N. Boronina, Nathan L. Board, James O. Wrabl, Kevin Shenderov, Robin A. Welsh, Weiming Yang, Andrew E. Timmons, Rebecca Hoh, Robert N. Cole, Steven G. Deeks, Janet D. Siliciano, Robert F. Siliciano, and Scheherazade Sadegh-Nasseri. A cell-free antigen processing system informs HIV-1 epitope selection and vaccine design. J Exp Med, 220(7):e20221654 doi, Jul 2023. PubMed ID: 37058141
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Shang2011
Hong Shang, Xiaoxu Han, Xuanling Shi, Teng Zuo, Mark Goldin, Dan Chen, Bing Han, Wei Sun, Hao Wu, Xinquan Wang, and Linqi Zhang. Genetic and Neutralization Sensitivity of Diverse HIV-1 env Clones from Chronically Infected Patients in China. J. Biol. Chem., 286(16):14531-14541, 22 Apr 2011. PubMed ID: 21325278.
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Sheng2016
Zizhang Sheng, Chaim A. Schramm, Mark Connors, Lynn Morris, John R. Mascola, Peter D. Kwong, and Lawrence Shapiro. Effects of Darwinian Selection and Mutability on Rate of Broadly Neutralizing Antibody Evolution during HIV-1 Infection. PLoS Comput. Biol., 12(5):e1004940, May 2016. PubMed ID: 27191167.
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Simonich2016
Cassandra A. Simonich, Katherine L. Williams, Hans P. Verkerke, James A. Williams, Ruth Nduati, Kelly K. Lee, and Julie Overbaugh. HIV-1 Neutralizing Antibodies with Limited Hypermutation from an Infant. Cell, 166(1):77-87, 30 Jun 2016. PubMed ID: 27345369.
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Sliepen2015
Kwinten Sliepen, Max Medina-Ramirez, Anila Yasmeen, John P. Moore, Per Johan Klasse, and Rogier W. Sanders. Binding of Inferred Germline Precursors of Broadly Neutralizing HIV-1 Antibodies to Native-Like Envelope Trimers. Virology, 486:116-120, Dec 2015. PubMed ID: 26433050.
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Sliepen2019
Kwinten Sliepen, Byung Woo Han, Ilja Bontjer, Petra Mooij, Fernando Garces, Anna-Janina Behrens, Kimmo Rantalainen, Sonu Kumar, Anita Sarkar, Philip J. M. Brouwer, Yuanzi Hua, Monica Tolazzi, Edith Schermer, Jonathan L. Torres, Gabriel Ozorowski, Patricia van der Woude, Alba Torrents de la Pena, Marielle J. van Breemen, Juan Miguel Camacho-Sanchez, Judith A. Burger, Max Medina-Ramirez, Nuria Gonzalez, Jose Alcami, Celia LaBranche, Gabriella Scarlatti, Marit J. van Gils, Max Crispin, David C. Montefiori, Andrew B. Ward, Gerrit Koopman, John P. Moore, Robin J. Shattock, Willy M. Bogers, Ian A. Wilson, and Rogier W. Sanders. Structure and immunogenicity of a stabilized HIV-1 envelope trimer based on a group-M consensus sequence. Nat Commun, 10(1):2355 doi, May 2019. PubMed ID: 31142746
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Smalls-Mantey2012
Adjoa Smalls-Mantey, Nicole Doria-Rose, Rachel Klein, Andy Patamawenu, Stephen A. Migueles, Sung-Youl Ko, Claire W. Hallahan, Hing Wong, Bai Liu, Lijing You, Johannes Scheid, John C. Kappes, Christina Ochsenbauer, Gary J. Nabel, John R. Mascola, and Mark Connors. Antibody-Dependent Cellular Cytotoxicity against Primary HIV-Infected CD4+ T Cells Is Directly Associated with the Magnitude of Surface IgG Binding. J. Virol., 86(16):8672-8680, Aug 2012. PubMed ID: 22674985.
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Spencer2021
David A. Spencer, Delphine C. Malherbe, Nestor Vazquez Bernat, Monika Adori, Benjamin Goldberg, Nicholas Dambrauskas, Heidi Henderson, Shilpi Pandey, Tracy Cheever, Philip Barnette, William F. Sutton, Margaret E. Ackerman, James J. Kobie, D. Noah Sather, Gunilla B. Karlsson Hedestam, Nancy L. Haigwood, and Ann J. Hessell. Polyfunctional Tier 2-Neutralizing Antibodies Cloned following HIV-1 Env Macaque Immunization Mirror Native Antibodies in a Human Donor. J Immunol, 206(5):999-1012 doi, Mar 2021. PubMed ID: 33472907
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Stefic2019
Karl Stefic, Mélanie Bouvin-Pley, Asma Essat, Clara Visdeloup, Alain Moreau, Cécile Goujard, Marie-Laure Chaix, Martine Braibant, Laurence Meyer, and Francis Barin. Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02\_AG Viruses with a Focus on Evolution over Time. J. Virol., 93(2), 15 Jan 2019. PubMed ID: 30404804.
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Steinhardt2018
James J. Steinhardt, Javier Guenaga, Hannah L. Turner, Krisha McKee, Mark K. Louder, Sijy O'Dell, Chi-I Chiang, Lin Lei, Andrey Galkin, Alexander K. Andrianov, Nicole A. Doria-Rose, Robert T. Bailer, Andrew B. Ward, John R. Mascola, and Yuxing Li. Rational Design of a Trispecific Antibody Targeting the HIV-1 Env with Elevated Anti-Viral Activity. Nat. Commun., 9(1):877, 28 Feb 2018. PubMed ID: 29491415.
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Stephenson2016
Kathryn E. Stephenson and Dan H. Barouch. Broadly Neutralizing Antibodies for HIV Eradication. Curr. HIV/AIDS Rep., 13(1):31-37, Feb 2016. PubMed ID: 26841901.
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Stewart-Jones2016
Guillaume B. E. Stewart-Jones, Cinque Soto, Thomas Lemmin, Gwo-Yu Chuang, Aliaksandr Druz, Rui Kong, Paul V. Thomas, Kshitij Wagh, Tongqing Zhou, Anna-Janina Behrens, Tatsiana Bylund, Chang W. Choi, Jack R. Davison, Ivelin S. Georgiev, M. Gordon Joyce, Young Do Kwon, Marie Pancera, Justin Taft, Yongping Yang, Baoshan Zhang, Sachin S. Shivatare, Vidya S. Shivatare, Chang-Chun D. Lee, Chung-Yi Wu, Carole A. Bewley, Dennis R. Burton, Wayne C. Koff, Mark Connors, Max Crispin, Ulrich Baxa, Bette T. Korber, Chi-Huey Wong, John R. Mascola, and Peter D. Kwong. Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G. Cell, 165(4):813-826, 5 May 2016. PubMed ID: 27114034.
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Sun2017
Youxiang Sun, Yuanyuan Qiao, Yuanmei Zhu, Huihui Chong, and Yuxian He. Identification of a Novel HIV-1-Neutralizing Antibody from a CRF07\_BC-Infected Chinese Donor. Oncotarget, 8(38):63047-63063, 8 Sep 2017. PubMed ID: 28968970.
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Sundling2012
Christopher Sundling, Yuxing Li, Nick Huynh, Christian Poulsen, Richard Wilson, Sijy O'Dell, Yu Feng, John R. Mascola, Richard T. Wyatt, and Gunilla B. Karlsson Hedestam. High-Resolution Definition of Vaccine-Elicited B Cell Responses Against the HIV Primary Receptor Binding Site. Sci. Transl. Med., 4(142):142ra96, 11 Jul 2012. PubMed ID: 22786681.
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Teh2014
Audrey Y-H. Teh, Daniel Maresch, Katja Klein, and Julian K-C. Ma. Characterization of VRC01, a Potent and Broadly Neutralizing Anti-HIV mAb, Produced in Transiently and Stably Transformed Tobacco. Plant Biotechnol. J., 12(3):300-311, Apr 2014. PubMed ID: 24256218.
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Thida2019
Win Thida, Takeo Kuwata, Yosuke Maeda, Tetsu Yamashiro, Giang Van Tran, Kinh Van Nguyen, Masafumi Takiguchi, Hiroyuki Gatanaga, Kazuki Tanaka, and Shuzo Matsushita. The Role of Conventional Antibodies Targeting the CD4 Binding Site and CD4-Induced Epitopes in the Control of HIV-1 CRF01\_AE Viruses. Biochem. Biophys. Res. Commun., 508(1):46-51, 1 Jan 2019. PubMed ID: 30470571.
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Tokatlian2018
Talar Tokatlian, Daniel W. Kulp, Andrew A. Mutafyan, Christopher A. Jones, Sergey Menis, Erik Georgeson, Mike Kubitz, Michael H. Zhang, Mariane B. Melo, Murillo Silva, Dong Soo Yun, William R. Schief, and Darrell J. Irvine. Enhancing Humoral Responses Against HIV Envelope Trimers via Nanoparticle Delivery with Stabilized Synthetic Liposomes. Sci. Rep., 8(1):16527, 8 Nov 2018. PubMed ID: 30410003.
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Tomaras2011
Georgia D. Tomaras, James M. Binley, Elin S. Gray, Emma T. Crooks, Keiko Osawa, Penny L. Moore, Nancy Tumba, Tommy Tong, Xiaoying Shen, Nicole L. Yates, Julie Decker, Constantinos Kurt Wibmer, Feng Gao, S. Munir Alam, Philippa Easterbrook, Salim Abdool Karim, Gift Kamanga, John A. Crump, Myron Cohen, George M. Shaw, John R. Mascola, Barton F. Haynes, David C. Montefiori, and Lynn Morris. Polyclonal B Cell Responses to Conserved Neutralization Epitopes in a Subset of HIV-1-Infected Individuals. J. Virol., 85(21):11502-11519, Nov 2011. PubMed ID: 21849452.
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Tong2012
Tommy Tong, Ema T. Crooks, Keiko Osawa, and James M. Binley. HIV-1 Virus-Like Particles Bearing Pure Env Trimers Expose Neutralizing Epitopes but Occlude Nonneutralizing Epitopes. J. Virol., 86(7):3574-3587, Apr 2012. PubMed ID: 22301141.
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Tran2012
Erin E. H. Tran, Mario J. Borgnia, Oleg Kuybeda, David M. Schauder, Alberto Bartesaghi, Gabriel A. Frank, Guillermo Sapiro, Jacqueline L. S. Milne, and Sriram Subramaniam. Structural Mechanism of Trimeric HIV-1 Envelope Glycoprotein Activation. PLoS Pathog., 8(7):e1002797, 2012. PubMed ID: 22807678.
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Umotoy2019
Jeffrey Umotoy, Bernard S. Bagaya, Collin Joyce, Torben Schiffner, Sergey Menis, Karen L. Saye-Francisco, Trevor Biddle, Sanjay Mohan, Thomas Vollbrecht, Oleksander Kalyuzhniy, Sharon Madzorera, Dale Kitchin, Bronwen Lambson, Molati Nonyane, William Kilembe, IAVI Protocol C Investigators, IAVI African HIV Research Network, Pascal Poignard, William R. Schief, Dennis R. Burton, Ben Murrell, Penny L. Moore, Bryan Briney, Devin Sok, and Elise Landais. Rapid and Focused Maturation of a VRC01-Class HIV Broadly Neutralizing Antibody Lineage Involves Both Binding and Accommodation of the N276-Glycan. Immunity, 51(1):141-154.e6, 16 Jul 2019. PubMed ID: 31315032.
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vandenKerkhof2013
Tom L. G. M. van den Kerkhof, K. Anton Feenstra, Zelda Euler, Marit J. van Gils, Linda W. E. Rijsdijk, Brigitte D. Boeser-Nunnink, Jaap Heringa, Hanneke Schuitemaker, and Rogier W. Sanders. HIV-1 Envelope Glycoprotein Signatures That Correlate with the Development of Cross-Reactive Neutralizing Activity. Retrovirology, 10:102, 23 Sep 2013. PubMed ID: 24059682.
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vandenKerkhof2016
Tom L. G. M. van den Kerkhof, Steven W. de Taeye, Brigitte D. Boeser-Nunnink, Dennis R. Burton, Neeltje A. Kootstra, Hanneke Schuitemaker, Rogier W. Sanders, and Marit J. van Gils. HIV-1 escapes from N332-directed antibody neutralization in an elite neutralizer by envelope glycoprotein elongation and introduction of unusual disulfide bonds. Retrovirology, 13(1):48, 7 Jul 2016. PubMed ID: 27388013.
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vanGils2011
Marit J. van Gils, Evelien M. Bunnik, Brigitte D. Boeser-Nunnink, Judith A. Burger, Marijke Terlouw-Klein, Naomi Verwer, and Hanneke Schuitemaker. Longer V1V2 Region with Increased Number of Potential N-Linked Glycosylation Sites in the HIV-1 Envelope Glycoprotein Protects against HIV-Specific Neutralizing Antibodies. J. Virol., 85(14):6986-6995, Jul 2011. PubMed ID: 21593147.
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vanMontfort2011
Thijs van Montfort, Mark Melchers, Gözde Isik, Sergey Menis, Po-Ssu Huang, Katie Matthews, Elizabeth Michael, Ben Berkhout, William R. Schief, John P. Moore, and Rogier W. Sanders. A Chimeric HIV-1 Envelope Glycoprotein Trimer with an Embedded Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Domain Induces Enhanced Antibody and T Cell Responses. J. Biol. Chem., 286(25):22250-22261, 24 Jun 2011. PubMed ID: 21515681.
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Veillette2014
Maxime Veillette, Anik Désormeaux, Halima Medjahed, Nour-Elhouda Gharsallah, Mathieu Coutu, Joshua Baalwa, Yongjun Guan, George Lewis, Guido Ferrari, Beatrice H. Hahn, Barton F. Haynes, James E. Robinson, Daniel E. Kaufmann, Mattia Bonsignori, Joseph Sodroski, and Andres Finzi. Interaction with Cellular CD4 Exposes HIV-1 Envelope Epitopes Targeted by Antibody-Dependent Cell-Mediated Cytotoxicity. J. Virol., 88(5):2633-2644, Mar 2014. PubMed ID: 24352444.
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Veselinovic2012
Milena Veselinovic, C. Preston Neff, Leila R. Mulder, and Ramesh Akkina. Topical Gel Formulation of Broadly Neutralizing Anti-HIV-1 Monoclonal Antibody VRC01 Confers Protection against HIV-1 Vaginal Challenge in A Humanized Mouse Model. Virology, 432(2):505-510, 25 Oct 2012. PubMed ID: 22832125.
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Virnik2018
Konstantin Virnik, Edmund Nesti, Cody Dail, Aaron Scanlan, Alexei Medvedev, Russell Vassell, Andrew T. McGuire, Leonidas Stamatatos, and Ira Berkower. Live Rubella Vectors Can Express Native HIV Envelope Glycoproteins Targeted by Broadly Neutralizing Antibodies and Prime the Immune Response to an Envelope Protein Boost. Vaccine, 36(34):5166-5172, 16 Aug 2018. PubMed ID: 30037665.
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vonBredow2016
Benjamin von Bredow, Juan F. Arias, Lisa N. Heyer, Brian Moldt, Khoa Le, James E. Robinson, Susan Zolla-Pazner, Dennis R. Burton, and David T. Evans. Comparison of Antibody-Dependent Cell-Mediated Cytotoxicity and Virus Neutralization by HIV-1 Env-Specific Monoclonal Antibodies. J. Virol., 90(13):6127-6139, 1 Jul 2016. PubMed ID: 27122574.
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Wagh2016
Kshitij Wagh, Tanmoy Bhattacharya, Carolyn Williamson, Alex Robles, Madeleine Bayne, Jetta Garrity, Michael Rist, Cecilia Rademeyer, Hyejin Yoon, Alan Lapedes, Hongmei Gao, Kelli Greene, Mark K. Louder, Rui Kong, Salim Abdool Karim, Dennis R. Burton, Dan H. Barouch, Michel C. Nussenzweig, John R. Mascola, Lynn Morris, David C. Montefiori, Bette Korber, and Michael S. Seaman. Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection. PLoS Pathog., 12(3):e1005520, Mar 2016. PubMed ID: 27028935.
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Wagh2018
Kshitij Wagh, Michael S. Seaman, Marshall Zingg, Tomas Fitzsimons, Dan H. Barouch, Dennis R. Burton, Mark Connors, David D. Ho, John R. Mascola, Michel C. Nussenzweig, Jeffrey Ravetch, Rajeev Gautam, Malcolm A. Martin, David C. Montefiori, and Bette Korber. Potential of Conventional \& Bispecific Broadly Neutralizing Antibodies for Prevention of HIV-1 Subtype A, C \& D Infections. PLoS Pathog., 14(3):e1006860, Mar 2018. PubMed ID: 29505593.
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Walker2010a
Laura M. Walker and Dennis R. Burton. Rational Antibody-Based HIV-1 Vaccine Design: Current Approaches and Future Directions. Curr. Opin. Immunol., 22(3):358-366, Jun 2010. PubMed ID: 20299194.
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Walker2011
Laura M. Walker, Michael Huber, Katie J. Doores, Emilia Falkowska, Robert Pejchal, Jean-Philippe Julien, Sheng-Kai Wang, Alejandra Ramos, Po-Ying Chan-Hui, Matthew Moyle, Jennifer L. Mitcham, Phillip W. Hammond, Ole A. Olsen, Pham Phung, Steven Fling, Chi-Huey Wong, Sanjay Phogat, Terri Wrin, Melissa D. Simek, Protocol G. Principal Investigators, Wayne C. Koff, Ian A. Wilson, Dennis R. Burton, and Pascal Poignard. Broad Neutralization Coverage of HIV by Multiple Highly Potent Antibodies. Nature, 477(7365):466-470, 22 Sep 2011. PubMed ID: 21849977.
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Walker2018
Laura M. Walker and Dennis R. Burton. Passive Immunotherapy of Viral Infections: `Super-Antibodies' Enter the Fray. Nat. Rev. Immunol., 18(5):297-308, May 2018. PubMed ID: 29379211.
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Wang2013
Wenbo Wang, Jianhui Nie, Courtney Prochnow, Carolyn Truong, Zheng Jia, Suting Wang, Xiaojiang S. Chen, and Youchun Wang. A Systematic Study of the N-Glycosylation Sites of HIV-1 Envelope Protein on Infectivity and Antibody-Mediated Neutralization. Retrovirology, 10:14, 2013. PubMed ID: 23384254.
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Wang2018a
Hongye Wang, Ting Yuan, Tingting Li, Yanpeng Li, Feng Qian, Chuanwu Zhu, Shujia Liang, Daniel Hoffmann, Ulf Dittmer, Binlian Sun, and Rongge Yang. Evaluation of Susceptibility of HIV-1 CRF01\_AE Variants to Neutralization by a Panel of Broadly Neutralizing Antibodies. Arch. Virol., 163(12):3303-3315, Dec 2018. PubMed ID: 30196320.
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Wang2019
Qian Wang, Lihong Liu, Wuze Ren, Agegnehu Gettie, Hua Wang, Qingtai Liang, Xuanling Shi, David C. Montefiori, Tongqing Zhou, and Linqi Zhang. A Single Substitution in gp41 Modulates the Neutralization Profile of SHIV during In Vivo Adaptation. Cell Rep., 27(9):2593-2607.e5, 28 May 2019. PubMed ID: 31141685.
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Wang2022
Lijie Wang, Shujia Liang, Jianhua Huang, Yibo Ding, Lin He, Yanling Hao, Li Ren, Meiling Zhu, Yi Feng, Abdur Rashid, Yue Liu, Shibo Jiang, Kunxue Hong, and Liying Ma. Neutralization Sensitivity of HIV-1 CRF07\_BC From an Untreated Patient With a Focus on Evolution Over Time. Front. Cell. Infect. Microbiol., 12:862754, 2022. PubMed ID: 35372102.
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Wang2023
Shuishu Wang, Flavio Matassoli, Baoshan Zhang, Tracy Liu, Chen-Hsiang Shen, Tatsiana Bylund, Timothy Johnston, Amy R. Henry, I-Ting Teng, Prabhanshu Tripathi, Jordan E. Becker, Anita Changela, Ridhi Chaudhary, Cheng Cheng, Martin Gaudinski, Jason Gorman, Darcy R. Harris, Myungjin Lee, Nicholas C. Morano, Laura Novik, Sijy O'Dell, Adam S. Olia, Danealle K. Parchment, Reda Rawi, Jesmine Roberts-Torres, Tyler Stephens, Yaroslav Tsybovsky, Danyi Wang, David J. Van Wazer, Tongqing Zhou, Nicole A. Doria-Rose, Richard A. Koup, Lawrence Shapiro, Daniel C. Douek, Adrian B. McDermott, and Peter D. Kwong. HIV-1 neutralizing antibodies elicited in humans by a prefusion-stabilized envelope trimer form a reproducible class targeting fusion peptide. Cell Rep, 42(7):112755 doi, Jul 2023. PubMed ID: 37436899
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Andrew B. Ward. Playing Chess with HIV. Immunity, 50(2):283-285 doi, Feb 2019. PubMed ID: 30784575
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Watkins2011
Jennifer D. Watkins, Juan Diaz-Rodriguez, Nagadenahalli B. Siddappa, Davide Corti, and Ruth M. Ruprecht. Efficiency of Neutralizing Antibodies Targeting the CD4-Binding Site: Influence of Conformational Masking by the V2 Loop in R5-Tropic Clade C Simian-Human Immunodeficiency Virus. J Virol, 85(23):12811-12814, Dec 2011. PubMed ID: 21957314.
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Webb2015
Nicholas E. Webb, David C. Montefiori, and Benhur Lee. Dose-Response Curve Slope Helps Predict Therapeutic Potency and Breadth of HIV Broadly Neutralizing Antibodies. Nat. Commun., 6:8443, 29 Sep 2015. PubMed ID: 26416571.
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Wen2018
Yingxia Wen, Hung V. Trinh, Christine E Linton, Chiara Tani, Nathalie Norais, DeeAnn Martinez-Guzman, Priyanka Ramesh, Yide Sun, Frank Situ, Selen Karaca-Griffin, Christopher Hamlin, Sayali Onkar, Sai Tian, Susan Hilt, Padma Malyala, Rushit Lodaya, Ning Li, Gillis Otten, Giuseppe Palladino, Kristian Friedrich, Yukti Aggarwal, Celia LaBranche, Ryan Duffy, Xiaoying Shen, Georgia D. Tomaras, David C. Montefiori, William Fulp, Raphael Gottardo, Brian Burke, Jeffrey B. Ulmer, Susan Zolla-Pazner, Hua-Xin Liao, Barton F. Haynes, Nelson L. Michael, Jerome H. Kim, Mangala Rao, Robert J. O'Connell, Andrea Carfi, and Susan W. Barnett. Generation and Characterization of a Bivalent Protein Boost for Future Clinical Trials: HIV-1 Subtypes CR01\_AE and B gp120 Antigens with a Potent Adjuvant. PLoS One, 13(4):e0194266, 2018. PubMed ID: 29698406.
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West2012
Anthony P. West, Jr., Rachel P. Galimidi, Priyanthi N. P. Gnanapragasam, and Pamela J. Bjorkman. Single-Chain Fv-Based Anti-HIV Proteins: Potential and Limitations. J. Virol., 86(1):195-202, Jan 2012. PubMed ID: 22013046.
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West2012a
Anthony P. West, Jr., Ron Diskin, Michel C. Nussenzweig, and Pamela J. Bjorkman. Structural Basis for Germ-Line Gene Usage of a Potent Class of Antibodies Targeting the CD4-Binding Site of HIV-1 gp120. Proc. Natl. Acad. Sci. U.S.A., 109(30):E2083-E2090, 24 Jul 2012. PubMed ID: 22745174.
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West2013
Anthony P. West, Jr., Louise Scharf, Joshua Horwitz, Florian Klein, Michel C. Nussenzweig, and Pamela J. Bjorkman. Computational Analysis of Anti-HIV-1 Antibody Neutralization Panel Data to Identify Potential Functional Epitope Residues. Proc. Natl. Acad. Sci. U.S.A., 110(26):10598-10603, 25 Jun 2013. PubMed ID: 23754383.
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Wieczorek2023
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Wiehe2018
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Wilen2011
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Williams2017a
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Wilson2021
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Witt2017
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Wright2012
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Wu2011
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Wu2012
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Wu2015
Xueling Wu, Zhenhai Zhang, Chaim A. Schramm, M. Gordon Joyce, Young Do Kwon, Tongqing Zhou, Zizhang Sheng, Baoshan Zhang, Sijy O'Dell, Krisha McKee, Ivelin S. Georgiev, Gwo-Yu Chuang, Nancy S. Longo, Rebecca M. Lynch, Kevin O. Saunders, Cinque Soto, Sanjay Srivatsan, Yongping Yang, Robert T. Bailer, Mark K. Louder, NISC Comparative Sequencing Program, James C. Mullikin, Mark Connors, Peter D. Kwong, John R. Mascola, and Lawrence Shapiro. Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection. Cell, 161(3):470-485, 23 Apr 2015. PubMed ID: 25865483.
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Wu2016
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Wu2018
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Yang2012
Lifei Yang, Yufeng Song, Xiaomin Li, Xiaoxing Huang, Jingjing Liu, Heng Ding, Ping Zhu, and Paul Zhou. HIV-1 Virus-Like Particles Produced by Stably Transfected Drosophila S2 Cells: A Desirable Vaccine Component. J. Virol., 86(14):7662-7676, Jul 2012. PubMed ID: 22553333.
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Yang2014
Lili Yang and Pin Wang. Passive Immunization against HIV/AIDS by Antibody Gene Transfer. Viruses, 6(2):428-447, Feb 2014. PubMed ID: 24473340.
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Yang2018
Zheng Yang, Xi Liu, Zehua Sun, Jingjing Li, Weiguo Tan, Weiye Yu, and Meiyun Zhang. Identification of a HIV gp41-Specific Human Monoclonal Antibody with Potent Antibody-Dependent Cellular Cytotoxicity. Front. Immunol., 9:2613, 2018. PubMed ID: 30519238.
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Yasmeen2014
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Yates2018
Nicole L. Yates, Allan C. deCamp, Bette T. Korber, Hua-Xin Liao, Carmela Irene, Abraham Pinter, James Peacock, Linda J. Harris, Sheetal Sawant, Peter Hraber, Xiaoying Shen, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapan, Phillip W. Berman, Merlin L. Robb, Giuseppe Pantaleo, Susan Zolla-Pazner, Barton F. Haynes, S. Munir Alam, David C. Montefiori, and Georgia D. Tomaras. HIV-1 Envelope Glycoproteins from Diverse Clades Differentiate Antibody Responses and Durability among Vaccinees. J. Virol., 92(8), 15 Apr 2018. PubMed ID: 29386288.
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Yu2018
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Zhang2013
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Zhou2010
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Zhou2013a
Tongqing Zhou, Jiang Zhu, Xueling Wu, Stephanie Moquin, Baoshan Zhang, Priyamvada Acharya, Ivelin S. Georgiev, Han R. Altae-Tran, Gwo-Yu Chuang, M. Gordon Joyce, Young Do Kwon, Nancy S. Longo, Mark K. Louder, Timothy Luongo, Krisha McKee, Chaim A. Schramm, Jeff Skinner, Yongping Yang, Zhongjia Yang, Zhenhai Zhang, Anqi Zheng, Mattia Bonsignori, Barton F. Haynes, Johannes F. Scheid, Michel C. Nussenzweig, Melissa Simek, Dennis R. Burton, Wayne C. Koff, NISC Comparative Sequencing Program, James C. Mullikin, Mark Connors, Lawrence Shapiro, Gary J. Nabel, John R. Mascola, and Peter D. Kwong. Multidonor Analysis Reveals Structural Elements, Genetic Determinants, and Maturation Pathway for HIV-1 Neutralization by VRC01-Class Antibodies. Immunity, 39(2):245-258, 22 Aug 2013. PubMed ID: 23911655.
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Zhou2015
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Tongqing Zhou, Nicole A. Doria-Rose, Cheng Cheng, Guillaume B. E. Stewart-Jones, Gwo-Yu Chuang, Michael Chambers, Aliaksandr Druz, Hui Geng, Krisha McKee, Young Do Kwon, Sijy O'Dell, Mallika Sastry, Stephen D. Schmidt, Kai Xu, Lei Chen, Rita E. Chen, Mark K. Louder, Marie Pancera, Timothy G. Wanninger, Baoshan Zhang, Anqi Zheng, S. Katie Farney, Kathryn E. Foulds, Ivelin S. Georgiev, M. Gordon Joyce, Thomas Lemmin, Sandeep Narpala, Reda Rawi, Cinque Soto, John-Paul Todd, Chen-Hsiang Shen, Yaroslav Tsybovsky, Yongping Yang, Peng Zhao, Barton F. Haynes, Leonidas Stamatatos, Michael Tiemeyer, Lance Wells, Diana G. Scorpio, Lawrence Shapiro, Adrian B. McDermott, John R. Mascola, and Peter D. Kwong. Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation. Cell Rep., 19(4):719-732, 25 Apr 2017. PubMed ID: 28445724.
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Zhu2013a
Jiang Zhu, Xueling Wu, Baoshan Zhang, Krisha McKee, Sijy O'Dell, Cinque Soto, Tongqing Zhou, Joseph P. Casazza, NISC Comparative Sequencing Program, James C. Mullikin, Peter D. Kwong, John R. Mascola, and Lawrence Shapiro. De Novo Identification of VRC01 Class HIV-1-Neutralizing Antibodies by Next-Generation Sequencing of B-Cell Transcripts. Proc. Natl. Acad. Sci. U.S.A., 110(43):E4088-E4097, 22 Oct 2013. PubMed ID: 24106303.
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Pegu2022
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Displaying record number 2165
Download this epitope
record as JSON.
MAb ID |
VRC03 (VRC03d45) |
HXB2 Location |
Env |
Env Epitope Map
|
Author Location |
gp120 |
Epitope |
|
Subtype |
B |
Ab Type |
gp120 CD4bs |
Neutralizing |
P View neutralization details |
Contacts and Features |
View contacts and features |
Species
(Isotype)
|
human(IgG1) |
Patient |
NIH45 |
Immunogen |
HIV-1 infection |
Keywords |
adjuvant comparison, antibody binding site, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autoantibody or autoimmunity, binding affinity, broad neutralizer, chronic infection, computational prediction, effector function, escape, germline, glycosylation, immunotherapy, kinetics, memory cells, mutation acquisition, neutralization, polyclonal antibodies, review, SIV, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity, viral fitness and/or reversion |
Notes
Showing 58 of
58 notes.
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VRC03: Eighty clusters of overlapping epitopes that could bind to MHC Class II HLA-DR1*01:01 (DR1) allele were identified by LC-MS/MS using a cell-free processing system that incorporated soluble DR1, HLA-DM (DM), cathepsins, and full-length protein antigens (Gag, Pol, Env, Vif, Tat, Rev, and Nef). Sixteen of Env CD4+ T cell epitopes identified in this study, which were primarily located in the vicinity of the gp120/gp41 interface or the CD4bs, were assessed for overlap with bnAb binding footprints. Only glycosylated EQF351-371 (EQFGNNKTIIFKQSSGGDPEIV) overlapped with the binding footprint of CD4bs-targeting bnAb VRC03.
Sengupta2023
(antibody binding site)
-
VRC03: Unbiased sequence analysis of B-cell receptor repertoirs from 57 uninfected and 46 chronic participants were used to inform a probabalistic model of bnAb likelihood of development. The lower the bnAb probability of development, the higher the predictive neutralization capacity and actual potency. The IGoR (Inference and Generation of Repertoires) tool was used to predict CDRH3 generation probability (Pgen) and point mutation accumulation probability (PSHM), and their combined probability score, S, along with giving a method of ranking bnAbs, was highly predictive of neutralization potency. Despite CDRH3 length and number of mutations being a strong determinant of bnAb probability, VRC03 was one Ab that did not have an elongated CDRH3, but is a potent bnAb. Untreated chronic individuals had a very slight correlation with longer CDRH3s but breadth of neutralization was not correlated with presence or absence of (ART) treatment. Overall, though, there is no difference in probability of bnAb development and generation with chronic disease state.
Kreer2023
(mutation acquisition, neutralization, computational prediction, antibody sequence, chronic infection)
-
VRC03: A panel of 30 contemporary subtype B pseudoviruses (PSVs) was generated. Neutralization sensitivities of these PSVs were compared with subtype B strains from earlier in the pandemic using 31 nAbs (PG9, PG16, PGT145, PGDM1400, CH02, CH03, CH04, 830A, PGT121, PGT126, PGT128, PGT130, 10-1074, 2192, 2219, 3074, 3869, 447-52D, b12, NIH45-46, VRC01, VRC03, 3BNC117, HJ16, sCD4, 10E8, 4E10, 2F5, 7H6, 2G12, 35O22). A significant reduction in Env neutralization sensitivity was observed for 27 out of 31 nAbs for the contemporary, as compared to earlier-decade subtype B PSVs. A decline in neutralization sensitivity was observed across all Env domains; the nAbs that were most potent early in the pandemic suffered the greatest decline in potency over time. A metaanalysis demonstrated this trend across multiple subtypes. As HIV-1 Env diversification continues, changes in Env antigenicity and neutralization sensitivity should continue to be evaluated to inform the development of improved vaccine and antibody products to prevent and treat HIV-1.
Wieczorek2023
(neutralization, viral fitness and/or reversion)
-
VRC03:This study identified a B cell lineage of bNAbs in an HIV-1 elite post-treatment controller (ePTC; donor: PTC-005002). Circulating viruses in PTC escaped bNAb pressure but remained sensitive to autologous neutralization by other Ab populations. VRC03 was used as a reference anti-CD4 Ab.
Molinos-Albert2023
(binding affinity)
-
VRC03: Two conserved tyrosine (Y) residues within the V2 loop of gp120, Y173 and Y177, were mutated individually or in combination, to either phenylalanine (F) or alanine (A) in several strains of diverse subtypes. In general, these mutations increased neutralization sensitivity, with a greater impact of Y177 over Y173 single mutations, of double over single mutations, and of A over F substitutions. The Y173A Y177A double mutation in HIV-1 BaL increased sensitivity to most of the weakly neutralizing MAbs tested (2158, 447-D, 268-D, B4e8, D19, 17b, 48d, 412d) and even rendered the virus sensitive to non-neutralizing antibodies against the CD4 binding site (F105, 654-30D, and b13). In the case of V2 mAb 697-30D, residue Y173 is part of its epitope, and thus abrogates its binding and has no effect on neutralization; the Y177A mutant alone did increase neutralization sensitivity to this mAb. When the double mutant was tested against bnAbs, there was a large decrease in neutralization sensitivity compared to WT for many bnAbs that target V1, V2, or V3 (PG9, PG16, VRC26.08, VRC38, PGT121, PGT122, PGT123, PGT126, PGT128, PGT130, PGT135, VRC24, CH103). The double mutation had lesser or no effect on neutralization by one V3 bnAb (2G12) and by most bnAbs targeting the CD4 binding site (VRC01, VRC07, VRC03, VRC-PG04, VRC-CH31, 12A12, 3BNC117, N6), the gp120-gp41 interface (35O22, PGT151), or the MPER (2F5, 4E10, 10E8).
Guzzo2018
(antibody binding site, neutralization)
-
VRC03: This study explored the basis of the neutralization resistance of tier 3 virus 253-11 (subtype CRF02_AG). Virus 253-11 was resistant to neutralization by 17b, b12, VRC03, F105, SCD4, CH12, Z13e1, PG16, PGT145, 2G12, PGT121, PGT126, PGT128, PGT130, 39F, F240, and 35O22; the virus was sensitive to 3BNC117, NIH45-46G54W, VRC01, 10E8, 2F5, 4E10, PG9, VRC26.26, 10-1074, and PGT151. Virus 253-11 was strikingly resistant to most tested antibodies that target V3/glycans, despite possessing key potential N-linked glycosylation sites, especially N301 and N332, needed for the recognition of this class of antibodies. The resistance of 253-11 was not associated with an unusually long V1/V2 loop, nor with polymorphisms in the V3 loop and N-linked glycosylation sites. The 253-11 MPER was rarely recognized by sera, but was more often recognized in a chimera consisting of a HIV-2 backbone with the 253-11 MPER, suggesting steric or kinetic hindrance of the MPER. Mutations in the 253-11 MPER previously reported to increase the lifetime of the prefusion Env conformation (Y681H, L669S), decreased the resistance of 253-11 to several mAbs, presumably destabilizing its otherwise stable, closed trimer structure. A crystal structure of a recombinant 253-11 SOSIP trimer revealed that the heptad repeat helices in gp41 are drawn in close proximity to the trimer axis and that gp120 protomers also showed a relatively compact form around the trimer axis.
Moyo2018
(neutralization, structure)
-
VRC03: Using subtype A BG505 Env structural information, improved variants of subtype B JRFL and subtype C 16055 Env native flexibly linked (NFL) trimers were generated. The trimer-derived (TD) residues that increased well-ordered, homogeneous, stable, and soluble trimers did not require positive or negative selection as previously needed [Guenaga2015, PLoS Pathos. 11(1):e1004570]. VRC03 recognition and avidity to the CD4bs was high, with binding to the JRFL NFL TD15 trimer being higher than to the 16055 NFL TD8 as was the case for other CD4bs-bnAbs tested, viz. VRC01 and VRC06.
Guenaga2015a
(antibody interactions, assay or method development, vaccine antigen design, structure)
-
VRC03: Cryo-electron microscopy (EM) of the cleaved, soluble SOSIP gp140 trimer complexed with CD4bs-binding bnAb PGV04 was studied at 5.8Å, facilitating study of Env V1/V2, V3, HR1 and HR2 domains and some shielding glycans. This provides further information on trimer assembly, gp120-gp41 interactions and the three-dimensional CD4bs epitope cluster. For instance, acidic residues in framework region 3 in the heavy chain (HFR3) of CD4bs antibodies VRC03 (also VRC06), 3BNC117 and 3BNC60 interact with basic residues on an adjacent protomer.
Lyumkis2013
(vaccine antigen design, structure)
-
VRC03: Native, well-ordered, soluble mimetics of the Env trimer from subtypes B (JRFL) and C (16055) were obtained from genetically identical samples of heterogeneous mixture of disordered Env SOSIPs. Negative selection by non-nAbs was used to remove disordered oligomers, leaving well-ordered trimers that were able to bind sCD4, a panel of bnAbs that bind CD4bs, and PGT15 which is a bnAb that binds only cleavage-dependent, well-ordered, Env trimer. Several biophysical techniques were used to interrogate the structure of the purified subtype B and C trimers. Trimer antigenicity was assessed by bio-layer interferometry against F105-like non-neutralizing Abs, and some bnAbs in solution. Quaternary epitope-preferring and trimer-specific (due to a long framework region that inserts into the Env V3 loops of adjacent promoters) Ab VRC03 does not bind open/disordered trimers well or recognize monomers, but recognizes these non-nAb negatively selected trimers.
Guenaga2015
(vaccine antigen design, subtype comparisons, structure)
-
VRC03: Some CD4-binding site Abs have greater env trimer binding due to quaternary contacts. This study engrafted the extended heavy-chain framework region 3 (FR3) loop of VRC03, which mediates quaternary interaction, onto several potent bnAbs, enabling them to reach an adjacent gp120 protomer. The interactive quaternary surface was delineated by solving the crystal structure of 2 of the chimeric antibodies. Chimerization enhances the neutralizing activity of several potent bNAbs against a majority of global HIV-1 strains. Compared to unmodified antibodies, the chimeric antibodies displayed lower autoreactivity and prolonged in vivo half-life in huFcRn mice and macaques. Thus, paratope engraftment may be used to expand the epitope repertory of natural antibodies, improving their functionality. VRC03 was tested for autoreactivity by 2 assays, and was not autoreactive in either assay.
Liu2019
(autoantibody or autoimmunity, neutralization)
-
VRC03: This study examined whether HIV-1-specific bnAbs are capable of cross-neutralizing simian immunodeficiency viruses (SIVs) from chimpanzees (n=11) or western gorillas (n=1). BnAbs directed against the epitopes at the CD4 binding site (VRC01, VRC03, VRC-PG04, VRC-CH03, VRC-CH31, F105, b13, NIH45-46G54W, 45-46m2, 45-46m7), V3 (10-1074, PGT121, PGT128, PGT135, and 2G12), and gp41-gp120 interface (8ANC195, 35O22, PGT151, PGT152, PGT158) failed to neutralize SIVcpz and SIVgor strains. V2-directed bNabs (PG9, PG16, PGT145) as well as llama-derived heavy-chain only antibodies recognizing the CD4 binding site or gp41 epitopes (JM4, J3, 3E3, 2E7, 11F1F, Bi-2H10) were either completely inactive or neutralized only a fraction of SIVcpz strains. In contrast, neutralization of SIVcpz and SIVgor strains was achieved with low-nanomolar potency by one antibody targeting the MPER region of gp41 (10E8), as well as functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Igmim2, CD4-218.3-E51, CD4-218.3-E51-mim2), mono- and bispecific anti-human CD4 mAbs (iMab, PG9-iMab, PG16-iMab, LM52, LM52-PGT128), and CCR5 receptor mAbs (PRO140, PRO140-10E8). Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5, and neutralized SIVcpz in chimpanzee CD4+ T cells. These findings provide new insight into the protective capacity of anti-HIV-1 bnAbs and identify candidates for further development to combat SIV infection.
Barbian2015
(neutralization, SIV, binding affinity)
-
VRC03: In vertically-infected infant AIIMS731, a rare HIV-1 mutation in hypervariable loop 2 (L184F) was studied. In patient sequences, this mutation was present in the majority of clones. A panel of 6 V2 bnAbs (PG9, PG16, PGT145, PGDM1400, CAP256.25, and CH01) was assayed for neutralization of 6 patient viral clones. The AIIMS731 viral variants segregated into 4 neutralization-sensitive and 2 resistant clones; sensitive clones carried 184F, while resistant clones carried the rare 184L mutation. A large panel of bnAbs targeting non-V2 epitopes was used to assess the neutralization of the 6 patient viral variants. The bnAb panel consisted of V3/N332 glycan supersite bnAbs (10-1074, BG18, AIIMS-P01, PGT121, PGT128, and PGT135), CD4bs bnAbs (VRC01, VRC03, VRC07-523LS, N6, 3BNC117, and NIH45-46 G54W), a silent face-targeting bnAb (PG05), fusion peptide and gp120-gp41 interface bnAbs (PGT151, 35O22, and N123-VRC34.01), and MPER bnAbs (10E8, 4E10, and 2F5). All of these bnAbs had similar neutralization efficiencies for all 6 clones, suggesting that the L184F mutation was specific for viral escape from neutralization by V2 apex bnAbs. A panel of non-neutralizing mAbs (V3 loop-targeting non-nAbs 447-52D and 19b, and CD4-induced non-nAbs 17b, A32, 48d, and b6), were also assessed; 2 of the variants (the same 2 susceptible to the V2 bnAbs) showed moderate neutralization by 447-52D, 19b, 17b, and 48d. The structure of ligand-free BG505 SOSIP trimer revealed that the side chain of L184 was outward facing and did not make significant intraprotomeric interactions, but upon mutating L184 to F184, a disruption of the accessible surface between the bulky side chain of F184 on one protomer and R165 on the neighboring protomer was seen. Thus, the L184F mutation resulted in increased susceptibility to neutralization by antibodies known to target the relatively more open conformation of Env on tier 1 viruses, suggesting that the rare L184F mutation allowed Env to sample more open states resembling the CD4-bound conformation where the CCR5 binding site is exposed.
Mishra2020
(neutralization, polyclonal antibodies)
-
VRC03: This study inferred a high-probability unmutated common ancestor (UCA) of the VRC01 lineage and reconstructed the stages of lineage maturation, including a phylogeny of 45 naturally-paired mAbs from donor NIH45. Nine new lineage members were isolated from donor NIH45, named DH651.1 - DH561.9. The study also derived VH and VL reverted forms of several VRC01-class mAbs derived from other donors (12A12, 3BNC60, 3BNC117, VRC20, VRC23, and VRC18b). Early mutations within the VRC01 lineage defined maturation pathways toward limited or broad neutralization, suggesting that focusing the immune response is likely required to steer B-cell maturation toward the development of neutralization breadth. VRC01 lineage bnAbs with long CDR H3s overcame the HIV-1 N276 glycan barrier without shortening their CDR L1, revealing a solution for broad neutralization in which the heavy chain, not CDR L1, is the determinant to accommodate the N276 glycan. An X-ray structure and molecular dynamics simulation of VRC08 were studied to elucidate this process.
Bonsignori2018
(neutralization, structure, antibody lineage)
-
VRC03: Since cross-reactive antibodies can interfere in immunoassays, HIV-1 mAbs were tested for binding to the SARS-COV-2 spike (S) protein (SARS-COV-2 S cross-reactivity). The following 9 gp120-epitope binding HIV-1 mAbs are cross-reactive with COV-2 S: 2G12, PGT121, PGT126, PGT128, PGT145, PG9, PG16, 10-1074, and 35O22. CD4bs Abs VRC01 and VRC03 are not cross-reactive. Cross-reactivity of the 9 HIV-1 Abs was through glycoepitopes. Glycan-dependent, V3-loop-binding PGT126 and PGT128 as well as 2G12 were the strongest binders of COV-2 S and were found to be immunoreactive but incapable of neutralization or antibody-dependent enhancement (ADE).
Mannar2021
(antibody interactions, effector function, glycosylation, computational prediction, antibody polyreactivity)
-
VRC03: This study demonstrated that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens eliciting Ab responses with greater neutralization breadth. Data from four large virus panels were used to comprehensively map viral signatures associated with bNAb sensitivity, hypervariable region characteristics, and clade effects. The bNAb signatures defined for the V2 epitope region were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine which resulted in increased breadth of nAb responses compared with Env 459C alone. VRC03 was used for analyzing clade sensitivity.
Bricault2019
(antibody binding site, neutralization, vaccine antigen design, computational prediction, broad neutralizer)
-
VRC03: The influence of a V2 State 2/3-stabilizing Env mutation, L193A, on ADCC responses mediated by sera from HIV-1-infected individuals was evaluated. Conformations spontaneously sampled by the Env trimer at the surface of infected cells had a significant impact on ADCC. State 1-preferring ligand VRC03 recognized L193A variants of CH58 and CH77 IMCs with less efficiently compared to the WT.
Prevost2018
(effector function)
-
VRC03: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. VRC03 was isolated from human B cell clones and is functionally similar to VRC01. Antigenic region CD4 binding site (Table:1)
Walker2018
(antibody binding site, review, broad neutralizer)
-
VRC03: A panel of bnAbs were studied to assess ongoing adaptation of the HIV-1 species to the humoral immunity of the human population. Resistance to neutralization is increasing over time, but concerns only the external glycoprotein gp120, not the MPER, suggesting a high selective pressure on gp120. Almost all the identified major neutralization epitopes of gp120 are affected by this antigenic drift, suggesting that gp120 as a whole has progressively evolved in less than 3 decades.
Bouvin-Pley2014
(neutralization)
-
VRC03: Assays of poly- and autoreactivity demonstrated that broadly neutralizing NAbs are significantly more poly- and autoreactive than non-neutralizing NAbs. VRC03 is neither autoreactive nor polyreactive.
Liu2015a
(autoantibody or autoimmunity, antibody polyreactivity)
-
VRC03: This study describes a computational method to calculate the binding affinities of antibodies and antigens. The method called free-energy perturbation (FEP) was developed using HIV-1 Env gp120 and 3 VRC01-class mAbs, VRC01, VRC03, and VRC-PG04.
Clark2017
(binding affinity, structure)
-
VRC03: This study performed cyclical permutation of the V1 loop of JRFL in order to develop better gp120 trimers to elicit neutralizing antibodies. Some mutated trimers showed improved binding to several mAbs, including VRC01, VRC03, VRC-PG04, PGT128, PGT145, PGDM1400, b6, and F105. Guinea pigs immunized with prospective trimers showed improved neutralization of a panel of HIV-1 pseudoviruses.
Kesavardhana2017
(vaccine antigen design, vaccine-induced immune responses)
-
VRC03: This study investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit NAbs. Rabbits were immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). N197 glycan- and residue 230- removal conferred sensitivity to Trimer VLP sera and DNA trimer sera respectively, showing for the first time that strain-specific holes in the "glycan fence" can allow the development of tier 2 NAbs to native spikes. All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. All the neutralizing rabbit sera showed significant competition with CD4bs mAbs VRC03, VRC07, b12 and 1F7.
Crooks2015
(glycosylation, neutralization)
-
VRC03: Env residue N197 on the BG505-SOSIP trimer was mutated to test the effect of its glycosylation on the binding kinetics of CD4BS and other mAbs. Removal of the glycan had little effect on the overall structure of the molecule. Its removal resulted in increased binding of CD4 and CD4BS antibodies (VRC01, VRC03, V3-3074), but little effect on bNAbs targeting other epitopes (PG9, PG16, PGT145, 17b, A32, 2G12, PGT121, PGT126). Two CD4BS-binding antibodies tested (b12, F105) had insufficient breadth to bind the BG505-SOSIP trimer. Removal of the N197 glycan may allow for the development of better SOSIP immunogens, particularly to elicit CD4BS-specific Abs.
Liang2016
(glycosylation, vaccine antigen design)
-
VRC03: Somatic hypermutation and affinity maturation improve an antibody's complementarity with its target epitope. Mass spectroscopy and X-ray structures were used to examine two classes of mAbs, CD4 binding Abs (VRC03, VRC-PG04) and V2 binding Abs (VRC26.01, VRC26.03, VRC26.10, PG16, CH03), to determine how specific mutations that occurred during maturation affected the binding of the mAbs to their target epitope.
Davenport2016
(structure, antibody lineage)
-
VRC03: Env trimer BG505 SOSIP.664 as well as the clade B trimer B41 SOSIP.664 were stabilized using a bifunctional aldehyde (glutaraldehye, GLA) or a heterobifunctional cross-linker, EDC/NHS with modest effects on antigenicity and barely any on biochemistry or structural morphology. ELISA, DSC and SPR were used to test recognition of the trimers by bNAbs, which was preserved and by weakly NAbs or non-NAbs, which was reduced. Cross-linking partially preserves quaternary morphology so that affinity chromatography by positive selection using quaternary epitope-specific bNAabs, and negative selection using non-NAbs, enriched antigenic characteristics of the trimers. Binding of the anti-CD4bs bNAb VRC03 to trimers was minimally affected by trimer cross-linking.
Schiffner2016
(assay or method development, binding affinity, structure)
-
VRC03: A new trimeric immunogen, BG505 SOSIP.664 gp140, was developed that bound and activated most known neutralizing antibodies but generally did not bind antibodies lacking neuralizing activity. This highly stable immunogen mimics the Env spike of subtype A transmitted/founder (T/F) HIV-1 strain, BG505. Anti-CD4bs bNAb VRC03 neutralized BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, and was shown to recognize and bind the immunogen too.
Sanders2013
(assay or method development, neutralization, binding affinity)
-
VRC03: This study described a natural interaction between Abs and mucin protein, especially, MUC16 that is enhanced in chronic HIV infection. Agalactosylated (G0) Abs demonstrated the highest binding to MUC16. Binding of Abs to epithelial cells was diminished following MUC16 knockdown, and the MUC16 N-linked glycans were critical for binding.These point to a novel opportunity to enrich Abs at mucosal sites by targeting Abs to MUC16 through changes in Fc glycosylation, potentially blocking viral movement. VRC03 produced in either wild-type or FUT8kd 293T cells to produce fucosylated or afucosylated Abs, respectively, was assayed for MUC16 binding by ELISA.
Gunn2016
-
VRC03: This study examined the neutralization of group N, O, and P primary isolates of HIV-1 by diverse antibodies. Cross-group neutralization was observed only with the bNAbs targeting the N160 glycan-V1/V2 site. Four group O isolates, 1 group N isolate, and the group P isolates were neutralized by PG9 and/or PG16 or PGT145 at low concentrations. None of the non-M primary isolates were neutralized by bNAbs targeting other regions, except 10E8, which weakly neutralized 2 group N isolates, and 35O22 which neutralized 1 group O isolate. Bispecific bNAbs (PG9-iMab and PG16-iMab) very efficiently neutralized all non-M isolates with IC50 below 1 ug/mL, except for 2 group O strains. Anti-CD4bs bNAb VRC03 was unable to neutralize any of the 16 tested non-M primary isolates at an IC50< 10µg/ml.
Morgand2015
(neutralization, subtype comparisons)
-
VRC03: The rate of maturation and extent of diversity for the VRC01 lineage were characterized through longitudinal sampling of peripheral B cell transcripts from donor 45 over 15 years and co-crystal structures. VRC01-lineage clades underwent continuous evolution, with rates of ˜2 substitutions per 100 nucleotides per year, comparable with HIV-1 evolution. 39 VRC01-lineage Abs segregated into three major clades, and all Abs from donor 45 contained a cysteine at position 98 (99 in some sequences due to a 1-aa insertion) which was used as a signature to assess membership in the VRC01 lineage. Of 1,041 curated NGS sequences assigned to the VRC01 lineage, six did not contain the cysteine while 1,035 did (99.4%). For this Ab CDR H3 length is 14 and VH changes 30%, Vk nucleotide change is 20%.
Wu2015
(antibody lineage)
-
VRC03: The human Ab gene repertoires of uninfected and HIV-1-infected individuals were studied at genomic DNA (gDNA) and cDNA levels to determine the frequencies of putative germline Ab genes of known HIV-1 bnAbs. All libraries were deep sequenced and analysed using IMGT/HighV-QUEST software (http://imgt.org/HighV-QUEST/index. The human gDNA Ab libraries were more diverse in heavy and light chain V-gene lineage usage than the cDNA libraries. This implied that the human gDNA Ab gene repertoires may have more potential than the cDNA repertoires to develop HIV-1 bnmAbs. Relatively high frequencies of the VH and VKs and VLs that used the same V-genes and had the same CDR3 lengths as known HIV-1 bnmAbs regardless of (D)J-gene usage. The putative germline genes were determined for a set of mAbs (b12, VRC01, VRC03, NIH45-46, 3BNC60, PG9, PGT127, and X5).
Zhang2013
(antibody lineage, germline)
-
VRC03: The effect of PNGS on viral infectivity and antibody neutralization (2F5, 4E10, b12, VRC01, VRC03, PG9, PG16, 3869) was evaluated through systemic mutations of each PNGS on CRF07_BC strain. Mutations at N197 (C2), N301 (V3), N442 (C4), and N625 (gp41) rendered the virus more susceptible to neutralization by MAbs that recognize the CD4 binding site or gp41. Generally, mutations on V4/V5 loops, C2/C3/C4 regions, and gp41 reduced the neutralization sensitivity to PG16. However, mutation of N289 (C2) made the virus more sensitive to both PG9 and PG16. Mutations at N142 (V1), N355 (C3) and N463 (V5) conferred resistance to neutralization by anti-gp41 MAbs. Available structural information of HIV Env and homology modeling was used to provide a structural basis for the observed biological effects of these mutations.
Wang2013
(neutralization, structure)
-
VRC03: The ability of bNAbs to inhibit the HIV cell entry was tested for b12, VRC01,VRC03, PG9, PG16, PGT121, 2F5, 10E8, 2G12. Among them, PGT121, VRC01, and VRC03 potently inhibited HIV entry into CD4+ T cells of infected individuals whose viremia was suppressed by ART.
Chun2014
(immunotherapy)
-
VRC03: Cross-group neutralization of HIV-1 isolates from groups M, N, O, and P was tested with diverse patient sera and bNAbs PG9, PG16, 4E10, b12, 2F5, 2G12, VRC01, VRC03, and HJ16. The primary isolates displayed a wide spectrum of sensitivity to neutralization by the human sera, with some cross-group neutralization clearly observed. Among the bNAbs, only PG9 and PG16 showed any cross-group neutralization. The group N prototype strain YBF30 was highly sensitive to neutralization by PG9, and the interaction between their key residues was confirmed by molecular modeling. The conservation of the PG9/PG16 epitope within groups M and N suggests its relevance as a vaccine immunogen.
Braibant2013
(neutralization, variant cross-reactivity)
-
VRC03: VCRC03 was one of 10 MAbs used to study chronic vs. consensus vs. transmitted/founder (T/F) gp41 Envs for immunogenicity. Consensus Envs were the most potent eliciters of response but could only neutralize tier 1 and some tier 2 viruses. T/F Envs elicited the greatest breadth of NAb response; and chronic Envs elicited the lowest level and narrowest response. This CD4BS binding Nab bound well at <10 nM to 1/5 chronic Envs, 0/6 Consensus Envs and 3/7 T/F Envs. It was the only antibody unable to bind Consensus-S gp140 Env.
Liao2013c
(antibody interactions, binding affinity)
-
VRC03: A highly conserved mechanism of exposure of ADCC epitopes on Env is reported, showing that binding of Env and CD4 within the same HIV-1 infected cell effectively exposes these epitopes. The mechanism might explain the evolutionary advantage of downregulation of cell surface CD4v by the Vpu and Nef proteins. VRC03 was used in CD4 coexpression and competitive binding assay.
Veillette2014
(effector function)
-
VRC03d45: The ontogeny of VRC01 class Abs was determined by enumerating VRC01-class characteristics in many donors by next-gen sequencing and X-ray crystallography. Analysis included VRC01 (donor NIH 45), VRC-PG04 (donor IAVI 74), VRC-CH31 (donor 0219), 3BNC117 (donor RU3), 12A21 (donor IAVI 57), and somatically related VRC-PG19,19b, 20, 20b MAbs from donor IAVI 23. Despite the sequence differences of VRC01-class Abs, exceeding 50%, Ab-gp120 cocrystal structures showed VRC01-class recognition to be remarkably similar.
Zhou2013a
(antibody sequence, structure, antibody lineage)
-
VRC03: Next generation sequencing was applied to a new donor C38 (different from donor NIH45) to identify VRC01 class bNAbs. VRC01 class heavy chains were selected through a cross-donor phylogenetic analysis. VRC01 class light chains were identified through a five-amino-acid sequence motif. (CDR L3 length of 5 amino acids and Q or E at position 96 (Kabat numbering) or position 4 within the CDR L3 sequence.) VRC03 was used to compare the heavy & light chain sequences as a template of VRC01 class Ab.
Zhu2013a
(antibody sequence)
-
VRC03: N276D was determined as the critical binding site of MAb HJ16 by resistance induction in a sensitive primary CRF02_AG strain. N-linked glycosylation site removing N276D mutation was responsible for resistance to HJ16 by site-directed mutagenesis in envs of the homologous CRF02_AG, as well as of a subtype A and a subtype C primary isolate. Sensitivity to the CD4bs VRC01 and VRC03 mAbs was increased in the N276D mutated viruses.
Balla-Jhagjhoorsingh2013
(glycosylation)
-
VRC03: A computational method to predict Ab epitopes at the residue level, based on structure and neutralization panels of diverse viral strains has been described. This method was evaluated using 19 Env-Abs, including VRC03, against 181 diverse HIV-1 strains with available Ab-Ag complex structures.
Chuang2013
(computational prediction)
-
VRC03: "Neutralization fingerprints" for 30 neutralizing antibodies were determined using a panel of 34 diverse HIV-1 strains. 10 antibody clusters were defined: VRC01-like, PG9-like, PGT128-like, 2F5-like, 10E8-like and separate clusters for b12, CD4, 2G12, HJ16, 8ANC195. This mAb belongs to VRC01-like cluster.
Georgiev2013
(neutralization)
-
VRC03: Cryoelectron tomography was used to determine structures of A12, m36, or m36/CD4 complexed to trimeric Env displayed on intact HIV-1 BaL virus. The steric interactions at the distal ends of the bound Ab moieties are likely to play a role in determining the rotation of gp120 as in A12 and b12 or without any quaternary structure change as in VRC03.
Meyerson2013
(antibody binding site, structure)
-
VRC03: Isolation of VRC06 and VRC06b MAbs from a slow progressor donor 45 is reported. This is the same donor from whom bnMAbs VRC01, VRC03 and NIH 45-46 were isolated and the new MAbs are clonal variants of VRC03. VRC03 was used as a control to compare neutralizing specificity of VRC06.
Li2012
-
VRC03: This is a comment on Tan2012. It is noted that Tran and colleagues used high-resolution 3D cryoelectron tomography to define the conformation of Env when bound to soluble CD4 and to a series of monoclonal antibodies. It was demonstrated that antibodies binding to the CD4 binding site or coreceptor binding site of Env may lead to significantly different conformations of the trimeric Env complex. VRC01 locks the complex in a closed conformation, while binding to soluble CD4 or the monoclonal antibody 17b fixed the trimer in an open conformation.
Wright2012
(review, structure)
-
VRC03: Previous cryo-electron tomographic studies were extended. A more complete picture of the HIV entry process was presented by showing that HIV-1 Env binding to either soluble CD4 (sCD4) or the co-receptor mimic 17b leads to the same structural opening, or activation, of the Env spike. Atudy also demonstrated structurally that the broadly neutralizing antibodies VRC01, VRC02, VRC03 are able to block this activation, locking Env in a state that resembles closed, native Env. The cryo-electron microscopic structure of soluble trimeric Env in the 17b-bound state is presented at ˜9 Å resolution, revealing it as a novel, activated intermediate conformation of trimeric Env that could serve as a new template for immunogen design.
Tran2012
(structure)
-
VRC03: A computational tool (Antibody Database) identifying Env residues affecting antibody activity was developed. As input, the tool incorporates antibody neutralization data from large published pseudovirus panels, corresponding viral sequence data and available structural information. The model consists of a set of rules that provide an estimated IC50 based on Env sequence data, and important residues are found by minimizing the difference between logarithms of actual and estimated IC50. The program was validated by analysis of MAb 8ANC195, which had unknown specificity. Predicted critical N-glycosylation for 8ANC195 were confirmed in vitro and in humanized mice. The key associated residues for each MAb are summarized in the Table 1 of the paper and also in the Neutralizing Antibody Contexts & Features tool at Los Alamos Immunology Database.
West2013
(glycosylation, computational prediction)
-
VRC03: Somatic hypermutations are preferably found in CDR loops, which alter the Ab combining sites, but not the overall structure of the variable domain. FWR of CDR are usually resistant to and less tolerant of mutations. This study reports that most bnAbs require somatic mutations in the FWRs which provide flexibility, increasing Ab breadth and potency. To determine the consequence of FWR mutations the framework residues were reverted to the Ab's germline counterpart (FWR-GL) and binding and neutralizing properties were then evaluated. Fig S4C described the comparison of Ab framework amino acid replacement vs. interactive surface area on VRC03.
Klein2013
(neutralization, structure, antibody lineage)
-
VRC03: Antigenic properties of 2 biochemically stable and homogeneous gp140 trimers (A clade 92UG037 and C clade CZA97012) were compared with the corresponding gp120 monomers derived from the same percursor sequences. The trimers had nearly all the antigenic properties expected for native viral spikes and were markedly different from monomeric gp120. VRC03 has been discussed as NAb against CD4BS.
Kovacs2012
(antibody binding site, neutralization, binding affinity)
-
VRC03: Existing structural and sequence data was analyzed. A set of signature features for potent VRC01-like (PVL) and almost PVL abs was proposed and verified by mutagenesis. VRC03 has been referred as an almost PVL in discussing the breadth and potency of antiCD4 abs.
West2012a
(antibody lineage)
-
VRC03: The use of computationally derived B cell clonal lineages as templates for HIV-1 immunogen design is discussed. VRC03 has been discussed in terms of immunogenic and functional characteristics of representative HIV-1 BnAbs and their reactions to antigens.
Haynes2012
(antibody interactions, memory cells, vaccine antigen design, review, antibody polyreactivity, broad neutralizer)
-
VRC03: Polyclonal B cell responses to conserved neutralization epitopes are reported. Cross-reactive plasma samples were identified and evaluated from 308 subjects tested. VRC03 was used as a control mAb in the comprehensive set of assays performed. Plasma sample C1-0219 showed binding and neutralizing activities against native Env trimers similar to VRC03 and b12. D368R mutant trimers completely knocked out VRC03 and b12 but partially reduced C1-0219 binding. C1-0219 was unaffected by the W479G mutant suggesting that its nAbs are more akin to b12 than to VRC03.
Tomaras2011
(neutralization, polyclonal antibodies)
-
VRC03: The rational design of vaccines to elicit broadly neutralizing antibodies to HIV-1 is discussed in relation to understanding of vaccine recognition sites, the structural basis of interaction with HIV-1 env and vaccine developmental pathways. Role of VRC03 has been discussed relating to humoral immune response during HIV1 infection and sites of HIV-1 vulnerability to neutralizing antibodies. VRC03 appears to target the site very effectively resulting in neutralization of ˜90% of circulating isolates.
Kwong2011
(antibody binding site, neutralization, vaccine antigen design, review)
-
VRC03: In order to increase recognition of CD4 by Env and to elicit stronger neutralizing antibodies against it, two Env probes were produced and tested - monomeric Env was stabilized by pocket filling mutations in the CD4bs (PF2) and trimeric Env was formed by appending trimerization motifs to soluble gp120/gp14. PF2-containing proteins were better recognized by bNMAb against CD4bs and more rapidly elicited neutralizing antibodies against the CD4bs. Trimeric Env, however, elicited a higher neutralization potency that mapped to the V3 region of gp120.
Feng2012
(neutralization)
-
VRC03: The strategy of incorporating extra glycans onto gp120 was explored, with the goal to occlude the epitopes of non-neutralizing MAbs while maintaining exposure of the b12 site. The focus was on the head-to-head comparison of the ability of 2 adjuvants, monophosphoryl lipid A (MPL) and Quil A, to promote CD4-specific Ab responses in mice immunized with the engineered mutant Q105N compared to gp120wt. Neutralizing and non-neutralizing antibodies targeting three areas on gp120 – the CD4bs (F105, b6, b12, b13, VRC01, VRC03 and CD4- IgG2), the glycosylated ‘silent face’ (2G12) and the V3 loop (B4e8) – were assessed for binding. The antibodies b6, b12, b13, VRC01 and 2G12 bound best to mutant Q105N, albeit with lower affinities than to gp120wt. Retention of b6 and b13 binding was not expected, but can be explained by their very similar mode of interaction with the CD4bs compared to b12. Abs F105 and VRC03 did not bind Q105N at all. The V3-specific antibody B4e8 did not bind to Q105N.
Ahmed2012
(adjuvant comparison, antibody binding site, glycosylation, neutralization, escape)
-
VRC03: VRC01 and VRC03 selection pressures were studied using viral quasispecies from 3 time points (2001, 2006, 2009) in donor 45, from whom VRC01 and VRC03 were initially isolated, and from several time points in 5 additional donors with broadly serum neutralizing Abs. 473 Envs were assessed in total. While most plasma derived autologous Env variants from donor 45 were highly resistant to VRC01, some 2001 Env clones (which are all resistant to VRC01) were sensitive to VRC03 and its clonal relatives VRC06 and VRC06b, suggesting that these mAbs might have evolved at a time point later than VRC01.
Wu2012
(escape)
-
VRC03: Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies was studied by isolation of VRC01-like neutralizers with CD4bs probe; structural definition of gp120 recognition by RSC3-identified antibodies from different donors; functional complementation of heavy and light chains among VRC01-like antibodies; identification of VRC01 antibodies by 454 pyrosequencing; and cross-donor phylogenetic analysis of sequences derived from the same precursor germline gene. VRC03 bound to YU2 gp120 wild type and several mutated proteins, HXB2 gp120 and antigenically resurfaced protein RSC3, but not bound to gp120 YU2 D368R, D368R/I420R and M475S/R476A mutants. gp120-Fab VRC03 complex was crystallized. Heavy- and light-chain cross-pairing chimeras of VRC01, VRC03, VRC-PG04, VRC-CH31 could neutralize up to 90% of 20 clade A, B and C viruses. Thousands of heavy and light chain sequences were found by 454 pyrosequencing, of which 109 sequences, all of IGHV1-2*02 origin, had >90% sequence identity to VRC03, although sequence identity to VRC01 and VRC02 heavy chains was below 75%. Dozens chimeric antibodies obtained by pairing heavy-chain sequences with VRC03 and PG04 light chains and light-chain sequences with VRC01, VRC03,PG04 heavy chains displayed potent neutralization (up to 90%) of A, B and C clade viruses.
Wu2011
(neutralization, antibody sequence, structure)
-
VRC03: Two SHIV-C mutants were designed: SHIV-1157ipEL-pΔ3N, a mutant of the early SHIV-1157ipEL-p which lacked the 3N residues in the V2 stem, and SHIV-1157ipd3N4+3N, a mutant of the late SHIV-1157ipd3N4 where 3N residues was added in the V2 stem. VRC03 neutralizes all four SHIV-Cs and avoids the conformational masking by the V2 loop in SHIV-Cs.
Watkins2011
(neutralization)
-
VRC03: This review discusses current understanding of Env neutralization by antibodies in relation to epitope exposure and how this insight might benefit vaccine design strategies. This MAb is in the list of current MAbs with notable cross-neutralizing activity.
Pantophlet2010
(neutralization, variant cross-reactivity, review)
-
VRC03: This broadly neutralizing Ab was derived from B-cells from a donor that were screened for CD4bs mAbs with resurfaced stabilized core 3 (RSC3) protein. The protein was designed to preserve the antigenic structure of the gp120 CD4bs neutralizing surface but eliminate other antigenic regions of HIV-1. VRC03 neutralized 57% of 190 virus strains of different HIV-1 clades. VRC03 bound strongly to RSC3 and was highly somatically mutated. Binding of VRC03 to gp120 was competed by b12 and F105. Unlike for VRC01 and VRC02, binding of 17b was not enhanced by the addition of VRC03.
Wu2010
(antibody binding site, antibody generation, antibody interactions, neutralization, variant cross-reactivity, kinetics, binding affinity, antibody sequence)
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Balla-Jhagjhoorsingh2013
Sunita S. Balla-Jhagjhoorsingh, Davide Corti, Leo Heyndrickx, Elisabeth Willems, Katleen Vereecken, David Davis, and Guido Vanham. The N276 Glycosylation Site Is Required for HIV-1 Neutralization by the CD4 Binding Site Specific HJ16 Monoclonal Antibody. PLoS One, 8(7):e68863, 2013. PubMed ID: 23874792.
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Barbian2015
Hannah J. Barbian, Julie M. Decker, Frederic Bibollet-Ruche, Rachel P. Galimidi, Anthony P. West, Jr., Gerald H. Learn, Nicholas F. Parrish, Shilpa S. Iyer, Yingying Li, Craig S. Pace, Ruijiang Song, Yaoxing Huang, Thomas N. Denny, Hugo Mouquet, Loic Martin, Priyamvada Acharya, Baoshan Zhang, Peter D. Kwong, John R. Mascola, C. Theo Verrips, Nika M. Strokappe, Lucy Rutten, Laura E. McCoy, Robin A. Weiss, Corrine S. Brown, Raven Jackson, Guido Silvestri, Mark Connors, Dennis R. Burton, George M. Shaw, Michel C. Nussenzweig, Pamela J. Bjorkman, David D. Ho, Michael Farzan, and Beatrice H. Hahn. Neutralization Properties of Simian Immunodeficiency Viruses Infecting Chimpanzees and Gorillas. mBio, 6(2), 21 Apr 2015. PubMed ID: 25900654.
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Bonsignori2018
Mattia Bonsignori, Eric Scott, Kevin Wiehe, David Easterhoff, S. Munir Alam, Kwan-Ki Hwang, Melissa Cooper, Shi-Mao Xia, Ruijun Zhang, David C. Montefiori, Rory Henderson, Xiaoyan Nie, Garnett Kelsoe, M. Anthony Moody, Xuejun Chen, M. Gordon Joyce, Peter D. Kwong, Mark Connors, John R. Mascola, Andrew T. McGuire, Leonidas Stamatatos, Max Medina-Ramirez, Rogier W. Sanders, Kevin O. Saunders, Thomas B. Kepler, and Barton F. Haynes. Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier. Immunity, 49(6):1162-1174.e8, 18 Dec 2018. PubMed ID: 30552024.
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Bouvin-Pley2014
M. Bouvin-Pley, M. Morgand, L. Meyer, C. Goujard, A. Moreau, H. Mouquet, M. Nussenzweig, C. Pace, D. Ho, P. J. Bjorkman, D. Baty, P. Chames, M. Pancera, P. D. Kwong, P. Poignard, F. Barin, and M. Braibant. Drift of the HIV-1 Envelope Glycoprotein gp120 Toward Increased Neutralization Resistance over the Course of the Epidemic: A Comprehensive Study Using the Most Potent and Broadly Neutralizing Monoclonal Antibodies. J. Virol., 88(23):13910-13917, Dec 2014. PubMed ID: 25231299.
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Braibant2013
Martine Braibant, Eun-Yeung Gong, Jean-Christophe Plantier, Thierry Moreau, Elodie Alessandri, François Simon, and Francis Barin. Cross-Group Neutralization of HIV-1 and Evidence for Conservation of the PG9/PG16 Epitopes within Divergent Groups. AIDS, 27(8):1239-1244, 15 May 2013. PubMed ID: 23343910.
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Bricault2019
Christine A. Bricault, Karina Yusim, Michael S. Seaman, Hyejin Yoon, James Theiler, Elena E. Giorgi, Kshitij Wagh, Maxwell Theiler, Peter Hraber, Jennifer P. Macke, Edward F. Kreider, Gerald H. Learn, Beatrice H. Hahn, Johannes F. Scheid, James M. Kovacs, Jennifer L. Shields, Christy L. Lavine, Fadi Ghantous, Michael Rist, Madeleine G. Bayne, George H. Neubauer, Katherine McMahan, Hanqin Peng, Coraline Chéneau, Jennifer J. Jones, Jie Zeng, Christina Ochsenbauer, Joseph P. Nkolola, Kathryn E. Stephenson, Bing Chen, S. Gnanakaran, Mattia Bonsignori, LaTonya D. Williams, Barton F. Haynes, Nicole Doria-Rose, John R. Mascola, David C. Montefiori, Dan H. Barouch, and Bette Korber. HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design. Cell Host Microbe, 25(1):59-72.e8, 9 Jan 2019. PubMed ID: 30629920.
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Chuang2013
Gwo-Yu Chuang, Priyamvada Acharya, Stephen D. Schmidt, Yongping Yang, Mark K. Louder, Tongqing Zhou, Young Do Kwon, Marie Pancera, Robert T. Bailer, Nicole A. Doria-Rose, Michel C. Nussenzweig, John R. Mascola, Peter D. Kwong, and Ivelin S. Georgiev. Residue-Level Prediction of HIV-1 Antibody Epitopes Based on Neutralization of Diverse Viral Strains. J. Virol., 87(18):10047-10058, Sep 2013. PubMed ID: 23843642.
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Chun2014
Tae-Wook Chun, Danielle Murray, Jesse S. Justement, Jana Blazkova, Claire W. Hallahan, Olivia Fankuchen, Kathleen Gittens, Erika Benko, Colin Kovacs, Susan Moir, and Anthony S. Fauci. Broadly Neutralizing Antibodies Suppress HIV in the Persistent Viral Reservoir. Proc. Natl. Acad. Sci. U.S.A., 111(36):13151-13156, 9 Sep 2014. PubMed ID: 25157148.
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Clark2017
Anthony J. Clark, Tatyana Gindin, Baoshan Zhang, Lingle Wang, Robert Abel, Colleen S. Murret, Fang Xu, Amy Bao, Nina J. Lu, Tongqing Zhou, Peter D. Kwong, Lawrence Shapiro, Barry Honig, and Richard A. Friesner. Free Energy Perturbation Calculation of Relative Binding Free Energy between Broadly Neutralizing Antibodies and the gp120 Glycoprotein of HIV-1. J. Mol. Biol., 429(7):930-947, 7 Apr 2017. PubMed ID: 27908641.
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Crooks2015
Ema T. Crooks, Tommy Tong, Bimal Chakrabarti, Kristin Narayan, Ivelin S. Georgiev, Sergey Menis, Xiaoxing Huang, Daniel Kulp, Keiko Osawa, Janelle Muranaka, Guillaume Stewart-Jones, Joanne Destefano, Sijy O'Dell, Celia LaBranche, James E. Robinson, David C. Montefiori, Krisha McKee, Sean X. Du, Nicole Doria-Rose, Peter D. Kwong, John R. Mascola, Ping Zhu, William R. Schief, Richard T. Wyatt, Robert G. Whalen, and James M. Binley. Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site. PLoS Pathog, 11(5):e1004932, May 2015. PubMed ID: 26023780.
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Davenport2016
Thaddeus M. Davenport, Jason Gorman, M. Gordon Joyce, Tongqing Zhou, Cinque Soto, Miklos Guttman, Stephanie Moquin, Yongping Yang, Baoshan Zhang, Nicole A. Doria-Rose, Shiu-Lok Hu, John R. Mascola, Peter D. Kwong, and Kelly K. Lee. Somatic Hypermutation-Induced Changes in the Structure and Dynamics of HIV-1 Broadly Neutralizing Antibodies. Structure, 20 Jul 2016. PubMed ID: 27477385.
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Feng2012
Yu Feng, Krisha McKee, Karen Tran, Sijy O'Dell, Stephen D. Schmidt, Adhuna Phogat, Mattias N. Forsell, Gunilla B. Karlsson Hedestam, John R. Mascola, and Richard T. Wyatt. Biochemically Defined HIV-1 Envelope Glycoprotein Variant Immunogens Display Differential Binding and Neutralizing Specificities to the CD4-Binding Site. J. Biol. Chem., 287(8):5673-5686, 17 Feb 2012. PubMed ID: 22167180.
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Georgiev2013
Ivelin S. Georgiev, Nicole A. Doria-Rose, Tongqing Zhou, Young Do Kwon, Ryan P. Staupe, Stephanie Moquin, Gwo-Yu Chuang, Mark K. Louder, Stephen D. Schmidt, Han R. Altae-Tran, Robert T. Bailer, Krisha McKee, Martha Nason, Sijy O'Dell, Gilad Ofek, Marie Pancera, Sanjay Srivatsan, Lawrence Shapiro, Mark Connors, Stephen A. Migueles, Lynn Morris, Yoshiaki Nishimura, Malcolm A. Martin, John R. Mascola, and Peter D. Kwong. Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization. Science, 340(6133):751-756, 10 May 2013. PubMed ID: 23661761.
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Guenaga2015
Javier Guenaga, Natalia de Val, Karen Tran, Yu Feng, Karen Satchwell, Andrew B. Ward, and Richard T. Wyatt. Well-Ordered Trimeric HIV-1 Subtype B and C Soluble Spike Mimetics Generated by Negative Selection Display Native-Like Properties. PLoS Pathog., 11(1):e1004570, Jan 2015. PubMed ID: 25569572.
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Guenaga2015a
Javier Guenaga, Viktoriya Dubrovskaya, Natalia de Val, Shailendra K. Sharma, Barbara Carrette, Andrew B. Ward, and Richard T. Wyatt. Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers. J. Virol., 90(6):2806-2817, 30 Dec 2015. PubMed ID: 26719252.
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Gunn2016
B. M. Gunn, J. R. Schneider, M. Shansab, A. R. Bastian, K. M. Fahrbach, A. D. Smith, A. E. Mahan, M. M. Karim, A. F. Licht, I. Zvonar, J. Tedesco, M. R. Anderson, A. Chapel, T. J. Suscovich, D. C. Malaspina, H. Streeck, B. D. Walker, A. Kim, G. Lauer, M. Altfeld, S. Pillai, I. Szleifer, N. L. Kelleher, P. F. Kiser, T. J. Hope, and G. Alter. Enhanced Binding of Antibodies Generated During Chronic HIV Infection to Mucus Component MUC16. Mucosal. Immunol., 9(6):1549-1558, Nov 2016. PubMed ID: 26960182.
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Guzzo2018
Christina Guzzo, Peng Zhang, Qingbo Liu, Alice L. Kwon, Ferzan Uddin, Alexandra I. Wells, Hana Schmeisser, Raffaello Cimbro, Jinghe Huang, Nicole Doria-Rose, Stephen D. Schmidt, Michael A. Dolan, Mark Connors, John R. Mascola, and Paolo Lusso. Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation. mBio, 9(6), 11 Dec 2018. PubMed ID: 30538178.
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Haynes2012
Barton F. Haynes, Garnett Kelsoe, Stephen C. Harrison, and Thomas B. Kepler. B-Cell-Lineage Immunogen Design in Vaccine Development with HIV-1 as a Case Study. Nat. Biotechnol., 30(5):423-433, May 2012. PubMed ID: 22565972.
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Kesavardhana2017
Sannula Kesavardhana, Raksha Das, Michael Citron, Rohini Datta, Linda Ecto, Nonavinakere Seetharam Srilatha, Daniel DiStefano, Ryan Swoyer, Joseph G. Joyce, Somnath Dutta, Celia C. LaBranche, David C. Montefiori, Jessica A. Flynn, and Raghavan Varadarajan. Structure-Based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies. J. Biol. Chem., 292(1):278-291, 6 Jan 2017. PubMed ID: 27879316.
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Klein2013
Florian Klein, Ron Diskin, Johannes F. Scheid, Christian Gaebler, Hugo Mouquet, Ivelin S. Georgiev, Marie Pancera, Tongqing Zhou, Reha-Baris Incesu, Brooks Zhongzheng Fu, Priyanthi N. P. Gnanapragasam, Thiago Y. Oliveira, Michael S. Seaman, Peter D. Kwong, Pamela J. Bjorkman, and Michel C. Nussenzweig. Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization. Cell, 153(1):126-138, 28 Mar 2013. PubMed ID: 23540694.
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Kovacs2012
James M. Kovacs, Joseph P. Nkolola, Hanqin Peng, Ann Cheung, James Perry, Caroline A. Miller, Michael S. Seaman, Dan H. Barouch, and Bing Chen. HIV-1 Envelope Trimer Elicits More Potent Neutralizing Antibody Responses than Monomeric gp120. Proc. Natl. Acad. Sci. U.S.A., 109(30):12111-12116, 24 Jul 2012. PubMed ID: 22773820.
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Kreer2023
Christoph Kreer, Cosimo Lupo, Meryem S. Ercanoglu, Lutz Gieselmann, Natanael Spisak, Jan Grossbach, Maike Schlotz, Philipp Schommers, Henning Gruell, Leona Dold, Andreas Beyer, Armita Nourmohammad, Thierry Mora, Aleksandra M. Walczak, and Florian Klein. Probabilities of developing HIV-1 bNAb sequence features in uninfected and chronically infected individuals. Nat Commun, 14(1):7137 doi, Nov 2023. PubMed ID: 37932288
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Kwong2011
Peter D. Kwong, John R. Mascola, and Gary J. Nabel. Rational Design of Vaccines to Elicit Broadly Neutralizing Antibodies to HIV-1. Cold Spring Harb. Perspect. Med., 1(1):a007278, Sep 2011. PubMed ID: 22229123.
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Li2012
Yuxing Li, Sijy O'Dell, Richard Wilson, Xueling Wu, Stephen D. Schmidt, Carl-Magnus Hogerkorp, Mark K. Louder, Nancy S. Longo, Christian Poulsen, Javier Guenaga, Bimal K. Chakrabarti, Nicole Doria-Rose, Mario Roederer, Mark Connors, John R. Mascola, and Richard T. Wyatt. HIV-1 Neutralizing Antibodies Display Dual Recognition of the Primary and Coreceptor Binding Sites and Preferential Binding to Fully Cleaved Envelope Glycoproteins. J. Virol., 86(20):11231-11241, Oct 2012. PubMed ID: 22875963.
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Liang2016
Yu Liang, Miklos Guttman, James A. Williams, Hans Verkerke, Daniel Alvarado, Shiu-Lok Hu, and Kelly K. Lee. Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan. J. Virol., 90(20):9224-9236, 15 Oct 2016. PubMed ID: 27489265.
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Liao2013c
Hua-Xin Liao, Chun-Yen Tsao, S. Munir Alam, Mark Muldoon, Nathan Vandergrift, Ben-Jiang Ma, Xiaozhi Lu, Laura L. Sutherland, Richard M. Scearce, Cindy Bowman, Robert Parks, Haiyan Chen, Julie H. Blinn, Alan Lapedes, Sydeaka Watson, Shi-Mao Xia, Andrew Foulger, Beatrice H. Hahn, George M. Shaw, Ron Swanstrom, David C. Montefiori, Feng Gao, Barton F. Haynes, and Bette Korber. Antigenicity and Immunogenicity of Transmitted/Founder, Consensus, and Chronic Envelope Glycoproteins of Human Immunodeficiency Virus Type 1. J. Virol., 87(8):4185-4201, Apr 2013. PubMed ID: 23365441.
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Liu2015a
Mengfei Liu, Guang Yang, Kevin Wiehe, Nathan I. Nicely, Nathan A. Vandergrift, Wes Rountree, Mattia Bonsignori, S. Munir Alam, Jingyun Gao, Barton F. Haynes, and Garnett Kelsoe. Polyreactivity and Autoreactivity among HIV-1 Antibodies. J. Virol., 89(1):784-798, Jan 2015. PubMed ID: 25355869.
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Liu2019
Qingbo Liu, Yen-Ting Lai, Peng Zhang, Mark K. Louder, Amarendra Pegu, Reda Rawi, Mangaiarkarasi Asokan, Xuejun Chen, Chen-Hsiang Shen, Gwo-Yu Chuang, Eun Sung Yang, Huiyi Miao, Yuge Wang, Anthony S. Fauci, Peter D. Kwong, John R. Mascola, and Paolo Lusso. Improvement of Antibody Functionality by Structure-Guided Paratope Engraftment. Nat. Commun., 10(1):721, 13 Feb 2019. PubMed ID: 30760721.
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Lyumkis2013
Dmitry Lyumkis, Jean-Philippe Julien, Natalia de Val, Albert Cupo, Clinton S. Potter, Per-Johan Klasse, Dennis R. Burton, Rogier W. Sanders, John P. Moore, Bridget Carragher, Ian A. Wilson, and Andrew B. Ward. Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV-1 Envelope Trimer. Science, 342(6165):1484-1490, 20 Dec 2013. PubMed ID: 24179160.
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Mannar2021
Dhiraj Mannar, Karoline Leopold, and Sriram Subramaniam. Glycan Reactive Anti-HIV-1 Antibodies bind the SARS-CoV-2 Spike Protein But Do Not Block Viral Entry. Sci. Rep., 11(1):12448, 14 Jun 2021. PubMed ID: 34127709.
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Meyerson2013
Joel R. Meyerson, Erin E. H. Tran, Oleg Kuybeda, Weizao Chen, Dimiter S. Dimitrov, Andrea Gorlani, Theo Verrips, Jeffrey D. Lifson, and Sriram Subramaniam. Molecular Structures of Trimeric HIV-1 Env in Complex with Small Antibody Derivatives. Proc. Natl. Acad. Sci. U.S.A., 110(2):513-518, 8 Jan 2013. PubMed ID: 23267106.
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Mishra2020
Nitesh Mishra, Shaifali Sharma, Ayushman Dobhal, Sanjeev Kumar, Himanshi Chawla, Ravinder Singh, Bimal Kumar Das, Sushil Kumar Kabra, Rakesh Lodha, and Kalpana Luthra. A Rare Mutation in an Infant-Derived HIV-1 Envelope Glycoprotein Alters Interprotomer Stability and Susceptibility to Broadly Neutralizing Antibodies Targeting the Trimer Apex. J. Virol., 94(19), 15 Sep 2020. PubMed ID: 32669335.
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Molinos-Albert2023
Luis M. Molinos-Albert, Eduard Baquero, Melanie Bouvin-Pley, Valerie Lorin, Caroline Charre, Cyril Planchais, Jordan D. Dimitrov, Valerie Monceaux, Matthijn Vos, Laurent Hocqueloux, Jean-Luc Berger, Michael S. Seaman, Martine Braibant, Veronique Avettand-Fenoel, Asier Saez-Cirion, and Hugo Mouquet. Anti-V1/V3-glycan broadly HIV-1 neutralizing antibodies in a post-treatment controller. Cell Host Microbe, 31(8):1275-1287e8 doi, Aug 2023. PubMed ID: 37433296
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Morgand2015
Marion Morgand, Mélanie Bouvin-Pley, Jean-Christophe Plantier, Alain Moreau, Elodie Alessandri, François Simon, Craig S. Pace, Marie Pancera, David D. Ho, Pascal Poignard, Pamela J. Bjorkman, Hugo Mouquet, Michel C. Nussenzweig, Peter D. Kwong, Daniel Baty, Patrick Chames, Martine Braibant, and Francis Barin. A V1V2 Neutralizing Epitope Is Conserved in Divergent Non-M Groups of HIV-1. J. Acquir. Immune Defic. Syndr., 21 Sep 2015. PubMed ID: 26413851.
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Moyo2018
Thandeka Moyo, June Ereño-Orbea, Rajesh Abraham Jacob, Clara E. Pavillet, Samuel Mundia Kariuki, Emily N. Tangie, Jean-Philippe Julien, and Jeffrey R. Dorfman. Molecular Basis of Unusually High Neutralization Resistance in Tier 3 HIV-1 Strain 253-11. J. Virol., 92(14), 15 Jul 2018. PubMed ID: 29618644.
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Pantophlet2010
Ralph Pantophlet. Antibody Epitope Exposure and Neutralization of HIV-1. Curr. Pharm. Des., 16(33):3729-3743, 2010. PubMed ID: 21128886.
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Prevost2018
Jérémie Prévost, Jonathan Richard, Shilei Ding, Beatriz Pacheco, Roxanne Charlebois, Beatrice H Hahn, Daniel E Kaufmann, and Andrés Finzi. Envelope Glycoproteins Sampling States 2/3 Are Susceptible to ADCC by Sera from HIV-1-Infected Individuals. Virology, 515:38-45, Feb 2018. PubMed ID: 29248757.
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Sanders2013
Rogier W. Sanders, Ronald Derking, Albert Cupo, Jean-Philippe Julien, Anila Yasmeen, Natalia de Val, Helen J. Kim, Claudia Blattner, Alba Torrents de la Peña, Jacob Korzun, Michael Golabek, Kevin de los Reyes, Thomas J. Ketas, Marit J. van Gils, C. Richter King, Ian A. Wilson, Andrew B. Ward, P. J. Klasse, and John P. Moore. A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but not Non-Neutralizing Antibodies. PLoS Pathog., 9(9):e1003618, Sep 2013. PubMed ID: 24068931.
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Schiffner2016
Torben Schiffner, Natalia de Val, Rebecca A. Russell, Steven W. de Taeye, Alba Torrents de la Peña, Gabriel Ozorowski, Helen J. Kim, Travis Nieusma, Florian Brod, Albert Cupo, Rogier W. Sanders, John P. Moore, Andrew B. Ward, and Quentin J. Sattentau. Chemical Cross-Linking Stabilizes Native-Like HIV-1 Envelope Glycoprotein Trimer Antigens. J. Virol., 90(2):813-828, 28 Oct 2015. PubMed ID: 26512083.
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Tomaras2011
Georgia D. Tomaras, James M. Binley, Elin S. Gray, Emma T. Crooks, Keiko Osawa, Penny L. Moore, Nancy Tumba, Tommy Tong, Xiaoying Shen, Nicole L. Yates, Julie Decker, Constantinos Kurt Wibmer, Feng Gao, S. Munir Alam, Philippa Easterbrook, Salim Abdool Karim, Gift Kamanga, John A. Crump, Myron Cohen, George M. Shaw, John R. Mascola, Barton F. Haynes, David C. Montefiori, and Lynn Morris. Polyclonal B Cell Responses to Conserved Neutralization Epitopes in a Subset of HIV-1-Infected Individuals. J. Virol., 85(21):11502-11519, Nov 2011. PubMed ID: 21849452.
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Tran2012
Erin E. H. Tran, Mario J. Borgnia, Oleg Kuybeda, David M. Schauder, Alberto Bartesaghi, Gabriel A. Frank, Guillermo Sapiro, Jacqueline L. S. Milne, and Sriram Subramaniam. Structural Mechanism of Trimeric HIV-1 Envelope Glycoprotein Activation. PLoS Pathog., 8(7):e1002797, 2012. PubMed ID: 22807678.
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Veillette2014
Maxime Veillette, Anik Désormeaux, Halima Medjahed, Nour-Elhouda Gharsallah, Mathieu Coutu, Joshua Baalwa, Yongjun Guan, George Lewis, Guido Ferrari, Beatrice H. Hahn, Barton F. Haynes, James E. Robinson, Daniel E. Kaufmann, Mattia Bonsignori, Joseph Sodroski, and Andres Finzi. Interaction with Cellular CD4 Exposes HIV-1 Envelope Epitopes Targeted by Antibody-Dependent Cell-Mediated Cytotoxicity. J. Virol., 88(5):2633-2644, Mar 2014. PubMed ID: 24352444.
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Walker2018
Laura M. Walker and Dennis R. Burton. Passive Immunotherapy of Viral Infections: `Super-Antibodies' Enter the Fray. Nat. Rev. Immunol., 18(5):297-308, May 2018. PubMed ID: 29379211.
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Wang2013
Wenbo Wang, Jianhui Nie, Courtney Prochnow, Carolyn Truong, Zheng Jia, Suting Wang, Xiaojiang S. Chen, and Youchun Wang. A Systematic Study of the N-Glycosylation Sites of HIV-1 Envelope Protein on Infectivity and Antibody-Mediated Neutralization. Retrovirology, 10:14, 2013. PubMed ID: 23384254.
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Watkins2011
Jennifer D. Watkins, Juan Diaz-Rodriguez, Nagadenahalli B. Siddappa, Davide Corti, and Ruth M. Ruprecht. Efficiency of Neutralizing Antibodies Targeting the CD4-Binding Site: Influence of Conformational Masking by the V2 Loop in R5-Tropic Clade C Simian-Human Immunodeficiency Virus. J Virol, 85(23):12811-12814, Dec 2011. PubMed ID: 21957314.
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West2012a
Anthony P. West, Jr., Ron Diskin, Michel C. Nussenzweig, and Pamela J. Bjorkman. Structural Basis for Germ-Line Gene Usage of a Potent Class of Antibodies Targeting the CD4-Binding Site of HIV-1 gp120. Proc. Natl. Acad. Sci. U.S.A., 109(30):E2083-E2090, 24 Jul 2012. PubMed ID: 22745174.
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West2013
Anthony P. West, Jr., Louise Scharf, Joshua Horwitz, Florian Klein, Michel C. Nussenzweig, and Pamela J. Bjorkman. Computational Analysis of Anti-HIV-1 Antibody Neutralization Panel Data to Identify Potential Functional Epitope Residues. Proc. Natl. Acad. Sci. U.S.A., 110(26):10598-10603, 25 Jun 2013. PubMed ID: 23754383.
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Wieczorek2023
Lindsay Wieczorek, Eric Sanders-Buell, Michelle Zemil, Eric Lewitus, Erin Kavusak, Jonah Heller, Sebastian Molnar, Mekhala Rao, Gabriel Smith, Meera Bose, Amy Nguyen, Adwitiya Dhungana, Katherine Okada, Kelly Parisi, Daniel Silas, Bonnie Slike, Anuradha Ganesan, Jason Okulicz, Tahaniyat Lalani, Brian K. Agan, Trevor A. Crowell, Janice Darden, Morgane Rolland, Sandhya Vasan, Julie Ake, Shelly J. Krebs, Sheila Peel, Sodsai Tovanabutra, and Victoria R. Polonis. Evolution of HIV-1 envelope towards reduced neutralization sensitivity, as demonstrated by contemporary HIV-1 subtype B from the United States. PLoS Pathog, 19(12):e1011780 doi, Dec 2023. PubMed ID: 38055771
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Wright2012
Elizabeth R. Wright and Paul W. Spearman. Unraveling the Structural Basis of HIV-1 Neutralization. Future Microbiol., 7(11):1251-1254, Nov 2012. PubMed ID: 23075444.
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Wu2011
Xueling Wu, Tongqing Zhou, Jiang Zhu, Baoshan Zhang, Ivelin Georgiev, Charlene Wang, Xuejun Chen, Nancy S. Longo, Mark Louder, Krisha McKee, Sijy O'Dell, Stephen Perfetto, Stephen D. Schmidt, Wei Shi, Lan Wu, Yongping Yang, Zhi-Yong Yang, Zhongjia Yang, Zhenhai Zhang, Mattia Bonsignori, John A. Crump, Saidi H. Kapiga, Noel E. Sam, Barton F. Haynes, Melissa Simek, Dennis R. Burton, Wayne C. Koff, Nicole A. Doria-Rose, Mark Connors, NISC Comparative Sequencing Program, James C. Mullikin, Gary J. Nabel, Mario Roederer, Lawrence Shapiro, Peter D. Kwong, and John R. Mascola. Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing. Science, 333(6049):1593-1602, 16 Sep 2011. PubMed ID: 21835983.
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Wu2012
Xueling Wu, Charlene Wang, Sijy O'Dell, Yuxing Li, Brandon F. Keele, Zhongjia Yang, Hiromi Imamichi, Nicole Doria-Rose, James A. Hoxie, Mark Connors, George M. Shaw, Richard T. Wyatt, and John R. Mascola. Selection Pressure on HIV-1 Envelope by Broadly Neutralizing Antibodies to the Conserved CD4-Binding Site. J. Virol., 86(10):5844-5856, May 2012. PubMed ID: 22419808.
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Wu2015
Xueling Wu, Zhenhai Zhang, Chaim A. Schramm, M. Gordon Joyce, Young Do Kwon, Tongqing Zhou, Zizhang Sheng, Baoshan Zhang, Sijy O'Dell, Krisha McKee, Ivelin S. Georgiev, Gwo-Yu Chuang, Nancy S. Longo, Rebecca M. Lynch, Kevin O. Saunders, Cinque Soto, Sanjay Srivatsan, Yongping Yang, Robert T. Bailer, Mark K. Louder, NISC Comparative Sequencing Program, James C. Mullikin, Mark Connors, Peter D. Kwong, John R. Mascola, and Lawrence Shapiro. Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection. Cell, 161(3):470-485, 23 Apr 2015. PubMed ID: 25865483.
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Zhang2013
Yu Zhang, Tingting Yuan, Jingjing Li, Yanyu Zhang, Jianqing Xu, Yiming Shao, Zhiwei Chen, and Mei-Yun Zhang. The Potential of the Human Immune System to Develop Broadly Neutralizing HIV-1 Antibodies: Implications for Vaccine Development. AIDS, 27(16):2529-2539, 23 Oct 2013. PubMed ID: 24100711.
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Zhou2013a
Tongqing Zhou, Jiang Zhu, Xueling Wu, Stephanie Moquin, Baoshan Zhang, Priyamvada Acharya, Ivelin S. Georgiev, Han R. Altae-Tran, Gwo-Yu Chuang, M. Gordon Joyce, Young Do Kwon, Nancy S. Longo, Mark K. Louder, Timothy Luongo, Krisha McKee, Chaim A. Schramm, Jeff Skinner, Yongping Yang, Zhongjia Yang, Zhenhai Zhang, Anqi Zheng, Mattia Bonsignori, Barton F. Haynes, Johannes F. Scheid, Michel C. Nussenzweig, Melissa Simek, Dennis R. Burton, Wayne C. Koff, NISC Comparative Sequencing Program, James C. Mullikin, Mark Connors, Lawrence Shapiro, Gary J. Nabel, John R. Mascola, and Peter D. Kwong. Multidonor Analysis Reveals Structural Elements, Genetic Determinants, and Maturation Pathway for HIV-1 Neutralization by VRC01-Class Antibodies. Immunity, 39(2):245-258, 22 Aug 2013. PubMed ID: 23911655.
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Zhu2013a
Jiang Zhu, Xueling Wu, Baoshan Zhang, Krisha McKee, Sijy O'Dell, Cinque Soto, Tongqing Zhou, Joseph P. Casazza, NISC Comparative Sequencing Program, James C. Mullikin, Peter D. Kwong, John R. Mascola, and Lawrence Shapiro. De Novo Identification of VRC01 Class HIV-1-Neutralizing Antibodies by Next-Generation Sequencing of B-Cell Transcripts. Proc. Natl. Acad. Sci. U.S.A., 110(43):E4088-E4097, 22 Oct 2013. PubMed ID: 24106303.
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Sengupta2023
Srona Sengupta, Josephine Zhang, Madison C. Reed, Jeanna Yu, Aeryon Kim, Tatiana N. Boronina, Nathan L. Board, James O. Wrabl, Kevin Shenderov, Robin A. Welsh, Weiming Yang, Andrew E. Timmons, Rebecca Hoh, Robert N. Cole, Steven G. Deeks, Janet D. Siliciano, Robert F. Siliciano, and Scheherazade Sadegh-Nasseri. A cell-free antigen processing system informs HIV-1 epitope selection and vaccine design. J Exp Med, 220(7):e20221654 doi, Jul 2023. PubMed ID: 37058141
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Displaying record number 2571
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record as JSON.
MAb ID |
VRC-PG04 (PG04,PGV04,VRC-PG04d74,PG-04,VRC-PG-04,VRC04,PV04) |
HXB2 Location |
Env |
Env Epitope Map
|
Author Location |
Env |
Epitope |
|
Subtype |
AD |
Ab Type |
gp120 CD4bs |
Neutralizing |
P View neutralization details |
Contacts and Features |
View contacts and features |
Species
(Isotype)
|
human(IgG) |
Patient |
Donor 74 |
Immunogen |
HIV-1 infection |
Keywords |
antibody binding site, antibody generation, antibody interactions, antibody lineage, antibody sequence, assay or method development, binding affinity, broad neutralizer, computational prediction, effector function, glycosylation, HIV-2, neutralization, review, SIV, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses |
Notes
Showing 51 of
51 notes.
-
VRC-PG04: Two conserved tyrosine (Y) residues within the V2 loop of gp120, Y173 and Y177, were mutated individually or in combination, to either phenylalanine (F) or alanine (A) in several strains of diverse subtypes. In general, these mutations increased neutralization sensitivity, with a greater impact of Y177 over Y173 single mutations, of double over single mutations, and of A over F substitutions. The Y173A Y177A double mutation in HIV-1 BaL increased sensitivity to most of the weakly neutralizing MAbs tested (2158, 447-D, 268-D, B4e8, D19, 17b, 48d, 412d) and even rendered the virus sensitive to non-neutralizing antibodies against the CD4 binding site (F105, 654-30D, and b13). In the case of V2 mAb 697-30D, residue Y173 is part of its epitope, and thus abrogates its binding and has no effect on neutralization; the Y177A mutant alone did increase neutralization sensitivity to this mAb. When the double mutant was tested against bnAbs, there was a large decrease in neutralization sensitivity compared to WT for many bnAbs that target V1, V2, or V3 (PG9, PG16, VRC26.08, VRC38, PGT121, PGT122, PGT123, PGT126, PGT128, PGT130, PGT135, VRC24, CH103). The double mutation had lesser or no effect on neutralization by one V3 bnAb (2G12) and by most bnAbs targeting the CD4 binding site (VRC01, VRC07, VRC03, VRC-PG04, VRC-CH31, 12A12, 3BNC117, N6), the gp120-gp41 interface (35O22, PGT151), or the MPER (2F5, 4E10, 10E8).
Guzzo2018
(antibody binding site, neutralization)
-
PGV04: The aggregation of SOSIP.681 soluble, cleaved KNH1144 subtype A trimers in the absence of nonionic detergent was circumvented by deletion of the MPER domain, resulting in SOSIP.664. These MPER-truncated trimers do not aggregate in the presence or absence of detergent, and are capable of binding CD4 as well as the CD4bs bnAb, PGV04. Trimer structure by negative- stain EM and interactions by surface plasmon resonance were unaffected.
Klasse2013
(vaccine antigen design, structure)
-
VRC PG04: Negative stain EM structural studies on complexes between VRC-PG04 and soluble cleaved timers of gp140 based on subtype A sequence KNH1144 were conducted using variants of the KNH1144 Env trimer. Variants of the Env trimer immunogen included deletions of of V1/V2 or V3 (variable loops), or MPER (membrane proximal external region) of gp41ECTO, studied free or complexed to sCD4 (soluble CD4), and observed against the Fab of bnAb VRC PG04. Lack of the variable loops or MPER (variant 664) did not change the morphology or binding of these SOSIP gp140 trimers, see PMID: 23824824 [Klasse2013, JVI: 87 (17):9873-9885]. Protein structure reconstructions are deposited in EMDB (Electron Microscopy Data Bank).
Khayat2013
(antibody interactions, neutralization, vaccine antigen design, structure)
-
PGV04: Cryo-electron microscopy (EM) of the cleaved, soluble SOSIP gp140 trimer complexed with CD4bs-binding bnAb PGV04 was studied at 5.8Å, facilitating study of Env V1/V2, V3, HR1 and HR2 domains and some shielding glycans. This provides further information on trimer assembly, gp120-gp41 interactions and the three-dimensional CD4bs epitope cluster. Glycan N276 interacts extensively with the Fab of PGV04. When the heavy chain of PGV04 binds the trimer at the CD4bs, it is within 5Å of a loop (residues 61–62) that precedes a short α-helix (α-0) in C1 of a neighboring gp120 protomer (similar to CD4 binding to CD4bs).
Lyumkis2013
(vaccine antigen design, structure)
-
PGV04: Native, well-ordered, soluble mimetics of the Env trimer from subtypes B (JRFL) and C (16055) were obtained from genetically identical samples of heterogeneous mixture of disordered Env SOSIPs. Negative selection by non-nAbs was used to remove disordered oligomers, leaving well-ordered trimers that were able to bind sCD4, a panel of bnAbs that bind CD4bs, and PGT15 which is a bnAb that binds only cleavage-dependent, well-ordered, Env trimer. Several biophysical techniques were used to interrogate the structure of the purified subtype B and C trimers. Trimer antigenicity was assessed by bio-layer interferometry against F105-like non-neutralizing Abs, and some bnAbs in solution. Like bnAb b12, PGV04 binds and neutralizes the parental JRFL strain but not the 16055 SOSIP trimer.
Guenaga2015
(vaccine antigen design, subtype comparisons, structure)
-
VRC-PG04: N-linked glycosylation of antibodies can increase their chemical heterogeneity, complicating their manufacture. VRC01-like antibodies were assessed for the presence of light chain (LC) glycosylation, with some showing the presence of LC glycosylation (N6, VRC01, 3BNC117, VRC-CH31,) and some not (12A12, VRC18, VRC-PG04, VRC-PG20, VRC23, DRVIA7). This study developed a method to remove variable domain (Fv) glycans from nAbs, and used this method to develop engineered versions of 4 antibodies (VRC26.25, N6, PGT121, and VRC07-523).
Chuang2020
(assay or method development, glycosylation)
-
VRC-PG04: This study examined whether HIV-1-specific bnAbs are capable of cross-neutralizing simian immunodeficiency viruses (SIVs) from chimpanzees (n=11) or western gorillas (n=1). BnAbs directed against the epitopes at the CD4 binding site (VRC01, VRC03, VRC-PG04, VRC-CH03, VRC-CH31, F105, b13, NIH45-46G54W, 45-46m2, 45-46m7), V3 (10-1074, PGT121, PGT128, PGT135, and 2G12), and gp41-gp120 interface (8ANC195, 35O22, PGT151, PGT152, PGT158) failed to neutralize SIVcpz and SIVgor strains. V2-directed bNabs (PG9, PG16, PGT145) as well as llama-derived heavy-chain only antibodies recognizing the CD4 binding site or gp41 epitopes (JM4, J3, 3E3, 2E7, 11F1F, Bi-2H10) were either completely inactive or neutralized only a fraction of SIVcpz strains. In contrast, neutralization of SIVcpz and SIVgor strains was achieved with low-nanomolar potency by one antibody targeting the MPER region of gp41 (10E8), as well as functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Igmim2, CD4-218.3-E51, CD4-218.3-E51-mim2), mono- and bispecific anti-human CD4 mAbs (iMab, PG9-iMab, PG16-iMab, LM52, LM52-PGT128), and CCR5 receptor mAbs (PRO140, PRO140-10E8). Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5, and neutralized SIVcpz in chimpanzee CD4+ T cells. These findings provide new insight into the protective capacity of anti-HIV-1 bnAbs and identify candidates for further development to combat SIV infection.
Barbian2015
(neutralization, SIV, binding affinity)
-
PGV04: Extensive analysis of new and existing crystal structures identifies conformation of soluble B41 SOSIP Env trimer intermediates induced by binding with CD4 alone or CD4 and mAb 17b or mAb b12 alone. CD4 or b12 binding induces large conformational rearrangements of gp41 subunits and consequent inaccessibility of the fusion peptide. A generated 7.4 Å cryo-EM structure of B41 SOSIP.664 in complex with VRC01-class mAb PGV04, which targets the CD4 binding site, was determined to be nearly identical to the structure of BG505 SOSIP.664 in complex with other VRC01-like mAbs.
Ozorowski2017
(structure)
-
VRC-PG04: An engineered Env outer domain(OD) eOD-GT8 60-mer nanoparticle has been reported as a priming immunogen for eliciting VRC01-class precursors. N-linked glycans were introduced into non-CD4bs surfaces of eOD-GT8 to mask irrelevant epitopes, and these mutants were evaluated in a mouse model that expressed diverse IgG heavy chains containing human IGHV1-2*02, the germline VRC01 VH segment. Compared to the parental eOD-GT8, a mutant with 5 added glycans stimulated significantly higher proportions of CD4bs-specific serum responses and VRC01-class precursors. The antibodies used to evaluate the antigens included VRC01, its V gene germline revertant VRC01 gl, the VRC-PG04 V gene germline revertant VRC-PG04 gl, a polyclonal rabbit anti-gp120 serum, two non-CD4bs monoclonal antibodies (X1A2 and X1C6) isolated from eOD-GT6 60-mer-immunized XenoMouse, and two non-CD4bs mAbs (mA9 and mE4) isolated from eOD-GT8 60-mer-immunized IGHV1-2 knockin mice.
Duan2018
(glycosylation, vaccine antigen design)
-
VRC-PG04: This paper presents the derivation of VRC-PG05, with details as previously noted in a patent application (Mascola2012). VRC-PG04 and VRC-PG05 were derived from the same patient sample, but are not clonally related and have different binding types. PG05 neutralized 27% of a 208-virus multiclade panel. The crystal structure and NMR of PG05 revealed that it recognizes the silent face of gp120, a region that is shielded by glycans and has had no previously reported antibody recognition.
Zhou2018
(antibody binding site, structure)
-
VRC-PG04: This study demonstrated that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens eliciting Ab responses with greater neutralization breadth. Data from four large virus panels were used to comprehensively map viral signatures associated with bNAb sensitivity, hypervariable region characteristics, and clade effects. The bNAb signatures defined for the V2 epitope region were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine which resulted in increased breadth of nAb responses compared with Env 459C alone. PG04 was used for analyzing clade sensitivity and the CD4b signature summaries.
Bricault2019
(antibody binding site, neutralization, vaccine antigen design, computational prediction, broad neutralizer)
-
VRC-PG04: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. VRC-PG04 was isolated from human B cell clones and is functionally similar to VRC01. Antigenic region CD4 binding site (Table:1).
Walker2018
(antibody binding site, review, broad neutralizer)
-
PGV04: The first cryo-EM structure of a cross-linked vaccine antigen was solved. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a bNAb PGV04 Fab fragment revealed how cross-linking affects key properties of the trimer. It was observed that density corresponding to highly specific glutaraldehyde (GLA) cross-links between gp120 monomers at the trimer apex and between gp120 and gp41 at the trimer interface that had strikingly little impact on overall trimer conformation, but critically enhanced trimer stability and improved Env antigenicity. Cross-links were also observed within gp120 at sites associated with the N241/N289 glycan hole that locally modified trimer antigenicity. SOSIP and GLA-SOSIP trimers were compared for antigenicity by ELISA, using a large panel of mAbs previously determined to react with BG505 Env. Non-NAbs globally lost reactivity (7-fold median loss of binding), likely because of covalent stabilization of the cross-linked ‘closed’ form of the GLA-SOSIP trimer that binds non-NAbs weakly or not at all. V3-specific non-NAbs showed 2.1–3.3-fold reduced binding. Three autologous rabbit monoclonal NAbs to the N241/N289 ‘glycan-hole’ surface, showed a median ˜1.5-fold reduction in binding. V3 non-NAb 4025 showed residual binding to the GLA-SOSIP trimer. By contrast, bNAbs like PGV04 broadly retained reactivity significantly better than non-NAbs, with exception of PGT145 (3.3-5.3 fold loss of binding in ELISA and SPR).
Schiffner2018
(vaccine antigen design, binding affinity, structure)
-
VRC-PG04: In the RV305 HIV-1 vaccine trial, two boosts of either ALVAC-HIV, AIDSVAX B/E gp120 or ALVAC-HIV + AIDSVAX B/E gp120 were given to HIV-1-uninfected RV144 vaccine-recipients. While no bNAb plasma activity was induced in this trial as well, an increased frequency of memory B cells that produce Env-specific anti-CD4bs antibodies with long HCDR3s was detected. In a binding assay, PGV04 binding was reduced by mutants of subtype B Env protein YU2.
Easterhoff2017
(binding affinity)
-
PGV04: Libraries of BG505 gp120 containing mutations were displayed on yeast and screened for binding to a panel of VRC01-class mAbs. Boosted VRC01 gH mice showed broad neutralization on a panel of N276A viruses, neutralization of fully native virus containing the N276 glycan site was limited to a single heterologous tier 2 isolate and was substantially less potent. The progress of vaccine-induced somatic hyper mutation, SHM, toward mature VRC01 was tested. For each VH1-2 sequence, the total number of amino-acid mutations and the number of amino-acid mutations shared with a panel of VRC01-class mAbs like VRC01, PGV04, PGV20, VRC-CH31, 3BNC60, and 12A12 were determined. Extremely deep Ab repertoire sequencing on two healthy HIV-naive individuals were performed to compute the frequency of randomly incorporated VRC01-class mutations in human VH1-2 Ab sequence.
Briney2016
(HIV-2, neutralization, vaccine antigen design)
-
VRC-PG04: This study describes a computational method to calculate the binding affinities of antibodies and antigens. The method called free-energy perturbation (FEP) was developed using HIV-1 Env gp120 and 3 VRC01-class mAbs, VRC01, VRC03, and VRC-PG04.
Clark2017
(binding affinity, structure)
-
PG04: The next generation of a computational neutralization fingerprinting (NFP) being used as a way to predict polyclonal Ab responses to HIV infection is presented. A new panel of 20 pseudoviruses, termed f61, was developed to aid in the assessment of experimental neutralization. This panel was used to assess 22 well-characterized bNAbs and mixtures thereof (HJ16, VRC01, 8ANC195, IGg1b12, PGT121, PGT128, PGT135, PG9, PGT151, 35O22, 10E8, 2F5, 4E10, VRC27, VRC-CH31, VRC-PG20, PG04, VRC23, 12A12, 3BNC117, PGT145, CH01). The new algorithms accurately predicted VRC01-like and PG9-like antibody specificities.
Doria-Rose2017
(neutralization, computational prediction)
-
PGV04: This study performed cyclical permutation of the V1 loop of JRFL in order to develop better gp120 trimers to elicit neutralizing antibodies. Some mutated trimers showed improved binding to several mAbs, including VRC01, VRC03, VRC-PG04, PGT128, PGT145, PGDM1400, b6, and F105. Guinea pigs immunized with prospective trimers showed improved neutralization of a panel of HIV-1 pseudoviruses.
Kesavardhana2017
(vaccine antigen design, vaccine-induced immune responses)
-
VRC-PG04: Somatic hypermutation and affinity maturation improve an antibody's complementarity with its target epitope. Mass spectroscopy and X-ray structures were used to examine two classes of mAbs, CD4 binding Abs (VRC03, VRC-PG04) and V2 binding Abs (VRC26.01, VRC26.03, VRC26.10, PG16, CH03), to determine how specific mutations that occurred during maturation affected the binding of the mAbs to their target epitope.
Davenport2016
(structure, antibody lineage)
-
VRC-PG04: This review classified and mapped the binding regions of 32 bNAbs isolated 2010-2016.
Wu2016
(review)
-
VRC-PG04: This study produced Env SOSIP trimers for clades A (strain BG505), B (strain JR-FL), and G (strain X1193). Based on simulations, the MAb-trimer structures of all MAbs tested needed to accommodate at least one glycan, including both antibodies known to require specific glycans (PG9, PGT121, PGT135, 8ANC195, 35O22) and those that bind the CD4-binding site (b12, CH103, HJ16, VRC01, VRC13). A subset of monoclonal antibodies bound to glycan arrays assayed on glass slides (VRC26.09, PGT121, 2G12, PGT128, VRC13, PGT151, 35O22), while most of the antibodies did not have affinity for oligosaccharide in the context of a glycan array (PG9, PGT145, PGDM1400, PGT135, b12, CH103, HJ16, VRC16, VRC01, VRC-PG04, VRC-CH31, VRC-PG20, 3BNC60, 12A12, VRC18b, VRC23, VRC27, 1B2530, 8ANC131, 8ANC134, 8ANC195).
Stewart-Jones2016
(antibody binding site, glycosylation, structure)
-
VRC-PG04: This study assessed the ADCC activity of antibodies of varied binding types, including CD4bs (b6, b12, VRC01, PGV04, 3BNC117), V2 (PG9, PG16), V3 (PGT126, PGT121, 10-1074), oligomannose (2G12), MPER (2F5, 4E10, 10E8), CD4i (17b, X5), C1/C5 (A32, C11), cluster I (240D, F240), and cluster II (98-6, 126-7). ADCC activity was correlated with binding to Env on the surfaces of virus-infected cells. ADCC was correlated with neutralization, but not always for lab-adapted viruses such as HIV-1 NLA-3. MAb PG04 had moderate to strong ADCC activity against cells infected with 3 of 3 strains tested.
vonBredow2016
(effector function)
-
PGV04: HIV-1 bNAb eptiope networks were predicted using 4 algorithms informed by neutralization assays using 282 Env from multiclade viruses. Patch clusters of possible Ab epitope regions were tested for significant sensitivity by site-directed mutagenesis. Epitope (Ab binding site) networks of critical Env residues for 21 bNAb (b12, PG9, PG16, PGT121, PGT122, PGT123, PGT125, PGT126, PGT127, PGT128, PGT130, PGT131, PGT135, PGT136, PGT137, PGT141, PGT142, PGT143, PGT144, PGT145 and PGV04) were delineated and found to be located mostly in variable loops of gp120, particularly in V1/V2.
Evans2014
(antibody binding site, computational prediction)
-
PGV04: Two stable homogenous gp140 Env trimer spikes, Clade A 92UG037.8 Env and Clade C C97ZA012 Env, were identified. 293T cells stably transfected with either presented fully functional surface timers, 50% of which were uncleaved. A panel of neutralizing and non-neutralizing Abs were tested for binding to the trimers. Consistent with CD4bs bNAbs, PGV04 bound cell surface tightly whether the trimer contained its C-terminal or not, and was competed out by sCD4. It was able to neutralize the 92UG037.8 HIV-1 isolate.
Chen2015
(neutralization, binding affinity)
-
PGV04: Factors that independently affect bNAb induction and evolution were identified as viral load, length of untreated infection, and viral diversity. Black subjects induced bNAbs more than white subjects, but this did not correlate with type of Ab response. Fingerprint analyses of induced bNAbs showed strong subtype dependency, with subtype B inducing significantly higher levels of CD4bs Abs and non-subtype B inducing V2-glycan specific Abs. Of the 239 bNAb antibody inducers found from 4,484 HIV-1 infected subjects,the top 105 inducers' neutralization fingerprint and epitope specificity was determined by comparison to the following antibodies - PG9, PG16, PGDM1400, PGT145 (V2 glycan); PGT121, PGT128, PGT130 (V3 glycan); VRC01, PGV04 (CD4bs) and PGT151 (interface) and 2F5, 4E10, 10E8 (MPER).
Rusert2016
(neutralization, subtype comparisons, broad neutralizer)
-
PGV04: PGT145 was used to positively isolate a subtype B Env trimer immunogen, B41 SOSIP.664-D7324, that exists in two conformations, closed and partially open. bNAbs tested against the trimer were able to neutralize the B41 pseudovirus with a wide range of potencies. All tested non-NAbs did not neutralize B41 (IC50 >50µg/ml). CD4bs bNAb, PGV04, was able to neutralize and bind B41 pseudovirus and trimer.
Pugach2015
-
PGV04: A new trimeric immunogen, BG505 SOSIP.664 gp140, was developed that bound and activated most known neutralizing antibodies but generally did not bind antibodies lacking neuralizing activity. This highly stable immunogen mimics the Env spike of subtype A transmitted/founder (T/F) HIV-1 strain, BG505. Anti-CD4bs bNAb PGV04 neutralized BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, and was shown to recognize and bind the immunogen too.
Sanders2013
(assay or method development, neutralization, binding affinity)
-
PG04: VRC01-class bNAb like PG04 protects animals from experimental infection and could contribute to an effective vaccine response. Their predicted germline forms (gl) bind Env inefficiently, which may explain why they are not elicited by HIV-1 Env-immunization. This paper describes modifications that expand the glVRC01-class antibody-recognition potential of the 426c Env.
McGuire2016
(antibody interactions, antibody lineage)
-
VRC-PG04: This study presented structures of germline-reverted VRC01-class bNAbs alone and complexed with 426c-based gp120 immunogens. Germline bNAb–426c gp120 complexes showed preservation of VRC01-class signature residues and gp120 contacts, but detectably different binding modes compared to mature bNAb-gp120 complexes. It reported that unlike most antibodies, the overall final structures of VRC01 class antibodies are formed before the antibodies mature. PG04 had the highest net charge of all the VRC01-class antibodies studied.
Scharf2016
(structure)
-
PG04: This patent describes the derivation and usage of PG04 and PG05. The donor is coded as 27-374, a participant in IAVI Protocol G. Both VRC-PG-04 and VRC-PG-05 were isolated from B cells of this donor by selection for binding to peptide RSC3. VRC-PG-04, but not VRC-PG-05, is cross competed by CD4bs antibodies. PG04 was able to neutralize a wide range of pseudovirus entry into TZM-bl cells, including pseudovirus from clade A - 87% (n=24), B - 96% (n=26), and C - 79% (n=34).
Mascola2012
(neutralization, broad neutralizer)
-
VRC-PG04: The rate of maturation and extent of diversity for the VRC01 lineage were characterized through longitudinal sampling of peripheral B cell transcripts from donor 45 over 15 years and co-crystal structures. VRC01-lineage clades underwent continuous evolution, with rates of ˜2 substitutions per 100 nucleotides per year, comparable with HIV-1 evolution. 39 VRC01-lineage Abs segregated into three major clades, and all Abs from donor 45 contained a cysteine at position 98 (99 in some sequences due to a 1-aa insertion) which was used as a signature to assess membership in the VRC01 lineage. Of 1,041 curated NGS sequences assigned to the VRC01 lineage, six did not contain the cysteine while 1,035 did (99.4%). Structural comparison of VRC-PG04 heavy and light chains and binding surfaces were reported (Table-S5).
Wu2015
(structure, antibody lineage)
-
VRC-PG04: This study isolated 4 novel antibodies that bind the CD4 binding site of Env. Population-level analysis classified a diverse group of CD4bs antibodies into two types: CDR H3-dominated or VH-gene-restricted, each with distinct ontogenies. Structural data revealed that neutralization breadth was correlated with angle of approach of the antibodies to the CD4 binding region. VRC-PG04 was one of the antibodies in the VH-gene-restricted VRC01 class.
Zhou2015
(neutralization, structure, antibody lineage, broad neutralizer)
-
PGV04: Incomplete neutralization may decrease the ability of bnAbs to protect against HIV exposure. In order to determine the extent of non-sigmoidal slopes that plateau at <100% neutralization, a panel of 24 bnMAbs targeting different regions on Env was tested in a quantitative pseudovirus neutralization assay on a panel of 278 viral clones. All bNAbs had some viruses that they neutralized with a plateau <100%, but those targeting the V2 apex and MPER did so more often. All bnMAbs assayed had some viruses for which they had incomplete neutralization and non-sigmoidal neutralization curves. bNAbs were grouped into 3 groups based on their neutralization curves: group 1 antibodies neutralized more than 90% of susceptible viruses to >95% (PGT121-123, PGT125-128, PGT136, PGV04); group 2 was less effective, resulting in neutralization of 60-84% of susceptible viruses to >95% (b12, PGT130-131, PGT135, PGT137, PGT141-143, PGT145, 2G12, PG9); group 3 neutralized only 36-60% of susceptible viruses to >95% (PG16, PGT144, 2F5, 4E10). Two CD4bs-targeting Abs, b12 and PGV04, had high potential neutralization values, perhaps reflecting relative insensitivity to Env glycan expression.
McCoy2015
(neutralization)
-
PGV04: Clade A Env sequence, BG505, was identified to bind to bNAbs representative of most of the known NAb classes. This sequence is the best natural sequence match (73%) to the MRCA sequence from 19 Env sequences derived from PG9 and PG16 MAbs' donor. A point mutation at position L111A of BG505 enabled more efficient production of a stable gp120 monomer, preserving the major neutralization epitopes. The antisera produced by this adjuvanted formulation of gp120 competed with bnAbs from 3 classes of non-overlapping epitopes. PGV04 showed very high neutralization titer against BG505 pseudovirus as shown in Table 1.
Hoffenberg2013
(antibody interactions, neutralization)
-
VRC-PG04d74: The ontogeny of VRC01 class Abs was determined by enumerating VRC01-class characteristics in many donors by next-gen sequencing and X-ray crystallography. Analysis included VRC01 (donor NIH 45), VRC-PG04 (donor IAVI 74), VRC-CH31 (donor 0219), 3BNC117 (donor RU3), 12A21 (donor IAVI 57), and somatically related VRC-PG19,19b, 20, 20b MAbs from donor IAVI 23. Despite the sequence differences of VRC01-class Abs, exceeding 50%, Ab-gp120 cocrystal structures showed VRC01-class recognition to be remarkably similar.
Zhou2013a
(antibody sequence, structure, antibody lineage)
-
VRC-PG04: Next generation sequencing was applied to a new donor C38 (different from donor NIH45) to identify VRC01 class bNAbs. VRC01 class heavy chains were selected through a cross-donor phylogenetic analysis. VRC01 class light chains were identified through a five-amino-acid sequence motif. (CDR L3 length of 5 amino acids and Q or E at position 96 (Kabat numbering) or position 4 within the CDR L3 sequence.) VRC-PG04 was used to compare the heavy & light chain sequences as a template of VRC01 class Ab.
Zhu2013a
(antibody sequence)
-
VRC-PG04: A computational method to predict Ab epitopes at the residue level, based on structure and neutralization panels of diverse viral strains has been described. This method was evaluated using 19 Env-Abs, including VRC-PG04, against 181 diverse HIV-1 strains with available Ab-Ag complex structures.
Chuang2013
(computational prediction)
-
VRC-PG04: "Neutralization fingerprints" for 30 neutralizing antibodies were determined using a panel of 34 diverse HIV-1 strains. 10 antibody clusters were defined: VRC01-like, PG9-like, PGT128-like, 2F5-like, 10E8-like and separate clusters for b12, CD4, 2G12, HJ16, 8ANC195. This mAb belongs to VRC01-like cluster.
Georgiev2013
(neutralization)
-
VRC-PG04: The antigenic properties of the HIV-1 Env outer domain were optimized to generate OD4.2.2 construct, from the KER2018 strain of clade A HIV-1, enabling it to bind antibodies such as VRC01 with nanomolar affinity. The crystal structure of OD4.2.2 in complex with VRC-PG04 was solved at 3.0-Å resolution and compared to known crystal structures. 1/3 of the outer domain structure appeared to be fixed in conformation, independent of alterations in termini, clade, or ligand, while other portions of the outer domain displayed substantial structural malleability.
Joyce2013
(structure)
-
VRC-PG04: A computational tool (Antibody Database) identifying Env residues affecting antibody activity was developed. As input, the tool incorporates antibody neutralization data from large published pseudovirus panels, corresponding viral sequence data and available structural information. The model consists of a set of rules that provide an estimated IC50 based on Env sequence data, and important residues are found by minimizing the difference between logarithms of actual and estimated IC50. The program was validated by analysis of MAb 8ANC195, which had unknown specificity. Predicted critical N-glycosylation for 8ANC195 were confirmed in vitro and in humanized mice. The key associated residues for each MAb are summarized in the Table 1 of the paper and also in the Neutralizing Antibody Contexts & Features tool at Los Alamos Immunology Database.
West2013
(glycosylation, computational prediction)
-
VRC-PG04: Identification of broadly neutralizing antibodies, their epitopes on the HIV-1 spike, the molecular basis for their remarkable breadth, and the B cell ontogenies of their generation and maturation are reviewed. Ontogeny and structure-based classification is presented, based on MAb binding site, type (structural mode of recognition), class (related ontogenies in separate donors) and family (clonal lineage). This MAb's classification: gp120 CD4-binding site, CD4-mimicry by heavy chain, VRC01 class, VRC-PG04 family.
Kwong2012
(review, structure, broad neutralizer)
-
VRC-PG04: This review discusses how analysis of infection and vaccine candidate-induced antibodies and their genes may guide vaccine design. This MAb is listed as CD4 binding site bnAb, isolated after 2009 by fluorescence-activated cell sorting (FACS) using a resurfaced core gp120 molecule (RSC3).
Bonsignori2012b
(vaccine antigen design, vaccine-induced immune responses, review)
-
VRC-PG04: Somatic hypermutations are preferably found in CDR loops, which alter the Ab combining sites, but not the overall structure of the variable domain. FWR of CDR are usually resistant to and less tolerant of mutations. This study reports that most bnAbs require somatic mutations in the FWRs which provide flexibility, increasing Ab breadth and potency. To determine the consequence of FWR mutations the framework residues were reverted to the Ab's germline counterpart (FWR-GL) and binding and neutralizing properties were then evaluated. VRC-PG04 was used in comparing the Ab framework amino acid replacement vs. interactive surface area on Ab.
Klein2013
(neutralization, structure, antibody lineage)
-
PGV04: Glycan shield of HIV Env protein helps to escape the Ab recognition. Several of the PGT BnAbs interact directly with the HIV glycan coat. Crystal structures of Fabs PGT127 and PGT128 showed that the high neutralizing potency was mediated by cross-linking Env trimers on the viral surface. PGT128 was compared and referred as an order of magnitude more potent than PGV04.
Pejchal2011
(glycosylation, structure, broad neutralizer)
-
PGV04: Computational and crystallographic analysis and in vitro screening were employed to design a gp120 outer domain immunogen (eOD-GT6) that could bind to VRC01-class bNAbs and to their germline precursors. When multimerized on nanoparticles, eOD-GT6 activated germline and mature VRC01-class B cells and thus can be a promising vaccine prime. eOD-GT6 had 10 mutations relative to HXB2. Removal of glycans at positions 276 and 463 was necessary for GL affinity and removal of glycans at positions 386 and 403 also improved affinity. T278R, I371F, N460V are involved in the binding interface. L260F, K357R, G471S stabilize loops involved in the interface. eOD-GT6 bound both PGV04 mature and germline antibodies.
Jardine2013
(glycosylation, vaccine antigen design, structure, antibody lineage)
-
VRC-PG04: In order to increase recognition of CD4 by Env and to elicit stronger neutralizing antibodies against it, two Env probes were produced and tested - monomeric Env was stabilized by pocket filling mutations in the CD4bs (PF2) and trimeric Env was formed by appending trimerization motifs to soluble gp120/gp14. PF2-containing proteins were better recognized by bNMAb against CD4bs and more rapidly elicited neutralizing antibodies against the CD4bs. Trimeric Env, however, elicited a higher neutralization potency that mapped to the V3 region of gp120.
Feng2012
(neutralization)
-
VRC-PG04: The sera of 113 HIV-1 seroconverters from three cohorts were analyzed for binding to a set of well-characterized gp120 core and resurfaced stabilized core (RSC3) protein probes, and their cognate CD4bs knockout mutants. VRC01-PG04 bound very strongly to the gp120 core and RSC3, strongly bound to RSC3/G367R and RSC3 Δ3711 and weakly bound to gp120 core D368R and RSC3 Δ3711/P363N.
Lynch2012
(binding affinity)
-
VRC-PG04: The interaction of CD4bs-binding MAbs (VRC01, VRC-PG04) and V1V2 glycan-dependent MAbs (PG9, PG16) was analyzed. MAb binding and neutralization studies showed that these two Env targets to not cross-compete and that their combination can mediate additive neutralization. The combination of MAbs VRC01 and PG9 provides a predicted coverage of 97% of 208 isolates at IC50 < 50 μg/ml and of 91% at IC50 < 50 μg/ml. In contrast, the combination of PG9 and PG16 (or the combination of VRC01 and VRC-PG04) was only marginally better than either MAb alone.
Doria-Rose2012
(antibody interactions)
-
PGV04: Using U87 target cells, PGV04 neutralized 88% of 162 viruses, with IC50<50 μm/mg, with U87 target cells compared to 75% neutralized by PG9. The potency of neutralization was comparable. On the 97-virus panel, using TZM-bl target cells, the breadth of neutralization was similar, but PGV04 had increased potency. The neutralization potency of PG9, PG16, VRC01 and PGV04 was approximately 10-fold greater than that of MAbs b12, 2G12, 2F5 and 4E10. Alanine substitutions D279A, I420A and I423A abrogated PGV04 neutralization, but varied in their effects on VRC01, CD4-IgG and b12. In contrast to VRC01, PGV04 did not enhance 17b or X5 binding to their epitopes in the co-receptor region on the gp120 monomer, and in contrast to CD4, none of the CD4bs MAbs tested induced the 17b site on trimeric cleaved Env, suggesting that a degree of mimicry of CD4 by anti-CD4bs bnMAbs may be a consequence of binding to the CD4 epitope on monomeric gp120 rather than a neutralization mechanism.
Falkowska2012
(antibody binding site, antibody interactions, neutralization, broad neutralizer)
-
PGV04: Neutralizing antibody repertoires of 4 HIV-infected donors with remarkably broad and potent neutralizing responses were probed. 17 new monoclonal antibodies that neutralize broadly across clades were rescued. All MAbs exhibited broad cross-clade neutralizing activity, but several showed exceptional potency. Although PGV04 neutralized 88% of 162 isolates at IC50<50 μg/ml, it was almost 10-fold less potent than several new antibodies PGT 121-123 and 125-128, for which the median antibody concentration required to inhibit HIV activity by 50% or 90% (IC50 and IC90 values) was almost 10-fold lower than that of PG9, VRC01 and PGV04.
Walker2011
(neutralization, broad neutralizer)
-
VRC-PG04: Somatically related VRC01-like Mabs VRC-PG04 and PG04b were isolated from donor 74 infected with an A/D recombinant virus. PG04 and RG04b strongly bound to YU2 gp120 wild type and mutated proteins, HXB2 gp120 and antigenically resurfaced protein RSC3, but showed >100-fold less binding to δRSC3. Binding by each of the new antibodies to the CD4bs was competed by VRC01-03, by other CD4-binding-site antibodies and by CD4-Ig, but not by antibodies known to bind gp120 at other sites. Sequence analysis revealed that, like other VRC01-like antibodies, RG04 and RG04b heavy chains originated from precursor gene allele IGHV1-2*02. The light chains originated from an IGkV3 allele. VRC-PG04 and PG04b displayed a heavy-chain–variable gene (VH) mutation frequency of 30% relative to the germline IGHV1-2*02 allele, a level of affinity maturation similar to that previously observed with VRC01-03. Both PG04 and PH04b are potent neutralizers - PG04 neutralized 76% of 178 isolates, representing major HIV-1 clades. The structure of VRC-PG04 in complex with gp120 showed striking similarity with the previously determined complex with VRC01, despite low sequence identity and different donors. Heavy- and light-chain cross-pairing chimeras of VRC01, VRC03, VRC-PG04, VRC-CH31 with each other and with sequences obtained by deep sequencing could neutralize up to 90% of 20 clade A, B and C viruses.
Wu2011
(antibody generation, neutralization, antibody sequence, structure)
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Hannah J. Barbian, Julie M. Decker, Frederic Bibollet-Ruche, Rachel P. Galimidi, Anthony P. West, Jr., Gerald H. Learn, Nicholas F. Parrish, Shilpa S. Iyer, Yingying Li, Craig S. Pace, Ruijiang Song, Yaoxing Huang, Thomas N. Denny, Hugo Mouquet, Loic Martin, Priyamvada Acharya, Baoshan Zhang, Peter D. Kwong, John R. Mascola, C. Theo Verrips, Nika M. Strokappe, Lucy Rutten, Laura E. McCoy, Robin A. Weiss, Corrine S. Brown, Raven Jackson, Guido Silvestri, Mark Connors, Dennis R. Burton, George M. Shaw, Michel C. Nussenzweig, Pamela J. Bjorkman, David D. Ho, Michael Farzan, and Beatrice H. Hahn. Neutralization Properties of Simian Immunodeficiency Viruses Infecting Chimpanzees and Gorillas. mBio, 6(2), 21 Apr 2015. PubMed ID: 25900654.
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Briney2016
Bryan Briney, Devin Sok, Joseph G. Jardine, Daniel W. Kulp, Patrick Skog, Sergey Menis, Ronald Jacak, Oleksandr Kalyuzhniy, Natalia de Val, Fabian Sesterhenn, Khoa M. Le, Alejandra Ramos, Meaghan Jones, Karen L. Saye-Francisco, Tanya R. Blane, Skye Spencer, Erik Georgeson, Xiaozhen Hu, Gabriel Ozorowski, Yumiko Adachi, Michael Kubitz, Anita Sarkar, Ian A. Wilson, Andrew B. Ward, David Nemazee, Dennis R. Burton, and William R. Schief. Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies. Cell, 166(6):1459-1470.e11, 8 Sep 2016. PubMed ID: 27610570.
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Chen2015
Jia Chen, James M. Kovacs, Hanqin Peng, Sophia Rits-Volloch, Jianming Lu, Donghyun Park, Elise Zablowsky, Michael S. Seaman, and Bing Chen. Effect of the Cytoplasmic Domain on Antigenic Characteristics of HIV-1 Envelope Glycoprotein. Science, 349(6244):191-195, 10 Jul 2015. PubMed ID: 26113642.
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Chuang2013
Gwo-Yu Chuang, Priyamvada Acharya, Stephen D. Schmidt, Yongping Yang, Mark K. Louder, Tongqing Zhou, Young Do Kwon, Marie Pancera, Robert T. Bailer, Nicole A. Doria-Rose, Michel C. Nussenzweig, John R. Mascola, Peter D. Kwong, and Ivelin S. Georgiev. Residue-Level Prediction of HIV-1 Antibody Epitopes Based on Neutralization of Diverse Viral Strains. J. Virol., 87(18):10047-10058, Sep 2013. PubMed ID: 23843642.
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Chuang2020
Gwo-Yu Chuang, Mangaiarkarasi Asokan, Vera B. Ivleva, Amarendra Pegu, Eun Sung Yang, Baoshan Zhang, Rajoshi Chaudhuri, Hui Geng, Bob C. Lin, Mark K. Louder, Krisha McKee, Sijy O'Dell, Hairong Wang, Tongqing Zhou, Nicole A. Doria-Rose, Lisa A. Kueltzo, Q. Paula Lei, John R. Mascola, and Peter D. Kwong. Removal of Variable Domain N-Linked Glycosylation as a Means To Improve the Homogeneity of HIV-1 Broadly Neutralizing Antibodies. mAbs, 12(1):1836719, 2020. PubMed ID: 33121334.
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Clark2017
Anthony J. Clark, Tatyana Gindin, Baoshan Zhang, Lingle Wang, Robert Abel, Colleen S. Murret, Fang Xu, Amy Bao, Nina J. Lu, Tongqing Zhou, Peter D. Kwong, Lawrence Shapiro, Barry Honig, and Richard A. Friesner. Free Energy Perturbation Calculation of Relative Binding Free Energy between Broadly Neutralizing Antibodies and the gp120 Glycoprotein of HIV-1. J. Mol. Biol., 429(7):930-947, 7 Apr 2017. PubMed ID: 27908641.
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Davenport2016
Thaddeus M. Davenport, Jason Gorman, M. Gordon Joyce, Tongqing Zhou, Cinque Soto, Miklos Guttman, Stephanie Moquin, Yongping Yang, Baoshan Zhang, Nicole A. Doria-Rose, Shiu-Lok Hu, John R. Mascola, Peter D. Kwong, and Kelly K. Lee. Somatic Hypermutation-Induced Changes in the Structure and Dynamics of HIV-1 Broadly Neutralizing Antibodies. Structure, 20 Jul 2016. PubMed ID: 27477385.
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Doria-Rose2012
Nicole A. Doria-Rose, Mark K. Louder, Zhongjia Yang, Sijy O'Dell, Martha Nason, Stephen D. Schmidt, Krisha McKee, Michael S. Seaman, Robert T. Bailer, and John R. Mascola. HIV-1 Neutralization Coverage Is Improved by Combining Monoclonal Antibodies That Target Independent Epitopes. J. Virol., 86(6):3393-3397, Mar 2012. PubMed ID: 22258252.
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Doria-Rose2017
Nicole A. Doria-Rose, Han R. Altae-Tran, Ryan S. Roark, Stephen D. Schmidt, Matthew S. Sutton, Mark K. Louder, Gwo-Yu Chuang, Robert T. Bailer, Valerie Cortez, Rui Kong, Krisha McKee, Sijy O'Dell, Felicia Wang, Salim S. Abdool Karim, James M. Binley, Mark Connors, Barton F. Haynes, Malcolm A. Martin, David C. Montefiori, Lynn Morris, Julie Overbaugh, Peter D. Kwong, John R. Mascola, and Ivelin S. Georgiev. Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting. PLoS Pathog., 13(1):e1006148, Jan 2017. PubMed ID: 28052137.
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Duan2018
Hongying Duan, Xuejun Chen, Jeffrey C. Boyington, Cheng Cheng, Yi Zhang, Alexander J. Jafari, Tyler Stephens, Yaroslav Tsybovsky, Oleksandr Kalyuzhniy, Peng Zhao, Sergey Menis, Martha C. Nason, Erica Normandin, Maryam Mukhamedova, Brandon J. DeKosky, Lance Wells, William R. Schief, Ming Tian, Frederick W. Alt, Peter D. Kwong, and John R. Mascola. Glycan Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies. Immunity, 49(2):301-311.e5, 21 Aug 2018. PubMed ID: 30076101.
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Easterhoff2017
David Easterhoff, M. Anthony Moody, Daniela Fera, Hao Cheng, Margaret Ackerman, Kevin Wiehe, Kevin O. Saunders, Justin Pollara, Nathan Vandergrift, Rob Parks, Jerome Kim, Nelson L. Michael, Robert J. O'Connell, Jean-Louis Excler, Merlin L. Robb, Sandhya Vasan, Supachai Rerks-Ngarm, Jaranit Kaewkungwal, Punnee Pitisuttithum, Sorachai Nitayaphan, Faruk Sinangil, James Tartaglia, Sanjay Phogat, Thomas B. Kepler, S. Munir Alam, Hua-Xin Liao, Guido Ferrari, Michael S. Seaman, David C. Montefiori, Georgia D. Tomaras, Stephen C. Harrison, and Barton F. Haynes. Boosting of HIV Envelope CD4 Binding Site Antibodies with Long Variable Heavy Third Complementarity Determining Region in the Randomized Double Blind RV305 HIV-1 Vaccine Trial. PLoS Pathog., 13(2):e1006182, Feb 2017. PubMed ID: 28235027.
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Evans2014
Mark C. Evans, Pham Phung, Agnes C. Paquet, Anvi Parikh, Christos J. Petropoulos, Terri Wrin, and Mojgan Haddad. Predicting HIV-1 Broadly Neutralizing Antibody Epitope Networks Using Neutralization Titers and a Novel Computational Method. BMC Bioinformatics, 15:77, 19 Mar 2014. PubMed ID: 24646213.
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Falkowska2012
Emilia Falkowska, Alejandra Ramos, Yu Feng, Tongqing Zhou, Stephanie Moquin, Laura M. Walker, Xueling Wu, Michael S. Seaman, Terri Wrin, Peter D. Kwong, Richard T. Wyatt, John R. Mascola, Pascal Poignard, and Dennis R. Burton. PGV04, an HIV-1 gp120 CD4 Binding Site Antibody, Is Broad and Potent in Neutralization but Does Not Induce Conformational Changes Characteristic of CD4. J. Virol., 86(8):4394-4403, Apr 2012. PubMed ID: 22345481.
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Feng2012
Yu Feng, Krisha McKee, Karen Tran, Sijy O'Dell, Stephen D. Schmidt, Adhuna Phogat, Mattias N. Forsell, Gunilla B. Karlsson Hedestam, John R. Mascola, and Richard T. Wyatt. Biochemically Defined HIV-1 Envelope Glycoprotein Variant Immunogens Display Differential Binding and Neutralizing Specificities to the CD4-Binding Site. J. Biol. Chem., 287(8):5673-5686, 17 Feb 2012. PubMed ID: 22167180.
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Georgiev2013
Ivelin S. Georgiev, Nicole A. Doria-Rose, Tongqing Zhou, Young Do Kwon, Ryan P. Staupe, Stephanie Moquin, Gwo-Yu Chuang, Mark K. Louder, Stephen D. Schmidt, Han R. Altae-Tran, Robert T. Bailer, Krisha McKee, Martha Nason, Sijy O'Dell, Gilad Ofek, Marie Pancera, Sanjay Srivatsan, Lawrence Shapiro, Mark Connors, Stephen A. Migueles, Lynn Morris, Yoshiaki Nishimura, Malcolm A. Martin, John R. Mascola, and Peter D. Kwong. Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization. Science, 340(6133):751-756, 10 May 2013. PubMed ID: 23661761.
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Guenaga2015
Javier Guenaga, Natalia de Val, Karen Tran, Yu Feng, Karen Satchwell, Andrew B. Ward, and Richard T. Wyatt. Well-Ordered Trimeric HIV-1 Subtype B and C Soluble Spike Mimetics Generated by Negative Selection Display Native-Like Properties. PLoS Pathog., 11(1):e1004570, Jan 2015. PubMed ID: 25569572.
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Hoffenberg2013
Simon Hoffenberg, Rebecca Powell, Alexei Carpov, Denise Wagner, Aaron Wilson, Sergei Kosakovsky Pond, Ross Lindsay, Heather Arendt, Joanne DeStefano, Sanjay Phogat, Pascal Poignard, Steven P. Fling, Melissa Simek, Celia LaBranche, David Montefiori, Terri Wrin, Pham Phung, Dennis Burton, Wayne Koff, C. Richter King, Christopher L. Parks, and Michael J. Caulfield. Identification of an HIV-1 Clade A Envelope That Exhibits Broad Antigenicity and Neutralization Sensitivity and Elicits Antibodies Targeting Three Distinct Epitopes. J. Virol., 87(10):5372-5383, May 2013. PubMed ID: 23468492.
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Jardine2013
Joseph Jardine, Jean-Philippe Julien, Sergey Menis, Takayuki Ota, Oleksandr Kalyuzhniy, Andrew McGuire, Devin Sok, Po-Ssu Huang, Skye MacPherson, Meaghan Jones, Travis Nieusma, John Mathison, David Baker, Andrew B. Ward, Dennis R. Burton, Leonidas Stamatatos, David Nemazee, Ian A. Wilson, and William R. Schief. Rational HIV Immunogen Design to Target Specific Germline B Cell Receptors. Science, 340(6133):711-716, 10 May 2013. PubMed ID: 23539181.
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Joyce2013
M. Gordon Joyce, Masaru Kanekiyo, Ling Xu, Christian Biertümpfel, Jeffrey C. Boyington, Stephanie Moquin, Wei Shi, Xueling Wu, Yongping Yang, Zhi-Yong Yang, Baoshan Zhang, Anqi Zheng, Tongqing Zhou, Jiang Zhu, John R. Mascola, Peter D. Kwong, and Gary J. Nabel. Outer Domain of HIV-1 gp120: Antigenic Optimization, Structural Malleability, and Crystal Structure with Antibody VRC-PG04. J. Virol., 87(4):2294-2306, Feb 2013. PubMed ID: 23236069.
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Kesavardhana2017
Sannula Kesavardhana, Raksha Das, Michael Citron, Rohini Datta, Linda Ecto, Nonavinakere Seetharam Srilatha, Daniel DiStefano, Ryan Swoyer, Joseph G. Joyce, Somnath Dutta, Celia C. LaBranche, David C. Montefiori, Jessica A. Flynn, and Raghavan Varadarajan. Structure-Based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies. J. Biol. Chem., 292(1):278-291, 6 Jan 2017. PubMed ID: 27879316.
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Khayat2013
Reza Khayat, Jeong Hyun Lee, Jean-Philippe Julien, Albert Cupo, Per Johan Klasse, Rogier W. Sanders, John P. Moore, Ian A. Wilson, and Andrew B. Ward. Structural Characterization of Cleaved, Soluble HIV-1 Envelope Glycoprotein Trimers. J. Virol., 87(17):9865-9872, Sep 2013. PubMed ID: 23824817.
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Klasse2013
Per Johan Klasse, Rafael S. Depetris, Robert Pejchal, Jean-Philippe Julien, Reza Khayat, Jeong Hyun Lee, Andre J. Marozsan, Albert Cupo, Nicolette Cocco, Jacob Korzun, Anila Yasmeen, Andrew B. Ward, Ian A. Wilson, Rogier W. Sanders, and John P. Moore. Influences on Trimerization and Aggregation of Soluble, Cleaved HIV-1 SOSIP Envelope Glycoprotein. J. Virol., 87(17):9873-9885, Sep 2013. PubMed ID: 23824824.
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Klein2013
Florian Klein, Ron Diskin, Johannes F. Scheid, Christian Gaebler, Hugo Mouquet, Ivelin S. Georgiev, Marie Pancera, Tongqing Zhou, Reha-Baris Incesu, Brooks Zhongzheng Fu, Priyanthi N. P. Gnanapragasam, Thiago Y. Oliveira, Michael S. Seaman, Peter D. Kwong, Pamela J. Bjorkman, and Michel C. Nussenzweig. Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization. Cell, 153(1):126-138, 28 Mar 2013. PubMed ID: 23540694.
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Kwong2012
Peter D. Kwong and John R. Mascola. Human Antibodies that Neutralize HIV-1: Identification, Structures, and B Cell Ontogenies. Immunity, 37(3):412-425, 21 Sep 2012. PubMed ID: 22999947.
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Lynch2012
Rebecca M. Lynch, Lillian Tran, Mark K. Louder, Stephen D. Schmidt, Myron Cohen, CHAVI 001 Clinical Team Members, Rebecca DerSimonian, Zelda Euler, Elin S. Gray, Salim Abdool Karim, Jennifer Kirchherr, David C. Montefiori, Sengeziwe Sibeko, Kelly Soderberg, Georgia Tomaras, Zhi-Yong Yang, Gary J. Nabel, Hanneke Schuitemaker, Lynn Morris, Barton F. Haynes, and John R. Mascola. The Development of CD4 Binding Site Antibodies during HIV-1 Infection. J. Virol., 86(14):7588-7595, Jul 2012. PubMed ID: 22573869.
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Lyumkis2013
Dmitry Lyumkis, Jean-Philippe Julien, Natalia de Val, Albert Cupo, Clinton S. Potter, Per-Johan Klasse, Dennis R. Burton, Rogier W. Sanders, John P. Moore, Bridget Carragher, Ian A. Wilson, and Andrew B. Ward. Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV-1 Envelope Trimer. Science, 342(6165):1484-1490, 20 Dec 2013. PubMed ID: 24179160.
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Mascola2012
J. Mascola, D. R. Burton, W. Koff, P. Kwong, G. Nabel, S. K. Phogat, P. R. G. Poignard, M. D. De Jean De St. Marcel Simek-Lemos, X. Wu, and Z. Y. Yang. HIV-1 Broadly Neutralizing Antibodies. US patent 9,382,311, 5 Jul 2016. URL: https://patentscope.wipo.int/search/en/detail.jsf?docId=US91507326.
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McCoy2015
Laura E. McCoy, Emilia Falkowska, Katie J. Doores, Khoa Le, Devin Sok, Marit J. van Gils, Zelda Euler, Judith A. Burger, Michael S. Seaman, Rogier W. Sanders, Hanneke Schuitemaker, Pascal Poignard, Terri Wrin, and Dennis R. Burton. Incomplete Neutralization and Deviation from Sigmoidal Neutralization Curves for HIV Broadly Neutralizing Monoclonal Antibodies. PLoS Pathog., 11(8):e1005110, Aug 2015. PubMed ID: 26267277.
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McGuire2016
Andrew T. McGuire, Matthew D. Gray, Pia Dosenovic, Alexander D. Gitlin, Natalia T. Freund, John Petersen, Colin Correnti, William Johnsen, Robert Kegel, Andrew B. Stuart, Jolene Glenn, Michael S. Seaman, William R. Schief, Roland K. Strong, Michel C. Nussenzweig, and Leonidas Stamatatos. Specifically Modified Env Immunogens Activate B-Cell Precursors of Broadly Neutralizing HIV-1 Antibodies in Transgenic Mice. Nat. Commun., 7:10618, 24 Feb 2016. PubMed ID: 26907590.
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Ozorowski2017
Gabriel Ozorowski, Jesper Pallesen, Natalia de Val, Dmitry Lyumkis, Christopher A. Cottrell, Jonathan L. Torres, Jeffrey Copps, Robyn L. Stanfield, Albert Cupo, Pavel Pugach, John P. Moore, Ian A. Wilson, and Andrew B. Ward. Open and Closed Structures Reveal Allostery and Pliability in the HIV-1 Envelope Spike. Nature, 547(7663):360-363, 20 Jul 2017. PubMed ID: 28700571.
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Pejchal2011
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Pugach2015
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Rusert2016
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Sanders2013
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Scharf2016
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Schiffner2018
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Walker2011
Laura M. Walker, Michael Huber, Katie J. Doores, Emilia Falkowska, Robert Pejchal, Jean-Philippe Julien, Sheng-Kai Wang, Alejandra Ramos, Po-Ying Chan-Hui, Matthew Moyle, Jennifer L. Mitcham, Phillip W. Hammond, Ole A. Olsen, Pham Phung, Steven Fling, Chi-Huey Wong, Sanjay Phogat, Terri Wrin, Melissa D. Simek, Protocol G. Principal Investigators, Wayne C. Koff, Ian A. Wilson, Dennis R. Burton, and Pascal Poignard. Broad Neutralization Coverage of HIV by Multiple Highly Potent Antibodies. Nature, 477(7365):466-470, 22 Sep 2011. PubMed ID: 21849977.
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Walker2018
Laura M. Walker and Dennis R. Burton. Passive Immunotherapy of Viral Infections: `Super-Antibodies' Enter the Fray. Nat. Rev. Immunol., 18(5):297-308, May 2018. PubMed ID: 29379211.
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West2013
Anthony P. West, Jr., Louise Scharf, Joshua Horwitz, Florian Klein, Michel C. Nussenzweig, and Pamela J. Bjorkman. Computational Analysis of Anti-HIV-1 Antibody Neutralization Panel Data to Identify Potential Functional Epitope Residues. Proc. Natl. Acad. Sci. U.S.A., 110(26):10598-10603, 25 Jun 2013. PubMed ID: 23754383.
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Wu2015
Xueling Wu, Zhenhai Zhang, Chaim A. Schramm, M. Gordon Joyce, Young Do Kwon, Tongqing Zhou, Zizhang Sheng, Baoshan Zhang, Sijy O'Dell, Krisha McKee, Ivelin S. Georgiev, Gwo-Yu Chuang, Nancy S. Longo, Rebecca M. Lynch, Kevin O. Saunders, Cinque Soto, Sanjay Srivatsan, Yongping Yang, Robert T. Bailer, Mark K. Louder, NISC Comparative Sequencing Program, James C. Mullikin, Mark Connors, Peter D. Kwong, John R. Mascola, and Lawrence Shapiro. Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection. Cell, 161(3):470-485, 23 Apr 2015. PubMed ID: 25865483.
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Wu2016
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Zhou2013a
Tongqing Zhou, Jiang Zhu, Xueling Wu, Stephanie Moquin, Baoshan Zhang, Priyamvada Acharya, Ivelin S. Georgiev, Han R. Altae-Tran, Gwo-Yu Chuang, M. Gordon Joyce, Young Do Kwon, Nancy S. Longo, Mark K. Louder, Timothy Luongo, Krisha McKee, Chaim A. Schramm, Jeff Skinner, Yongping Yang, Zhongjia Yang, Zhenhai Zhang, Anqi Zheng, Mattia Bonsignori, Barton F. Haynes, Johannes F. Scheid, Michel C. Nussenzweig, Melissa Simek, Dennis R. Burton, Wayne C. Koff, NISC Comparative Sequencing Program, James C. Mullikin, Mark Connors, Lawrence Shapiro, Gary J. Nabel, John R. Mascola, and Peter D. Kwong. Multidonor Analysis Reveals Structural Elements, Genetic Determinants, and Maturation Pathway for HIV-1 Neutralization by VRC01-Class Antibodies. Immunity, 39(2):245-258, 22 Aug 2013. PubMed ID: 23911655.
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Zhou2015
Tongqing Zhou, Rebecca M. Lynch, Lei Chen, Priyamvada Acharya, Xueling Wu, Nicole A. Doria-Rose, M. Gordon Joyce, Daniel Lingwood, Cinque Soto, Robert T. Bailer, Michael J. Ernandes, Rui Kong, Nancy S. Longo, Mark K. Louder, Krisha McKee, Sijy O'Dell, Stephen D. Schmidt, Lillian Tran, Zhongjia Yang, Aliaksandr Druz, Timothy S. Luongo, Stephanie Moquin, Sanjay Srivatsan, Yongping Yang, Baoshan Zhang, Anqi Zheng, Marie Pancera, Tatsiana Kirys, Ivelin S. Georgiev, Tatyana Gindin, Hung-Pin Peng, An-Suei Yang, NISC Comparative Sequencing Program, James C. Mullikin, Matthew D. Gray, Leonidas Stamatatos, Dennis R. Burton, Wayne C. Koff, Myron S. Cohen, Barton F. Haynes, Joseph P. Casazza, Mark Connors, Davide Corti, Antonio Lanzavecchia, Quentin J. Sattentau, Robin A. Weiss, Anthony P. West, Jr., Pamela J. Bjorkman, Johannes F. Scheid, Michel C. Nussenzweig, Lawrence Shapiro, John R. Mascola, and Peter D. Kwong. Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors. Cell, 161(6):1280-1292, 4 Jun 2015. PubMed ID: 26004070.
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Zhou2018
Tongqing Zhou, Anqi Zheng, Ulrich Baxa, Gwo-Yu Chuang, Ivelin S. Georgiev, Rui Kong, Sijy O'Dell, Syed Shahzad-Ul-Hussan, Chen-Hsiang Shen, Yaroslav Tsybovsky, Robert T. Bailer, Syna K. Gift, Mark K. Louder, Krisha McKee, Reda Rawi, Catherine H. Stevenson, Guillaume B. E. Stewart-Jones, Justin D. Taft, Eric Waltari, Yongping Yang, Baoshan Zhang, Sachin S. Shivatare, Vidya S. Shivatare, Chang-Chun D. Lee, Chung-Yi Wu, NISC Comparative Sequencing Program, James C. Mullikin, Carole A. Bewley, Dennis R. Burton, Victoria R. Polonis, Lawrence Shapiro, Chi-Huey Wong, John R. Mascola, Peter D. Kwong, and Xueling Wu. A Neutralizing Antibody Recognizing Primarily N-Linked Glycan Targets the Silent Face of the HIV Envelope. Immunity, 48(3):500-513.e6, 20 Mar 2018. PubMed ID: 29548671.
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Zhu2013a
Jiang Zhu, Xueling Wu, Baoshan Zhang, Krisha McKee, Sijy O'Dell, Cinque Soto, Tongqing Zhou, Joseph P. Casazza, NISC Comparative Sequencing Program, James C. Mullikin, Peter D. Kwong, John R. Mascola, and Lawrence Shapiro. De Novo Identification of VRC01 Class HIV-1-Neutralizing Antibodies by Next-Generation Sequencing of B-Cell Transcripts. Proc. Natl. Acad. Sci. U.S.A., 110(43):E4088-E4097, 22 Oct 2013. PubMed ID: 24106303.
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Guzzo2018
Christina Guzzo, Peng Zhang, Qingbo Liu, Alice L. Kwon, Ferzan Uddin, Alexandra I. Wells, Hana Schmeisser, Raffaello Cimbro, Jinghe Huang, Nicole Doria-Rose, Stephen D. Schmidt, Michael A. Dolan, Mark Connors, John R. Mascola, and Paolo Lusso. Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation. mBio, 9(6), 11 Dec 2018. PubMed ID: 30538178.
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Displaying record number 2642
Download this epitope
record as JSON.
MAb ID |
PGT128 (PGT-128) |
HXB2 Location |
Env |
Env Epitope Map
|
Author Location |
|
Epitope |
|
Ab Type |
gp120 V3 // V3 glycan (V3g) |
Neutralizing |
P View neutralization details |
Contacts and Features |
View contacts and features |
Species
(Isotype)
|
human(IgG1) |
Patient |
Donor 36 |
Immunogen |
HIV-1 infection |
Keywords |
anti-idiotype, antibody binding site, antibody gene transfer, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autoantibody or autoimmunity, autologous responses, binding affinity, broad neutralizer, chimeric antibody, computational prediction, contact residues, dynamics, effector function, elite controllers and/or long-term non-progressors, escape, germline, glycosylation, immunoprophylaxis, immunotherapy, kinetics, memory cells, mimics, mutation acquisition, neutralization, polyclonal antibodies, rate of progression, review, SIV, structure, subtype comparisons, therapeutic vaccine, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity, viral fitness and/or reversion |
Notes
Showing 110 of
110 notes.
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PGT128: Eighty clusters of overlapping epitopes that could bind to MHC Class II HLA-DR1*01:01 (DR1) allele were identified by LC-MS/MS using a cell-free processing system that incorporated soluble DR1, HLA-DM (DM), cathepsins, and full-length protein antigens (Gag, Pol, Env, Vif, Tat, Rev, and Nef). Sixteen of Env CD4+ T cell epitopes identified in this study, which were primarily located in the vicinity of the gp120/gp41 interface or the CD4bs, were assessed for overlap with bnAb binding footprints. Only unglycosylated TGE320-328 (TGEIIGDIR) overlapped with the binding footprint of V3 glycan-targeting bnAb PGT127/128.
Sengupta2023
(antibody binding site)
-
PGT128: The study describes the generation, crystal structure, and immunogenic properties of a native-like Env SOSIP trimer based on a group M consensus (ConM) sequence. A crystal structure of ConM SOSIP.v7 trimer together with nAbs PGT124 and 35O22 revealed that ConM SOSIP.v7 is structurally similar to other Env trimers. In rabbits, the ConM SOSIP trimer induced serum nAbs that neutralized the autologous Tier 1A virus (ConM from 2004) and a related Tier 1B ConS virus (ConM from 2001). These responses target the trimer apex and were enhanced when the trimers were presented on ferritin nanoparticles. The neutralization of ConM and ConS pseudoviruses was tested against a large panel of nAbs and non-nAbs (2219, 2557, 3074, 3869, 447-52D, 830A, 654-30D, 1008-30D, 1570D, 729-30D, F105, 181D, 246D, 50-69D, sCD4, VRC01, 3BNC117, CH31, PG9, PG16, CH01, PGDM1400, PGT128, PGT121, 10-1074, PGT151, VRC43.01, 2G12, DH511.2_K3, 10E8, 2F5, 4E10); most nAbs were able to neutralize these pseudoviruses. Soluble ConM trimers were able to weakly activate B cells expressing PGT121 and PG16 BCRs but were inactive against those expressing VRC01 and PGT145. In contrast, at the same molar amount of trimers, the ConM SOSIP.v7-ferritin nanoparticles activated all 4 B cells efficiently. Binding of bnAbs 2G12 and PGT145 and non-nAbs F105 and 19b to ConM SOSIP.v7 trimer and SOSIP showed that the ferritin-bound trimer bound more avidly than the soluble trimer. This study shows that native-like HIV-1 Env trimers can be generated from consensus sequences, and such immunogens might be suitable vaccine components to prime and/or boost desirable nAb responses.
Sliepen2019
(neutralization, vaccine antigen design)
-
PGT128: A SHIV carrying a highly neutralization-sensitive Env (SHIVCNE40) was passaged in macaques. SHIVCNE40 developed enhanced replication kinetics associated with neutralization resistance against autologous serum, CD4-Ig, and several nAbs (17b, 3BNC117, N6, PGT145, PGT121, PGT128, 35O22, 2F5, 10E8). A gp41 substitution, E658K, was the major determinant for this resistance. Structural modeling and functional verification indicate that the substitution disrupts an intermolecular salt bridge with the neighboring protomer, thereby promoting fusion and facilitating immune evasion. This effect is applicable across many HIV-1 viruses of diverse subtypes. These results highlight the critical role of gp41 in shaping the neutralization profile and conformation of Env during viral adaptation. The unique intermolecular salt bridge could potentially be utilized for rational vaccine design involving more stable HIV-1 Env trimers.
Wang2019
(mutation acquisition, neutralization, structure)
-
PGT128: A panel of 30 contemporary subtype B pseudoviruses (PSVs) was generated. Neutralization sensitivities of these PSVs were compared with subtype B strains from earlier in the pandemic using 31 nAbs (PG9, PG16, PGT145, PGDM1400, CH02, CH03, CH04, 830A, PGT121, PGT126, PGT128, PGT130, 10-1074, 2192, 2219, 3074, 3869, 447-52D, b12, NIH45-46, VRC01, VRC03, 3BNC117, HJ16, sCD4, 10E8, 4E10, 2F5, 7H6, 2G12, 35O22). A significant reduction in Env neutralization sensitivity was observed for 27 out of 31 nAbs for the contemporary, as compared to earlier-decade subtype B PSVs. A decline in neutralization sensitivity was observed across all Env domains; the nAbs that were most potent early in the pandemic suffered the greatest decline in potency over time. A metaanalysis demonstrated this trend across multiple subtypes. As HIV-1 Env diversification continues, changes in Env antigenicity and neutralization sensitivity should continue to be evaluated to inform the development of improved vaccine and antibody products to prevent and treat HIV-1.
Wieczorek2023
(neutralization, viral fitness and/or reversion)
-
PGT128:This study identified a B cell lineage of bNAbs in an HIV-1 elite post-treatment controller (ePTC; donor: PTC-005002). Circulating viruses in PTC escaped bNAb pressure but remained sensitive to autologous neutralization by other Ab populations. PGT128 was used as a reference control IgG. Inhibition of EPTC112 binding to SOSIP was mainly evidenced with anti-V3-glycan bNAb PGT128 (55%–77% blocking range)
Molinos-Albert2023
(binding affinity)
-
PGT128: Two conserved tyrosine (Y) residues within the V2 loop of gp120, Y173 and Y177, were mutated individually or in combination, to either phenylalanine (F) or alanine (A) in several strains of diverse subtypes. In general, these mutations increased neutralization sensitivity, with a greater impact of Y177 over Y173 single mutations, of double over single mutations, and of A over F substitutions. The Y173A Y177A double mutation in HIV-1 BaL increased sensitivity to most of the weakly neutralizing MAbs tested (2158, 447-D, 268-D, B4e8, D19, 17b, 48d, 412d) and even rendered the virus sensitive to non-neutralizing antibodies against the CD4 binding site (F105, 654-30D, and b13). In the case of V2 mAb 697-30D, residue Y173 is part of its epitope, and thus abrogates its binding and has no effect on neutralization; the Y177A mutant alone did increase neutralization sensitivity to this mAb. When the double mutant was tested against bnAbs, there was a large decrease in neutralization sensitivity compared to WT for many bnAbs that target V1, V2, or V3 (PG9, PG16, VRC26.08, VRC38, PGT121, PGT122, PGT123, PGT126, PGT128, PGT130, PGT135, VRC24, CH103). The double mutation had lesser or no effect on neutralization by one V3 bnAb (2G12) and by most bnAbs targeting the CD4 binding site (VRC01, VRC07, VRC03, VRC-PG04, VRC-CH31, 12A12, 3BNC117, N6), the gp120-gp41 interface (35O22, PGT151), or the MPER (2F5, 4E10, 10E8).
Guzzo2018
(antibody binding site, neutralization)
-
PGT128: This study explored the basis of the neutralization resistance of tier 3 virus 253-11 (subtype CRF02_AG). Virus 253-11 was resistant to neutralization by 17b, b12, VRC03, F105, SCD4, CH12, Z13e1, PG16, PGT145, 2G12, PGT121, PGT126, PGT128, PGT130, 39F, F240, and 35O22; the virus was sensitive to 3BNC117, NIH45-46G54W, VRC01, 10E8, 2F5, 4E10, PG9, VRC26.26, 10-1074, and PGT151. Virus 253-11 was strikingly resistant to most tested antibodies that target V3/glycans, despite possessing key potential N-linked glycosylation sites, especially N301 and N332, needed for the recognition of this class of antibodies. The resistance of 253-11 was not associated with an unusually long V1/V2 loop, nor with polymorphisms in the V3 loop and N-linked glycosylation sites. The 253-11 MPER was rarely recognized by sera, but was more often recognized in a chimera consisting of a HIV-2 backbone with the 253-11 MPER, suggesting steric or kinetic hindrance of the MPER. Mutations in the 253-11 MPER previously reported to increase the lifetime of the prefusion Env conformation (Y681H, L669S), decreased the resistance of 253-11 to several mAbs, presumably destabilizing its otherwise stable, closed trimer structure. A crystal structure of a recombinant 253-11 SOSIP trimer revealed that the heptad repeat helices in gp41 are drawn in close proximity to the trimer axis and that gp120 protomers also showed a relatively compact form around the trimer axis.
Moyo2018
(neutralization, structure)
-
PGT128: This study assessed the ability of single bNAbs and triple bNAb combinations to mediate polyfunctional antiviral activity against a panel of cross-clade simian-human immunodeficiency viruses (SHIVs), which are commonly used as tools for validation of therapeutic strategies in nonhuman primate models. Most bnAbs assayed were capable of mediating both neutralizing and nonneutralizing effector functions (ADCC and ADCP) against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs was highly strain dependent. Several triple bNAb combinations were identified comprising of CD4 binding site-, V2-glycan-, and gp120-gp41 interface-targeting bNAbs that are capable of mediating synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. In assays using the transmitted/founder SHIV.C.CH505, there was a correlation between the neutralization potencies and nonneutralizing effector functions of bnAbs: PGT128 was negative for neutralization, ADCC, and binding to infected cells.
Berendam2021
(effector function, neutralization, binding affinity, broad neutralizer)
-
PGT128: This study used directed evolution to overcome the instability and heterogeneity of a primary Env isolate (ADA) in order to design better immunogens. HIV-1 virions were subjected to iterative cycles of destabilization and replication to select for Envs with enhanced stability. Several mutations in Env were associated with increased trimer stability, primarily in the heptad repeat regions of gp41 and V1 of gp120. Mutations from the most stable Envs were combined into a variant Env, termed "comb-mut", with superior homogeneity and stability. Comb-mut had greater binding affinity for PGT128, PG9, PG16, 2G12, VRC01, b12, and CD4-IgG2, but decreased binding to 4E10, 2F5, b6, 19b, 17b, 7B2, and D50. Comb-mut was more sensitive to neutralization by PG9. One specific mutation (K574) was shown to decrease the neutralization IC50 of mAbs b12, 2F5, 4E10, b6, 2G12, 8K8 and inhibitors sCD4, T-20, and PF-68742. Several of the Env substitutions were shown to stabilize Env spikes from HIV-1 clades A, B, and C. Spike stabilizing mutations may be useful in the development of Env immunogens that stably retain native, trimeric structure.
Leaman2013
(mimics, vaccine antigen design, binding affinity)
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PGT128: Using subtype A BG505 Env structural information, improved variants of subtype B JRFL and subtype C 16055 Env native flexibly linked (NFL) trimers were generated. The trimer-derived (TD) residues that increased well-ordered, homogeneous, stable, and soluble trimers did not require positive or negative selection as previously needed [Guenaga2015, PLoS Pathos. 11(1):e1004570]. PGT128 and PGT121 both bound the NFL TD Env with high avidity, this was particularly relevant to the 16055 TD trimer in which N332 was introduced into the supersite for glycan presence as opposed to the native 16055 Env.
Guenaga2015a
(antibody interactions, assay or method development, vaccine antigen design, structure)
-
PGT128: Most published structures of bnAbs, yet none of non- or poorly-neutralizing mAbs, were structurally compatible with a newly generated crystal structure of a mature ligand-free endoglycosidase H-treated BG505 SOSIP.664 Env trimer. Robust binding of the structurally incompatible V3- and CD4-bs targeting nAbs could be induced with CD4. A “DS” variant of BG505 SOSIP.664, containing a stabilizing disulfide bond between 201C and 433C mutations, was developed and appeared to represent an obligate intermediate in that it bound only a single CD4 and remained in a prefusion closed conformation. BnAb PGT128 was structurally compatible with BG505 SOSIP.664 and had a breadth of 64% (IC50 < 50 μg/ml) in a panel of 170 diverse HIV-1 pseudoviruses. PGT128 had SPR KD values of 158 and 78.4 nM, respectively, when binding to BG505 SOSIP.664 wildtype and DS variant.
Kwon2015
(neutralization, vaccine antigen design, binding affinity, structure)
-
PGT128: This study reports on bispecific antibodies in which one arm is a single-chain (scFv) form of a V2-glycan antibody (VRC26.25 or PGT145), and the other arm is a V3-glycan Fab (10-1074, PGT121, or PGT128). A linker was used consisting of 10 repeats of tetraglycine-serine (10GS); additionally, KIH (knob in hole) mutations were introduced for stabilization. Some of these bispecific antibodies are markedly more potent than their parental bNAbs, likely because they simultaneously engage both the V2-apex and V3-glycan epitopes of Env.
Davis-Gardner2020
(neutralization, broad neutralizer)
-
PGT128: This study examined whether HIV-1-specific bnAbs are capable of cross-neutralizing simian immunodeficiency viruses (SIVs) from chimpanzees (n=11) or western gorillas (n=1). BnAbs directed against the epitopes at the CD4 binding site (VRC01, VRC03, VRC-PG04, VRC-CH03, VRC-CH31, F105, b13, NIH45-46G54W, 45-46m2, 45-46m7), V3 (10-1074, PGT121, PGT128, PGT135, and 2G12), and gp41-gp120 interface (8ANC195, 35O22, PGT151, PGT152, PGT158) failed to neutralize SIVcpz and SIVgor strains. V2-directed bNabs (PG9, PG16, PGT145) as well as llama-derived heavy-chain only antibodies recognizing the CD4 binding site or gp41 epitopes (JM4, J3, 3E3, 2E7, 11F1F, Bi-2H10) were either completely inactive or neutralized only a fraction of SIVcpz strains. In contrast, neutralization of SIVcpz and SIVgor strains was achieved with low-nanomolar potency by one antibody targeting the MPER region of gp41 (10E8), as well as functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Igmim2, CD4-218.3-E51, CD4-218.3-E51-mim2), mono- and bispecific anti-human CD4 mAbs (iMab, PG9-iMab, PG16-iMab, LM52, LM52-PGT128), and CCR5 receptor mAbs (PRO140, PRO140-10E8). Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5, and neutralized SIVcpz in chimpanzee CD4+ T cells. These findings provide new insight into the protective capacity of anti-HIV-1 bnAbs and identify candidates for further development to combat SIV infection.
Barbian2015
(neutralization, SIV, binding affinity)
-
PGT128: A recombinant native-like Env SOSIP trimer, AMC009, was developed based on viral founder sequences of elite neutralizer H18877. The subtype B AMC009 Env was defined as a Tier 2 virus based on a neutralization assay against well known nAbs (VRC01, 3BNC117, CH31, CH01, PG9, PG16, PGDM1400, 10-1074, PGT128, PGT121, PGT151, VRC34.01, 2G12, 2F5, 4E10, DH511.2.K3_4, 10E8, and the mAb mixture CH01-31).The AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bnAb epitopes. Its overall structure was similar to that of BG505 SOSIP.664, and it resembled one from another elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, AMC009 trimers did not induce autologous neutralizing antibody responses efficiently, while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous tier 2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009, and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the nAb activity from rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers.
Schorcht2020
(neutralization, vaccine-induced immune responses, structure)
-
PGT128: A macaque sequential immunization protocol with increasingly native-like V3-glycan-targeting Env trimers multimerized onto virus-like particles elicited multiple on-target mAbs with heterologous, yet generally weak, neutralization activity and minimal protection in a subsequent intrarectal heterologous challenge with SHIVDH12-V3AD8. The priming immunogen was RC1-4fill (clade A/E, RC1 with 4 additional glycans), a low affinity Env trimer with additional glycans to facilitate V3-glycan targeting and mask BG505 glycan hole, while the boosting immunogens were 11MUTB-4fill (clade A/E), B41-5MUT or B41 wildtype (clade B), AMC011/Du422 (clade B/C), and consensus group M/consensus clade C Env trimers. Rabbits were also immunized once with RC1-4 fill-VLP and produced V3-targeting mAbs with binding poses distinct from the known V3-targeting bnAbs (10-1074, PGT135, PGT128 and BG18). In a RC1 binding assay, PGT128 Fab competed substantially with the shared PGT121/10-1074 inferred germline precursor and moderately with isolated macaque mAbs (Ab1271, Ab1368, Ab1456, Ab1457, and Ab1461), bnAb 10-1074 and itself. After priming, serum from the 8 immunized macaques also displayed strong competition with V3-glycan-targeting PGT128 but this effect diminished after each boost, despite increasing serum responses to RC1. This suggests increasing off-target responses as the immunization protocol progressed, consistent with nsEMPEM observations.
Escolano2021
(antibody interactions, vaccine antigen design, vaccine-induced immune responses)
-
PGT128: HIV-1 bnAbs require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations. Probable mutations occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. The paper introduced the ARMADiLLO program, which estimates how probable a particular mAb mutation is, and thus the key improbable mutations were defined for a panel of 26 bnAbs. The number of improbable mutations ranged from 7 (PGT128) to 23 (VRC01 and 35O22); PGT128 had 7 improbable mutations out of 53 total AA mutations, and 11 indels. Single-amino acid reversion mutants were made for key improbable mutations of 3 bnAbs (CH235, VRC01, and BF520.1), and these mutant mAbs were tested for their neutralization ability. The study also noted that bnAbs that had relatively small numbers of improbable single somatic mutations had other unusual characteristics that were due to additional improbable events, such as indels (PGT128) or extraordinary CDR H3 lengths (VRC26.25).
Wiehe2018
(neutralization)
-
PGT128: 3 clonally-related autologously-neutralizing mAbs (43A, 43A1, and 43A2), isolated from rabbit 5743 which was co-immunized with BG505- and B41-based SOSIP soluble trimers [Klasse2016, PMID: 27627672], bind to an immunodominant epitope in V1 overlapping the bnAb N332 glycan supersite without interacting with glycans. All 43A family members, at 2-50 μg/ml concentrations, competed strongly with PGT128 with 8-17% residual binding in a BG505 SOSIP.664 binding assay. Negative-stain electron microscopy determined that the 43A family has an overlapping epitope near the base of V3 and a similar angle of approach as bnAb PGT128. PGT128 made more extensive contacts with Env using its approx. 20 aa-long CDRH3, when compared to 43A2 which interacted with its 13 aa CDRL3. Analysis of known crystal structure of putative precursor of PGT128 Fab bound to BG505 SOSIP.664 (PDB 5ACO) revealed that, compared to an unbound state, the V1 loop has undergone a conformational change to provide PGT121 with access to the GDIR motif. The structures of PGT128 and 43A2 had substantial overlap which suggested that they directly compete for D325, a component of the GDIR motif. Contacts with gp120 side chains can be found in the Env Features and Contacts database at hiv.lanl.gov.
Nogal2020
(antibody interactions, structure, contact residues)
-
PGT128: Of 40 total Env trimer-targeting mAbs isolated from 6 macaques either after 3 priming immunizations with artificial consensus stabilized native-like HIV-1 immunogen ConM SOSIP.v7 or subsequent 2 boosting immunizations with the closely related ConSOSL.UFO.664 immunogen, the V1V2V3 region was immunodominant for the 22 (55%) mAbs that neutralized ConM and/or ConS virus. PGT128 had 75% and 79% residual binding, respectively, when competing individually against biotinylated V1V2V3-targeting mAbs CM02A and CM05A1.
Reiss2022
(antibody interactions, vaccine antigen design)
-
PGT128: To understand early bnAb responses, 51 HIV-1 clade C infected infants were assayed for neutralization of a 12-virus multi-clade panel. Plasma bnAbs targeting V2-apex on Env were predominant in infant elite and broad neutralizers. In infant elite neutralizers, multi-variant infection was associated with plasma bnAbs targeting diverse autologous viruses. A panel of mAbs (PG9, PG16, PGT145, PGDM1400, VRC26.25, 10-1074, BG18, AIIMS-P01, PGT121, PGT128, PGT135, VRC01, N6, 3BNC117, PGT151, 35O22, 10E8, 4E10, F105, 17b, A32, 48d, b6, 447-52d) was assayed for their ability to neutralize Env clones from infant elite neutralizers; circulating viral variants in infant elite neutralizers were most susceptible to V2-apex bnAbs.
Mishra2020a
(neutralization, polyclonal antibodies)
-
PGT128: In vertically-infected infant AIIMS731, a rare HIV-1 mutation in hypervariable loop 2 (L184F) was studied. In patient sequences, this mutation was present in the majority of clones. A panel of 6 V2 bnAbs (PG9, PG16, PGT145, PGDM1400, CAP256.25, and CH01) was assayed for neutralization of 6 patient viral clones. The AIIMS731 viral variants segregated into 4 neutralization-sensitive and 2 resistant clones; sensitive clones carried 184F, while resistant clones carried the rare 184L mutation. A large panel of bnAbs targeting non-V2 epitopes was used to assess the neutralization of the 6 patient viral variants. The bnAb panel consisted of V3/N332 glycan supersite bnAbs (10-1074, BG18, AIIMS-P01, PGT121, PGT128, and PGT135), CD4bs bnAbs (VRC01, VRC03, VRC07-523LS, N6, 3BNC117, and NIH45-46 G54W), a silent face-targeting bnAb (PG05), fusion peptide and gp120-gp41 interface bnAbs (PGT151, 35O22, and N123-VRC34.01), and MPER bnAbs (10E8, 4E10, and 2F5). All of these bnAbs had similar neutralization efficiencies for all 6 clones, suggesting that the L184F mutation was specific for viral escape from neutralization by V2 apex bnAbs. A panel of non-neutralizing mAbs (V3 loop-targeting non-nAbs 447-52D and 19b, and CD4-induced non-nAbs 17b, A32, 48d, and b6), were also assessed; 2 of the variants (the same 2 susceptible to the V2 bnAbs) showed moderate neutralization by 447-52D, 19b, 17b, and 48d. The structure of ligand-free BG505 SOSIP trimer revealed that the side chain of L184 was outward facing and did not make significant intraprotomeric interactions, but upon mutating L184 to F184, a disruption of the accessible surface between the bulky side chain of F184 on one protomer and R165 on the neighboring protomer was seen. Thus, the L184F mutation resulted in increased susceptibility to neutralization by antibodies known to target the relatively more open conformation of Env on tier 1 viruses, suggesting that the rare L184F mutation allowed Env to sample more open states resembling the CD4-bound conformation where the CCR5 binding site is exposed.
Mishra2020
(neutralization, polyclonal antibodies)
-
PGT128: This report characterizes an additional antiviral activity of some bnAbs to block HIV-1 release by tethering viral particles at the surface of infected cells in vitro in a bivalency-dependent manner. After cultivation of infected primary CD4+ T cells with individual bnAbs, supernatant p24 levels were negatively correlated with cell-associated Gag levels, Env binding and neutralization potency while cell-associated Gag levels and Env binding positively correlated with each other and individually with neutralization potency. The capacity to mediate this tethering activity varied among different classes of mAbs: 0/3 non-neutralizing mAbs, 1/5 bnAbs targeting the MPER or gp120/gp41 interface and 9/9 of the bnAbs targeting the V3 and V1/V1 loops or the CD4bs demonstrated this activity against at least 1/3 diverse viral strains (AD8, CH058 and vKB18). Five of these latter 9 bnAbs, including bnAb 10-1074 which had the most potent effect observed in study when cultivated with vKB18-infected CD4+ T cells, displayed tethering activity against all 3 strains. Surface aggregation of mature virions and bnAb 10-1074 was observed in CH058-infected primary CD4+ T cells and CHME macrophage-like cells. V3-targeting bnAb PGT128 displayed tethering activity against all 3 strains.
Dufloo2022
(binding affinity)
-
PGT128: A plant-based expression system was used to produce different glycoforms of the bnAbs PG9, PG16, 10–1074, NIH45–46G54W, 10E8, PGT121, PGT128, PGT145, PGT135, and b12. Also produced were mutated forms (N92T) of VRC01 (mVRC01) and NIH45–46G54W (mNIH45–46G54W). The in vivo properties of these mAbs were assessed in macaques to distinguish those most likely to comprise or become a component of an affordable and efficacious immunotherapeutic cocktails. N-glycans within the VL domain impaired the plasma stability of plant-derived bnAbs. While PGT121 and b12 exhibited no immunogenicity in rhesus macaques, VRC01, 10-1074 and NIH45-46G54W elicited high titer anti-idiotypic antibodies. The results indicated that that specific mutations in certain bnAbs caused immunogenicity in macaques. Such immunogenicity in humans would potentially compromise their value for immunotherapy. CHO1-31 was used as a positive control in a neutralization assay.
Rosenberg2015
(anti-idiotype, neutralization, immunotherapy)
-
PGT128: Since cross-reactive antibodies can interfere in immunoassays, HIV-1 mAbs were tested for binding to the SARS-COV-2 spike (S) protein (SARS-COV-2 S cross-reactivity). The following 9 gp120-epitope binding HIV-1 mAbs are cross-reactive with COV-2 S: 2G12, PGT121, PGT126, PGT128, PGT145, PG9, PG16, 10-1074, and 35O22. CD4bs Abs VRC01 and VRC03 are not cross-reactive. Cross-reactivity of the 9 HIV-1 Abs was through glycoepitopes. Glycan-dependent, V3-loop-binding PGT126 and PGT128 as well as 2G12 were the strongest binders of COV-2 S and were found to be immunoreactive but incapable of neutralization or antibody-dependent enhancement (ADE).
Mannar2021
(antibody interactions, effector function, glycosylation, computational prediction, antibody polyreactivity)
-
PGT128: The crystal structure of Fab NC-Cow1 was determined. The NC-Cow1 structure was then determined in a quaternary complex with BG505 SOSIP.664, in which human Fabs PGT128 and 35022 were added to facilitate formation of diffraction-quality crystals. The exceptionally long (60 residues) CDR H3 of the heavy chain of NC-Cow1 forms a mini domain (knob) on an extended stalk that navigates through the dense glycan shield on Env to target a small footprint on the gp120 CD4bs with no contact of the other CDRs to the rest of the Env trimer.
Stanfield2020
(structure)
-
PGT128: Analyses of all PDB HIV1-Env trimer (prefusion, closed) structures fulfilling certain parameters of resolution were performed to classify them on the basis of (a) antibody class which was informed by parental B cells as well as structural recognition, and (b) Env residues defining recognized HIV epitopes. Structural features of the 206 HIV epitope and bNAb paratopes were correlated with functional properties of the breadth and potency of neutralization against a 208-strain panel. Broadly nAbs with >25% breadth of neutralization belonged to 20 classes of antibodies with a large number of protruding loops and high degree of somatic hypermutation (SHM). Analysis of recognized HIV epitopes placed the bNAbs into 6 categories (viz. V1V2, glycan-V3, CD4-binding site, silent face center, fusion peptide and subunit interface). The epitopes contained high numbers of independent sequence segments and glycosylated surface area. PGT128-Env formed a distinct group within the Glycan-V3 category, Class PGT128. Cryo-EM data on PGT128 complexed to BG505 SOSIP.664 trimer was found in PDB ID: 5ACO.
Chuang2019
(antibody binding site, antibody interactions, neutralization, binding affinity, antibody sequence, structure, antibody lineage, broad neutralizer)
-
PGT128: An elite controller patient (VA40774) was identified as having an Env V1 domain that was unusually long and contained 2 additional N-glycosylation sites and 2 additional cysteine residues, relative to HXB2. When this V1 region was put into other viral backbones, the resulting virus had lower infectivity. The long V1 domain is sufficient for partial or complete escape from neutralization by V3-glycan targeting antibodies 10-1074 and PGT121, but not by another V3-glycan bNAb (PGT128) nor by other classes of bNAbs.
Silver2019
(elite controllers and/or long-term non-progressors, neutralization)
-
PGT128: In an effort to identify new Env immunogens able to elicit bNAbs, this study looked at Envs derived from rare individuals who possess bNAbs and are elite viral suppressors, hypothesizing that in at least some people the antibodies may mediate durable virus control. The Env proteins recovered from these individuals may more closely resemble the Envs that gave rise to bNAbs compared to the highly diverse viruses isolated from normal progressors. This study identified a treatment-naive elite suppressor, EN3 (patient record #4929), whose serum had broad neutralization. The Env sequences of EN3 had much fewer polymorphisms, compared to those of a normal progressor, EN1 (patient record #4928), who also had broad serum neutralization. This result confirmed other reports of slower virus evolution in elite suppressors. EN3 Envelope proteins were unusual in that most possessed two extra cysteines within an elongated V1 region. The impact of the extra cysteines on the binding to bNAbs, virus infectivity, and sensitivity to neutralization suggested that structural motifs in V1 can affect infectivity, and that rare viruses may be prevented from developing escape. As part of this study, the neutralization of pseudotype viruses for EN3 Env clones was assayed for several bNAbs (PG9, PG16, PGT145, PGT121, PGT128, VRC01, 4E10, and 35O22).
Hutchinson2019
(elite controllers and/or long-term non-progressors, neutralization, vaccine antigen design, polyclonal antibodies)
-
PGT128: An ART-naive HIV-controlling patient SA003 was found to have a high level of serum bNAb activity, and broadly neutralizing mAb LN01 IgG3 was isolated from patient serum. MAb PGT128 was used as a comparison in an assay of ADCC; PGT128 had moderate to strong ADCC activity against cells infected with 4 tested strains.
Pinto2019
(effector function)
-
PGT128: An R5 virus isolated from chronic patient NAB01 (Patient Record# 4723) was adapted in culture to growth in the presence of target cells expressing reduced levels of CD4. Entry kinetics of the virus were altered, and these alterations resulted in extended exposure of CD4-induced neutralization-sensitive epitopes to CD4. Adapted and control viruses were assayed for their neutralization by a panel of neutralizing antibodies targeting several different regions of Env (PGT121, PGT128, 1-79, 447-52d, b6, b12, VRC01, 17b, 4E10, 2F5, Z13e1). Adapted viruses showed greater sensitivity to antibodies targeting the CD4 binding site and the V3 loop. This evolution of Env resulted in increased CD4 affinity but decreased viral fitness, a phenomenon seen also in the immune-privileged CNS, particularly in macrophages.
Beauparlant2017
(neutralization, viral fitness and/or reversion, dynamics, kinetics)
-
PGT128: Chemoenzymatic synthesis, antigenicity, and immunogenicity of the V3 N334 glycopeptides from HIV-1 A244 gp120 have been reported. A synthetic V3 glycopeptide carrying a N334 high-mannose glycan was recognized by bNAb PGT128 and PGT126 but not by 10-1074. Rabbit immunization with the synthetic three-component A244 glycopeptide immunogen elicited substantial glycan-dependent antibodies with broad reactivity to various HIV-1 gp120/gp140 carrying N332 or N334 glycosylation sites. PGT128 could bind to all the V3 glycopeptides and carrying a high-mannose glycan at the N334, N301, or N295 site with moderate affinity, but no binding was observed to V3 glycopeptides bearing sialylated complex-type glycan (Fig: S1).
Cai2018
(glycosylation, vaccine antigen design, structure)
-
PGT128: Without SOSIP changes, cleaved Env trimers disintegrate into their gp120 and gp41-ectodomain (gp41_ECTO) components. This study demonstrates that the gp41_ECTO component is the primary source of this Env metastability and that replacing wild-type gp41_ECTO with BG505 gp41_ECTO of the uncleaved prefusion-optimized design is a general and effective strategy for trimer stabilization. A panel of 11 bNAbs, including the the N332 supersite recognized by PGT121, PGT128, PGT135, and 2G12, was used to assess conserved neutralizing epitopes on the trimer surface, and the main result was that the substitution was found to significantly improve trimer binding to bNAbs VRC01, PGT151, and 35O22, with P values (paired t test) of 0.0229, 0.0269, and 0.0407, respectively.
He2018
(antibody interactions, glycosylation, vaccine antigen design)
-
PGT128: This study looks at the role of somatic mutations within antibody variable and framework regions (FWR) in bNAbs and how these mutations alter thermostability and neutralization as the Ab lineage reaches maturation. The emergence and selection of different mutations in the complementarity-determining and framework regions are necessary to maintain a balance between antibody function and stability. The study shows that all major classes of bNAbs (DH270, CH103, CH235, VRC01, PGT lineage etc.) have lower thermostability than their corresponding inferred UCA antibodies. Fab interdomain flexibility mutations are selected early in Ab development.
Henderson2019
(neutralization, antibody lineage, broad neutralizer)
-
PGT128: This study demonstrated that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens eliciting Ab responses with greater neutralization breadth. Data from four large virus panels were used to comprehensively map viral signatures associated with bNAb sensitivity, hypervariable region characteristics, and clade effects. The bNAb signatures defined for the V2 epitope region were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine which resulted in increased breadth of nAb responses compared with Env 459C alone. PGT128 was used for machine learning regression prediction and to analyze statistical details (Table S4).
Bricault2019
(antibody binding site, neutralization, vaccine antigen design, computational prediction, broad neutralizer)
-
PGT128: A simple method to quantify and compare serum neutralization probabilities in described. The method uses logistic regression to model the probability that a serum neutralizes a virus with an ID50 titer above a cutoff. The neutralization potency (NP) identifies where the probabilities of neutralizing and not neutralizing a virus are equal and is not absolute as it depends on the ID50 cutoff. It provides a continuous measure for sera, which builds upon established tier categories now used to rate virus sensitivity. These potency comparisons are similar to comparing geometric mean neutralization titers, but instead are represented in tier-like terms. Increasing the number of bNAbs increases NP and slope, where the higher the slope, the sharper the boundary (lower scatter) between viruses neutralized and not neutralized. PGT128 was used in analysis of monoclonal bNAb combinations.
Hraber2018
(assay or method development, neutralization)
-
PGT128: This review discusses how the identification of super-antibodies, where and how such antibodies may be best applied and future directions for the field. PGT121, a prototype super-Ab, was isolated from human B cell clones. Antigenic region V3 glycan (Table:1).
Walker2018
(antibody binding site, review, broad neutralizer)
-
PGT128: The authors selected an optimal panel of diverse HIV-1 envelope glycoproteins to represent the antigenic diversity of HIV globally in order to be used as antigen candidates. The selection was based on genetic and geographic diversity, and experimentally and computationally evaluated humoral responses. The eligibility of the envelopes as vaccine candidates was evaluated against a panel of antibodies for breadth, affinity, binding and durability of vaccine-elicited responses. The antigen panel was capable of detecting the spectrum of V2-specific antibodies that target epitopes from the V2 strand C (V2p), the integrin binding motif in V2 (V2i), and the quaternary epitope at the apex of the trimer (V2q).
Yates2018
(vaccine antigen design, vaccine-induced immune responses, binding affinity)
-
PGT128: Polyreactive properties of natural and artificially engineered HIV-1 bNAbs were studied, with almost 60% of the tested HIV-1 bNAbs (including this one) exhibiting low to high polyreactivity in different immunoassays. A previously unappreciated polyreactive binding for PGT121, PGT128, NIH45-46W, m2, and m7 was reported. Binding affinity, thermodynamic, and molecular dynamics analyses revealed that the co-emergence of enhanced neutralizing capacities and polyreactivity was due to an intrinsic conformational flexibility of the antigen-binding sites of bNAbs, allowing a better accommodation of divergent HIV-1 Env variants.
Prigent2018
(antibody polyreactivity)
-
PGT128: A systems glycobiology approach was applied to reverse engineer the relationship between bNAb binding and glycan effects on Env proteins. Glycan occupancy was interrogated across every potential N-glycan site in 94 recombinant gp120 antigens. Using a Bayesian machine learning algorithm, bNAb-specific glycan footprints were identified and used to design antigens that selectively alter bNAb antigenicity. The novel synthesized antigens unsuccessfully bound to target bNAbs with enhanced and selective antigenicity.
Yu2018
(glycosylation, vaccine antigen design)
-
PGT128: This review discusses current HIV bNAb immunogen design strategies, recent progress made in the development of animal models to evaluate potential vaccine candidates, advances in the technology to analyze antibody responses, and emerging concepts in understanding B cell developmental pathways that may facilitate HIV vaccine design strategies.
Andrabi2018
(vaccine antigen design, review)
-
PGT128: A panel of bnAbs were studied to assess ongoing adaptation of the HIV-1 species to the humoral immunity of the human population. Resistance to neutralization is increasing over time, but concerns only the external glycoprotein gp120, not the MPER, suggesting a high selective pressure on gp120. Almost all the identified major neutralization epitopes of gp120 are affected by this antigenic drift, suggesting that gp120 as a whole has progressively evolved in less than 3 decades.
Bouvin-Pley2014
(neutralization)
-
PGT128: The first cryo-EM structure of a cross-linked vaccine antigen was solved. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a bNAb PGV04 Fab fragment revealed how cross-linking affects key properties of the trimer. ISOSIP and GLA-SOSIP trimers were compared for antigenicity by ELISA, using a large panel of mAbs previously determined to react with BG505 Env. Non-NAbs globally lost reactivity (7-fold median loss of binding), likely because of covalent stabilization of the cross-linked ‘closed’ form of the GLA-SOSIP trimer that binds non-NAbs weakly or not at all. V3-specific non-NAbs showed 2.1–3.3-fold reduced binding. Three autologous rabbit monoclonal NAbs to the N241/N289 ‘glycan-hole’ surface, showed a median ˜1.5-fold reduction in binding. V3 non-NAb 4025 showed residual binding to the GLA-SOSIP trimer. By contrast, bNAbs like PGT128 broadly retained reactivity significantly better than non-NAbs, with exception of PGT145 (3.3-5.3 fold loss of binding in ELISA and SPR).
Schiffner2018
(vaccine antigen design, binding affinity, structure)
-
PGT128: This study describes the generation of CHO cell lines stably expressing the following vaccine Env Ags: CRF01_AE A244 Env gp120 protein (A244.AE) and 6240 Env gp120 protein (6240.B). The antigenic profiles of the molecules were assessed with a panel of well-characterized mAbs recognizing critical epitopes and glycosylation analysis confirming previously identified sites and revealing unknown sites at non-consensus motifs. A244.AE gp120 bound to PGT128 in ELISA EC50 and Surface Plasmon Resonance (SPR) assays. 6240.B gp120 exhibited binding to PGT128.
Wen2018
(glycosylation, vaccine antigen design)
-
PGT128: The prophylactic and therapeutic potential of an engineered single gene–encoded tandem bispecific immunoadhesin (IA) molecule BiIA-SG was studied. Before engineering BiIAs, codon-optimized scFvs of bNAbs PG9, PG16, PGT128, VRC01, and Hu5A8 were synthesized. The VL/VH domain of each scFv was engineered as a corresponding IA by fusion with human IgG1-Fc to generate IA-PG9, IA-PG16, IA-PGT128, IA-VRC01, and IA-Hu5A8. While all IAs exhibited specific anti–HIV-1 activity, only IA-PGT128 displayed similar potency and the same sigmoidal slope of 100% neutralization as previously described for the native PGT128, and IA-PGT128 in combination with IA-Hu5A8 exhibited the best synergistic effect based on computational synergy volumes. IA-PGT128 and IA-Hu5A8 were therefore used for BiIA construction. 2 BiIAs were constructed: a double gene–encoded (DG) bispecific IA (BiIA-DG) with the modified IgG1-Fc domain, and a single gene–encoded (SG) BiIA (BiIA-SG) through fusion of the PGT128 VL/VH to the N-terminal of IA-Hu5A8 VL/VH in tandem, resulting in a structurally unique molecule with 4 scFv binding domains (2 for HIV-1 gp120 and 2 for CD4) as compared with BiIA-DG or other bispecific bnAbs that contain 2 scFv binding domains (1 for each of the 2 target antigens). The neutralizing breadth and potency of the new BiIA-SG molecule were higher than those of the original neutralizing PGT128 mAb, or the BiIA-DG with a single scFv domain. BiIA-SG neutralized all 124 HIV-1–pseudotyped viruses tested, and in humanized mice, an injection of BiIA-SG conferred sterile protection when administered prior to challenges with diverse live HIV-1 stains.
Wu2018
-
PGT128: Assays of poly- and autoreactivity demonstrated that broadly neutralizing NAbs are significantly more poly- and autoreactive than non-neutralizing NAbs. PGT128 is polyreactive, but not autoreactive.
Liu2015a
(autoantibody or autoimmunity, antibody polyreactivity)
-
PGT128: Panels of C clade pseudoviruses were computationally downselected from the panel of 200 C clade viruses defined by Rademeyer et al. 2016. A 12-virus panel was defined for the purpose of screening sera from vaccinees. Panels of 50 and 100 viruses were defined as smaller sets for use in testing magnitude and breadth against C clade. Published neutralization data for 16 mAbs was taken from CATNAP for the computational selections: 10-1074, 10-1074V, PGT121, PGT128, VRC26.25, VRC26.08, PGDM1400, PG9, PGT145, VRC07-523, 10E8, VRC13, 3BNC117, VRC07, VRC01, 4E10.
Hraber2017
(assay or method development, neutralization)
-
PGT128: Repetitive immunization of macaques over 3 years with an Env expressing V3-high mannose glycan, CON-S gp140CFI, elicited plasma antibodies neturalizing HIV-1 expressing high mannose glycans only. NAb DH501 was isolated and found to possess a structure where 3 VH chain CDRs formed a cavity into which the HIV-1 Env V3-glycan could insert. Rhesus DH501 possessed characteristics of V3-glycan bNAb precursors, and it could block PGT128 binding to V3.
Saunders2017
(vaccine-induced immune responses, structure)
-
PGT128: This study showed evidence of escape of circulating HIV-1 clade C in an individual from autologous BCN antibodies by three distinct mechanisms, 1) due to a N332S mutation (2) by increasing V1 loop length and (3) incorporation of protective N-glycan residues in V1 loop. Pseudotyped viruses expressing autologous Envs were found to be resistant to autologous BCN plasma, PGT121 and PGT128 despite the majority of Envs containing an intact N332 residue. Resistance of the Envs to neutralization was found to be correlated with a N332S mutation and acquisition of protective N-glycans.
Deshpande2016
(autologous responses, glycosylation, escape)
-
PGT128: DS-SOSIP.4mut (4mut) was identified as the most immunogenic and stable of 4 engineered, soluble, closed prefusion HIV-1 Env trimers. 4mut contained 4 mutations (M154, M300, M302 and L320) designed to form hydrophobic interactions between V1V1 and V3 loops. After V3-negative selection, V3-glycan-targeted mAb PGT128 recognized 4mut, the other 3 designed trimers (DS-SOSIP.6mut containing 4mut mutations, Y177W and I420M, DS-SOSIP.I423F and DS-SOSIP.A316W), and related trimers DS-SOSIP and BG505 SOSIP.664. Each DS-SOSIP variant was able to elicit trimer-specific responses, comparable to BG505 SOSIP.664, in guinea pigs after 4 immunizations, but none elicited heterologous neutralizing activity. Crystal structures were generated for 4mut and 6mut.
Chuang2017
(vaccine antigen design, vaccine-induced immune responses)
-
PGT128: Env from of a highly neutralization-resistant isolate, CH120.6, was shown to be very stable and conformationally-homogeneous. Its gp140 trimer retains many antigenic properties of the intact Env, while its monomeric gp120 exposes more epitopes. Thus trimer organization and stability are important determinants for occluding epitopes and conferring resistance to antibodies. Among a panel of 21 mAbs, CH120.6 was resistant to neutralization by all non-neutralizing and strain-specific mAbs, regardless of the location of their epitopes. It was weakly neutralized by several broadly-neutralizing mAbs (VRC01, NIH45-46, 12A12, PG9, PG16, PGT128, 4E10, and 10E8), and well neutralized by only 2 (PGT145 and 10-1074).
Cai2017
(neutralization)
-
PGT128: Man9-V3, a synthetic minimal immunogen designed to reflect the HIV-1 native Env V3-glycan bNAb epitope, binds memory B cells and V3-glycan bNAbs as well as germline bNAbs. Man9-V3 was used to isolate a bNAb from an HIV-1+ subject and also induce V3-glycan-targeting antibodies in rhesus macaques. Using the crystal structure of PGT128-gp120 Env OD (outer domain), Man9-V3 glycopeptide was synthesized based on Clade B JRFL with deletion of residues 305-320, retention of P321 and stabilization of disulfide bridge C296-C331. PGT128 neutralization of Man9-V3 was biphasic. Lower-order oligomannose glycans (Man5 and Man6) did not bind PGT128.
Alam2017
(antibody binding site)
-
PGT128: Mice twice-primed with DNA plasmids encoding HIV-1 gp120 and gag and given a double boost with HIV-1 virus-like particles (VLPs) i.e. DDVV immunization, elicited Env-specific antibody responses as well as Env- and Gag-specific CTL responses. In vivo electroporation (EP) was used to increase breadth and potency of response. Human anti-gp120 high mannose patch (centered on N137, N301, N332, N397) PGT128 was used to prove that the VLP spike included the broad neutralization epitope recognized by it.
Huang2017a
(therapeutic vaccine, variant cross-reactivity)
-
PGT128: The next generation of a computational neutralization fingerprinting (NFP) being used as a way to predict polyclonal Ab responses to HIV infection is presented. A new panel of 20 pseudoviruses, termed f61, was developed to aid in the assessment of experimental neutralization. This panel was used to assess 22 well-characterized bNAbs and mixtures thereof (HJ16, VRC01, 8ANC195, IGg1b12, PGT121, PGT128, PGT135, PG9, PGT151, 35O22, 10E8, 2F5, 4E10, VRC27, VRC-CH31, VRC-PG20, PG04, VRC23, 12A12, 3BNC117, PGT145, CH01). The new algorithms accurately predicted VRC01-like and PG9-like antibody specificities.
Doria-Rose2017
(neutralization, computational prediction)
-
PGT128: This review summarizes vaccine approaches to counter HIV diversity. A structural map illustrated the contact regions of several bNAbs: VRC26.09, PGT128, CH235.12, and 10E8. Structures illustrating the bNAbs' tolerance for sequence variation were illustrated for CH235.12, PGT128, VRC26.09, and 10E8. CD4BS bNAbs such as VRC01 and CH235.12 illustrate that bNAbs bind to both conserved and hypervariable regions of Env.
Korber2017
(antibody binding site, vaccine antigen design, review)
-
PGT128: The study isolated 3 new V3-glycan antibody lineages (DH270, DH272, DH475) from donor CH848, who was followed for 5 years starting from the time of transmission. The DH272 and DH475 lineages had neutralization patterns that likely selected for observed viral escape variants, which, in turn, stimulated the DH270 lineage to potent neutralization breadth. DH270 antibodies were recovered from memory B cells at all three sampling times (weeks 205, 232, and 234 post-infection). Like some previously-characterized Abs (PGT121, PGT128, 10-1074), the DH270 lineage mAbs bound to Env N332, and their neutralization was reduced or abrogated by mutation of this residue. PGT128 neutralized 128/207 heterologous pseudoviruses with IC50 value of <50 μ/ml and demonstrated an inverse correlation between potency and V1 length. Structural analysis determined that gp140 trimer-bound DH270.1 Fabs, compared to PGT124, PGT128 or PGT135 Fabs, had a more horizontal orientation.
Bonsignori2017
(antibody binding site, neutralization, structure)
-
PGT128: This study performed cyclical permutation of the V1 loop of JRFL in order to develop better gp120 trimers to elicit neutralizing antibodies. Some mutated trimers showed improved binding to several mAbs, including VRC01, VRC03, VRC-PG04, PGT128, PGT145, PGDM1400, b6, and F105. Guinea pigs immunized with prospective trimers showed improved neutralization of a panel of HIV-1 pseudoviruses. Binding of PGT128 to JRFL was abolished by mutation N332T.
Kesavardhana2017
(vaccine antigen design, vaccine-induced immune responses)
-
PGT128: The study compared the binding characteristics of V3-glycan antibodies, specifically PGT121, PGT128, PGT135, PCDN38A, and 3 newly-derived lineages of mAbs from Donor N170. The gene usage for PGT128 is given as: IGHV 4-39*07, IGHJ 5*02, IGLV L3-8*01, IGLJ L2 or 3.
Longo2016
(antibody binding site, antibody sequence, germline)
-
PGT128: This study investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit NAbs. Rabbits were immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). N197 glycan- and residue 230- removal conferred sensitivity to Trimer VLP sera and DNA trimer sera respectively, showing for the first time that strain-specific holes in the "glycan fence" can allow the development of tier 2 NAbs to native spikes. All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. PGT128 was 1 of 2 reference PGT128-like bNAbs - PGT121 and PGT128.
Crooks2015
(glycosylation, neutralization)
-
PGT128: New antibodies were isolated from 3 patients: Donor 14 (PDGM11, PGDM12, PGDM13, PGDM14), Donor 82 (PGDM21), and Donor 26 (PGDM31). These bnAbs bound both the GDIR peptide (Env 324-327) and the high-mannose patch glycans, enabling broad reactivity. N332 glycan was absolutely required for neutralization, while N301 glycan modestly affected neutralization. Removing N156 and N301 glycans together while retaining N332 glycan abrogated neutralization for PGDM12 and PGDM21. Neutralization by PGDM11-14 bnAbs depended on R327A and H330A substitutions and neutralization by PGDM21 depended on D325A and H330A substitutions. G324A mutation resulted in slight loss of neutralization for both antibody families. In comparison, 2G12 and PGT135 did not show any dependence on residues in the 324GDIR327 region for neutralization activity, although PGT135 did show dependence on H330.
Sok2016
(antibody binding site, glycosylation)
-
PGT128: Chimeric antigen receptors, i.e., fusion proteins made from single-chain antibodies, may be a useful approach to immunotherapy. A set of mAbs were chosen based on their binding to a variety of sites on Env and availability of antibody sequences. The chimeric receptors were created by fusing the antibody's heavy chain, light chain, and two signaling domains into a single molecule. All 7 antibodies used to make the chimeric receptors (10E8, 3BNC117, PGT126, VRC01, X5, PGT128, PG9) showed specific killing of HIV-1 infected cells and suppression of viral replication against a panel of HIV-1 strains.
Ali2016
(immunotherapy, chimeric antibody)
-
PGT128: This review classified and mapped the binding regions of 32 bNAbs isolated 2010-2016.
Wu2016
(review)
-
PGT128: This study produced Env SOSIP trimers for clades A (strain BG505), B (strain JR-FL), and G (strain X1193). Based on simulations, the MAb-trimer structures of all MAbs tested needed to accommodate at least one glycan, including both antibodies known to require specific glycans (PG9, PGT121, PGT135, 8ANC195, 35O22) and those that bind the CD4-binding site (b12, CH103, HJ16, VRC01, VRC13). A subset of monoclonal antibodies bound to glycan arrays assayed on glass slides (VRC26.09, PGT121, 2G12, PGT128, VRC13, PGT151, 35O22), while most of the antibodies did not have affinity for oligosaccharide in the context of a glycan array (PG9, PGT145, PGDM1400, PGT135, b12, CH103, HJ16, VRC16, VRC01, VRC-PG04, VRC-CH31, VRC-PG20, 3BNC60, 12A12, VRC18b, VRC23, VRC27, 1B2530, 8ANC131, 8ANC134, 8ANC195).
Stewart-Jones2016
(antibody binding site, glycosylation, structure)
-
PGT128: This review summarizes representative anti-HIV MAbs of the first generation (2G12, b12, 2F5, 4E10) and second generation (PG9, PG16, PGT145, VRC26.09, PGDM1400, PGT121, PGT124, PGT128, PGT135, 10-1074, VRC01, 3BNC117, CH103, PGT151, 35O22, 8ANC195, 10E8). Structures, epitopes, VDJ usage, CDR usage, and degree of somatic hypermutation are compared among these antibodies. The use of SOSIP trimers as immunogens to elicit B-cell responses is discussed.
Burton2016
(review, structure)
-
PGT128: HIV-1 bNAb eptiope networks were predicted using 4 algorithms informed by neutralization assays using 282 Env from multiclade viruses. Patch clusters of possible Ab epitope regions were tested for significant sensitivity by site-directed mutagenesis. Epitope (Ab binding site) networks of critical Env residues for 21 bNAb (b12, PG9, PG16, PGT121, PGT122, PGT123, PGT125, PGT126, PGT127, PGT128, PGT130, PGT131, PGT135, PGT136, PGT137, PGT141, PGT142, PGT143, PGT144, PGT145 and PGV04) were delineated and found to be located mostly in variable loops of gp120, particularly in V1/V2.
Evans2014
(antibody binding site, computational prediction)
-
PGT128: Two stable homogenous gp140 Env trimer spikes, Clade A 92UG037.8 Env and Clade C C97ZA012 Env, were identified. 293T cells stably transfected with either presented fully functional surface timers, 50% of which were uncleaved. A panel of neutralizing and non-neutralizing Abs were tested for binding to the trimers. V3 glycan bNAb PGT128 bound cell surface tightly whether the trimer contained its C-terminal or not, and was sometimes weakly competed out by sCD4. It was able to neutralize the 92UG037.8 HIV-1 isolate weakly.
Chen2015
(neutralization, binding affinity)
-
PGT128: Factors that independently affect bNAb induction and evolution were identified as viral load, length of untreated infection, and viral diversity. Black subjects induced bNAbs more than white subjects, but this did not correlate with type of Ab response. Fingerprint analyses of induced bNAbs showed strong subtype dependency, with subtype B inducing significantly higher levels of CD4bs Abs and non-subtype B inducing V2-glycan specific Abs. Of the 239 bNAb antibody inducers found from 4,484 HIV-1 infected subjects,the top 105 inducers' neutralization fingerprint and epitope specificity was determined by comparison to the following antibodies - PG9, PG16, PGDM1400, PGT145 (V2 glycan); PGT121, PGT128, PGT130 (V3 glycan); VRC01, PGV04 (CD4bs) and PGT151 (interface) and 2F5, 4E10, 10E8 (MPER).
Rusert2016
(neutralization, subtype comparisons, broad neutralizer)
-
PGT128: The first generation of HIV trimer soluble immunogens, BG505 SOSIP.664 were tested in a mouse model for generation of nAb to neutralization-resistant circulating HIV strains. No such NAbs were induced, as mouse Abs targeted the bottom of soluble Env trimers, suggesting that the glycan shield of Env trimers is impenetrable to murine B cell receptors and that epitopes at the trimer base should be obscured in immunogen design in order to avoid non-nAb responses. Association and dissociation of known anti-trimer bNAbs (VRC01, PGT121, PGT128, PGT151, PGT135, PG9, 35O22, 3BC315 and PGT145) were found to be far greater than murine generated non-NAbs.
Hu2015
-
PGT128: A comprehensive antigenic map of the cleaved trimer BG505 SOSIP.664 was made by bNAb cross-competition. Epitope clusters at the CD4bs, quaternary V1/V2 glycan, N332-oligomannose patch and new gp120-gp41 interface and their interactions were delineated. Epitope overlap, proximal steric inhibition, allosteric inhibition or reorientation of glycans were seen in Ab cross-competition. Thus bNAb binding to trimers can affect surfaces beyond their epitopes. PGT128, PGT121, PGT122, PGT123, PGT125 and PGT126, all N332-V3 glycan oligomannose patch bNAbs, were strongly, reciprocally competitive with one another. PGT128 also inhibited binding of CD4bs Abs, CH31 and VRC01 and markedly but incompletely inhibited CD4-IgG2. Reciprocal enhancement of binding was seen between NIH45-46 and PGT128.
Derking2015
(antibody interactions, neutralization, binding affinity, structure)
-
PGT128: Env trimer BG505 SOSIP.664 as well as the clade B trimer B41 SOSIP.664 were stabilized using a bifunctional aldehyde (glutaraldehye, GLA) or a heterobifunctional cross-linker, EDC/NHS with modest effects on antigenicity and barely any on biochemistry or structural morphology. ELISA, DSC and SPR were used to test recognition of the trimers by bNAbs, which was preserved and by weakly NAbs or non-NAbs, which was reduced. Cross-linking partially preserves quaternary morphology so that affinity chromatography by positive selection using quaternary epitope-specific bNAabs, and negative selection using non-NAbs, enriched antigenic characteristics of the trimers. Binding of the anti-N332-supersite glycan bNAb PGT128 to trimers was minimally affected by trimer cross-linking.
Schiffner2016
(assay or method development, binding affinity, structure)
-
PGT128: A new trimeric immunogen, BG505 SOSIP.664 gp140, was developed that bound and activated most known neutralizing antibodies but generally did not bind antibodies lacking neuralizing activity. This highly stable immunogen mimics the Env spike of subtype A transmitted/founder (T/F) HIV-1 strain, BG505. Anti-V3 glycan bNAb PGT128, neutralized BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, and was shown to recognize and bind the immunogen too.
Sanders2013
(assay or method development, neutralization, binding affinity)
-
PGT128: Using an escape virus isolated from the PGT125-131 donor, this study found that mutating the V3 core and repositioning critical N-linked glycosylations N295 and N332 could restore virus sensitivity. PGT128 and PGT130 required different sets of changes in order to restore sensitivity, suggesting that this family of bNAbs has two recognition classes (Fig. 2). For example N332 repositioning and 7 amino acid mutations V307I, H308R, E321D, V322I, N325D, P326I, F320H restored PGT128 but not PGT130 virus sensitivity.
Krumm2016
(glycosylation, escape)
-
PGT128: This paper analyzed site-specific glycosylation of a soluble, recombinant trimer (BG505 SOSIP.664). This trimer mapped the extremes of simplicity and diversity of glycan processing at individual sites and revealed a mosaic of dense clusters of oligomannose glycans on the outer domain. Although individual sites usually minimally affect the global integrity of the glycan shield, they identified examples of how deleting some glycans can subtly influence neutralization by bNAbs that bind at distant sites. The network of bNAb-targeted glycans should be preserved on vaccine antigens. Neutralization profiles for mannose-patch binding Ab, PGT128, to multiple epitopes were determined. Deleting the N137 glycan rendered both BG505 test viruses more sensitive to PGT128. Removing the N262, N295 and N301 glycans from either of the BG505 test viruses reduced the neutralization activities of PGT128. The glycan epitopes for PGT128 are particularly strongly impaired when the N448 glycan is deleted from the BG505.T332 virus.
Behrens2016
(antibody binding site, glycosylation)
-
PGT128: A mathematical model was developed to predict the Ab concentration at which antibody escape variants outcompete their ancestors, and this concentration was termed the mutant selection window (MSW). The MSW was determined experimentally for 12 pairings of diverse HIV strains against 7 bnAbs (b12, 2G12, PG9, PG16, PGT121, PGT128, 2F5). The neutralization of PGT128 was assayed against BG505 (resistant strain) and BG505-T332N (sensitive strain).
Magnus2016
(neutralization, escape)
-
PGT128: The study detailed binding kinetics of the interaction between BG505 SOSIP.664 trimer or its variants (gp120 monomer; first study of disulfide-stabilized variant gp120-gp41ECTO protomer) and several mAbs, both neutralizing (VRC01, PGV04, PG9, PG16, PGT121, PGT122, PGT123, PGT145, PGT151, 2G12) and non-neutralizing (b6, b12, 14e, 19b, F240). V3-base-dependent bNAb, PGT128, recognized trimer better than protomer and monomer, but dissociated faster from protomer, monomer.
Yasmeen2014
(antibody binding site, assay or method development)
-
PGT128: A new, current, mostly tier2 panel of 200 C-clade Env-psuedotyped viruses from early (< 100d) infection in southern Africa was used to assess antibody responses to natural infection and to vaccines. Viruses were assayed with bNAbs targeting the V2 glycan (PG9, VRC26.25), the MPER site (4E10), the CD4 binding site (VRC01), and the V3/C3 glycan site (PGT128). For PGT128 (but no other Abs tested) pre-seroconversion viruses were significantly more resistant to neutralization than were post-seroconversion viruses. Viruses collected pre-seroconversion were also more resistant to neutralization by serum than those post-seroconversion. As the epidemic matured over 13 years, viruses became more resistant to mAbs tested as well.
Rademeyer2016
(assay or method development, neutralization)
-
PGT128: This study examined the neutralization of group N, O, and P primary isolates of HIV-1 by diverse antibodies. Cross-group neutralization was observed only with the bNAbs targeting the N160 glycan-V1/V2 site. Four group O isolates, 1 group N isolate, and the group P isolates were neutralized by PG9 and/or PG16 or PGT145 at low concentrations. None of the non-M primary isolates were neutralized by bNAbs targeting other regions, except 10E8, which weakly neutralized 2 group N isolates, and 35O22 which neutralized 1 group O isolate. Bispecific bNAbs (PG9-iMab and PG16-iMab) very efficiently neutralized all non-M isolates with IC50 below 1 ug/mL, except for 2 group O strains. Anti-V3 bNAb PGT128 was unable to neutralize any of the 16 tested non-M primary isolates at an IC50< 10µg/ml.
Morgand2015
(neutralization)
-
PGT128: Using improved technologies in high-resolution, single-particle cryoelectron microscopy, this study refines and builds natively glycosylated high mannose patch-binding bnAb PGT128 HIV-1 Env structures in solution to 4.36 angstrom resolution. This structure was used to analyze the complete epitope of PGT128, in the context of the trimer expressed with native glycans for the first time. Differences seen from the previous X-ray structure include (1) a more disordered, less helical structure for both the α0 of gp12059-63 and C-terminus gp41 as well as (2) a downward shift in the HR2 helix of gp41 with respect to PGT128.
Lee2015a
(structure)
-
PGT128: The neutralization of 14 bnAbs was assayed against a global panel of 12 or 17 Env pseudoviruses. From IC50, IC80, IC90, and IC99 values, the slope of the dose-response curve was calculated. Each class of Ab had a fairly consistent slope. Neutralization breadth was strongly correlated with slope. An IIP (Instantaneous Inhibitory Potential) value was calculated, based on both the slope and IC50, and this value may be predictive of clinical efficacy. PGT128, a V3-glycan bnAb belonged to a group with slopes >1.
Webb2015
(neutralization)
-
PGT128: This study evaluated the binding of 15 inferred germline (gl) precursors of bNAbs that are directed to different epitope clusters, to 3 soluble native-like SOSIP.664 Env trimers - BG505, B41 and ZM197M. The trimers bound to some gl precursors, particularly those of V1V2-targeted Abs. These trimers may be useful for designing immunogens able to target gl precursors. V3 glycan-binding gl-PGT128 did not bind to any trimers.
Sliepen2015
(binding affinity, antibody lineage)
-
PGT128: The crystal structure of the BG505 SOSIP Env trimer in complex with PGT128 and 8ANC195 revealed the antibody epitopes and sites of Env vulnerability. PGT128 was shown to bind N137, N156, N301,and N332, with an indirect interaction with N262. 8ANC195 was shown to bind to N234, N276, and N637.
Kong2015a
(structure)
-
PGT128: Computational modeling was used to examine antibody recognition of glycans, using a V1V2 bNAb (PG9) and a V3 bnAb (PGT128). Both PG9 and PGT128 have a long CDR H3 loop that can penetrate the glycan shield and form interactions with gp120. The modeling results showed that the tip of the CDR H3 loop is flexible in the free antibodies and is able to move within the bound conformation, which likely increases the possibility to penetrate the glycan shield.
Qi2016
(glycosylation)
-
PGT128: The IGHV region is central to Ag binding and consists of 48 functional genes. IGHV repertoire of 28 HIV-infected South African women, 13 of whom developed bNAbs, was sequenced. Novel IGHV repertoires were reported, including 85 entirely novel sequences and 38 sequences that matched rearranged sequences in non-IMGT databases. There were no significant differences in germline IGHV repertoires between individuals who do and do not develop bNAbs. IGHV gene usage of multiple well known HIV-1 bNAbs was also analyzed and 14 instances were identified where the novel non-IMGT alleles identified in this study, provided the same or a better match than their currently defined IMGT allele. For PGT128 the published IMGT predicted allele was IGHV4-39*07 and alternate allele predicted from IGHV alleles in 28 South African individuals was IGHV4-39*7m2, with synonymous G298C nucleotide change.
Scheepers2015
(antibody lineage)
-
PGT128: This review summarized bNAb immunotherapy studies. Several bnAbs have been shown to decrease viremia in vivo, and are a prospect for preventative vaccinations. bNAbs have 3 possible immune effector functions: (1) directly neutralizing virions, (2) mediating anti-viral activity through Fc-FcR interactions, and (3) binding to viral antigen to be taken up by dendritic cells. In contrast to anti-HIV mAbs, antibodies against host cell CD4 and CCR5 receptors (iMab and PRO 140) are hindered by their short half-life in vivo. MAb PGT128 has been associated with viral suppression in humanized mice.
Halper-Stromberg2016
(immunotherapy, review)
-
PGT128: A large cross-sectional study of sera from 205 ART-naive patients infected with different HIV clades was tested against a panel of 219 cross-clade Env-pseudotyped viruses. Their neutralization was compared to the neutralization of 10 human bNAbs (10E8, 4E10, VRC01, PG9, PGT145, PGT128, 2F5, CH01, b12, 2G12) tested with a panel of 119 Env-pseudotyped viruses. Results from b12 and 2G12 suggested that these bnAbs may not be as broadly neutralizing as previously thought. PGT128 neutralized 59% of the 199 viruses tested.
Hraber2014
(neutralization)
-
PGT128: Double, triple or quadruple combinations of fifteen bNAbs that target 4 distinct epitope regions: the CD4 binding site (3BNC117, VRC01, VRC07, VRC07-523, VRC13), the V3-glycan supersite (10–1074, 10-1074V, PGT121, PGT128), the V1/V2-glycan site (PG9, PGT145, PGDM1400, CAP256-VRC26.08, CAP256-VRC26.25), and the gp41 MPER epitope (10E8) were studied. Their neutralization potency and breadth were assayed against a panel of 200 acute/early subtype C strains, and compared to a novel, highly accurate predictive mathematical model (no-overlap Bliss Hill model, CombiNaber tool, LANL HIV Immunology database). These data were used to predict the best combinations of bNAbs for immunotherapy.
Wagh2016
(neutralization, immunotherapy)
-
PGT128: This study describes a new level of complexity in antibody recognition of the mixed glycan-protein epitopes of the N332 region of HIV gp120. A combination of three antibody families that target the high-mannose patch can lead to 99% neutralization coverage of a large panel of viruses containing the N332/334 glycan site and up to 66% coverage for viruses that lack the N332/334 glycan site. PGT128 was only capable of neutralizing half of the N334 isolates.The PGT121 family of antibodies neutralized N332 glycan site viruses more effectively overall than the PGT128 family or PGT135.
Sok2014a
(antibody interactions, glycosylation)
-
PGT128: Incomplete neutralization may decrease the ability of bnAbs to protect against HIV exposure. In order to determine the extent of non-sigmoidal slopes that plateau at <100% neutralization, a panel of 24 bnMAbs targeting different regions on Env was tested in a quantitative pseudovirus neutralization assay on a panel of 278 viral clones. All bNAbs had some viruses that they neutralized with a plateau <100%, but those targeting the V2 apex and MPER did so more often. All bnMAbs assayed had some viruses for which they had incomplete neutralization and non-sigmoidal neutralization curves. bNAbs were grouped into 3 groups based on their neutralization curves: group 1 antibodies neutralized more than 90% of susceptible viruses to >95% (PGT121-123, PGT125-128, PGT136, PGV04); group 2 was less effective, resulting in neutralization of 60-84% of susceptible viruses to >95% (b12, PGT130-131, PGT135, PGT137, PGT141-143, PGT145, 2G12, PG9); group 3 neutralized only 36-60% of susceptible viruses to >95% (PG16, PGT144, 2F5, 4E10).
McCoy2015
(neutralization)
-
PGT128: Vectored Immuno Prophylaxis (VIP), involves passive immunization by viral vector-mediated delivery of genes encoding bnAbs for in vivo expression. Robust protection against virus infection was observed in preclinical settings when animals were given VIP to express monoclonal neutralizing Abs. This review article surveyed the status of antibody gene transfer, VIP experiments against HIV and its related virus conduced in humanized mice and macaque monkeys, and discuss the pros and cons of VIP and its opportunities and challenges towards clinical applications to control HIV/AIDS endemics.
Yang2014
(immunoprophylaxis, review, antibody gene transfer)
-
PGT128: Computational prediction of bNAb epitopes from experimental neutralization activity data is presented. The approach relies on compressed sensing (CS) and mutual information (MI) methodologies and requires the sequences of the viral strains but does not require structural information. For PGT128, CS predicted 23 and MI predicted 2 positions, overlapping in positions 332, 334.
Ferguson2013
(computational prediction, broad neutralizer)
-
PGT128: To focus the immune response to sites of NAb vulnerability while avoiding immune-evasion by the rest of Env, MPER, V1/V2, and V3 glycan sites were transplanted onto algorithm-identified acceptor scaffolds (proteins with a backbone geometry that recapitulates the antigenicity of the transplanted site). 7/22 short V3 glycan transplants (contained only 3 N-linked glycans and 25 Env residues), were highly successful in eliciting a robust PGT128 response.
Zhou2014
(vaccine antigen design)
-
PGT128: The crystal structure of PGT135 with gp120, CD4 and Fab 17b was analyzed to study how PGT135 recognizes its Asn332 glycan-dependent epitope. The combined structural studies of PGT 135, PGT 128 and 2G12 show this Asn332-dependent epitope is highly accessible and much more extensive than initially appreciated, allowing for multiple binding modes and varied angles of approach, thus representing a supersite of vulnerability for antibody neutralization.
Kong2013
(structure)
-
PGT128: This is a review of identified bNAbs, including the ontogeny of B cells that give rise to these antibodies. Breadth and magnitude of neutralization, unique features and similar bNAbs are listed. PGT128 is a V3-glycan Ab, with breadth 56%, IC50 0.11 μg per ml, and its unique feature listed is that it recognizes V3 glycan. Similar MAbs include PGT125-127, PGT130, PGT131.
Kwong2013
(review)
-
PGT128: The newly identified and defined epitope for PGT151 family MAbs binds to a site of vulnerability that does not overlap with any other bnAb epitopes. PGT128 was used as an anti-gp41 mAb to compare its binding with other PGT151 family Abs.
Blattner2014
-
PGT128: 8 bNAbs (PGT151 family) were isolated from an elite neutralizer. The new bNAbs bind a previously unknown glycan-dependent epitope on the prefusion conformation of gp41. These MAbs are specific for the cleaved Env trimer and do not recognize uncleaved Env trimer. PGT128 was used for comparison.
Falkowska2014
-
PGT128: A statistical model selection method was used to identify a global panel of 12 reference Env clones among 219 Env-pseudotyped viruses that represent the spectrum of neutralizing activity seen with sera from 205 chronically HIV-1-infected individuals. This small final panel was also highly sensitive for detection of many of the known bNAbs, including this one. The small panel of 12 Env clones should facilitate assessments of vacine-elicited NAbs.
Decamp2014
(assay or method development)
-
PGT128:X-ray crystallography, surface plasmon resonance and pseudovirus neutralization were used to characterize a heavy chain only llama antibody, named JM4. The full-length IgG2b version of JM4 neutralizes over 95% of circulating HIV-1 isolates. JM4 targets a hybrid epitope on gp120 that combines elements from both the CD4 binding region and the coreceptor binding surface. JM4 IgG2b was able to potently neutralize the HIV-1 isolates that were resistant to PGT128.
Acharya2013
(neutralization)
-
PGT128: This is a review of a satellite symposium at the AIDS Vaccine 2012 conference, focusing on antibody gene transfer. Michel Nussenzweig presented studies exploring the possibility that antibodies might also be used to treat established infections. They found that combinations of five broadly neutralizing antibodies NIH45-46G54W, PG16, PGT128, 10-1074 and 3BC176 MAbs, controlled HIV-1 infection and suppressed the viral load to below the limit of detection during the entire therapy period of up to 60 days.
Balazs2013
(immunoprophylaxis, immunotherapy)
-
PGT128: Diversity of Ab recognition at the N332 site was assessed using chimeric antibodies made of heavy and light chains of N332-directed bNAbs PGT121-137. Recognition was good when heavy and light chains came from the same donor, and poor when they came from different donors, indicating multiple modes of recognition.
Pancera2013a
(chimeric antibody)
-
PGT128: "Neutralization fingerprints" for 30 neutralizing antibodies were determined using a panel of 34 diverse HIV-1 strains. 10 antibody clusters were defined: VRC01-like, PG9-like, PGT128-like, 2F5-like, 10E8-like and separate clusters for b12, CD4, 2G12, HJ16, 8ANC195.
Georgiev2013
(neutralization)
-
PGT128: This study uncovered a potentially significant contribution of VH replacement products which are highly enriched in IgH genes for the generation of anti-HIV Abs including anti-gp41, anti-V3 loop, anti-gp120, CD4i and PGT Abs. IgH encoding PGT Abs are likely generated from multiple rounds of VH replacements. The details of PGT128 VH replacement products in IgH gene and mutations and amino acid sequence analysis are described in Table 1, Table 2 and Fig 4.
Liao2013a
(antibody sequence)
-
PGT128: Neutralization profiles of 7 bnAbs were analyzed against 45 Envs (A, C, D clades), obtained soon after infection (median 59 days). The transmitted variants have distinct characteristics compared to variants from chronic patients, such as shorter variable loops and fewer potential N-linked glycosylation sites (PNGS). PGT128 neutralized only 27% of these viruses. However, PGT128 and NIH45-46W did not compete for neutralization and a combination of these mAbs neutralized 96% of these viruses, with PGT121 neutralizing the only 2 viruses not neutralized by this combination. This suggests that optimal neutralization coverage of transmitted variants can be achieved by combining a potent CD4bs NAb with one or more glycan-dependent mAbs.
Goo2012
(antibody interactions, neutralization, rate of progression)
-
PGT128: Identification of broadly neutralizing antibodies, their epitopes on the HIV-1 spike, the molecular basis for their remarkable breadth, and the B cell ontogenies of their generation and maturation are reviewed. Ontogeny and structure-based classification is presented, based on MAb binding site, type (structural mode of recognition), class (related ontogenies in separate donors) and family (clonal lineage). This MAb's classification: gp120 glycan-V3 site, type penetrating CDR H3 binds two glycans and strand, PGT128 class, PGT128 family.
Kwong2012
(review, structure, broad neutralizer)
-
PGT128: This review discusses the new research developments in bnAbs for HIV-1, Influenza, HCV. Models of the HIV-1 Env spike and of Influenza visrus spike with select bnAbs bound are shown.
Burton2012
(review)
-
PGT128: This review discusses how analysis of infection and vaccine candidate-induced antibodies and their genes may guide vaccine design. This MAb is listed as V3 epitope involving carbohydrates bnAb, isolated after 2009 by neutralization screening of cultured, unselected IgG+ memory B cells.
Bonsignori2012b
(vaccine antigen design, vaccine-induced immune responses, review)
-
PGT128: Somatic hypermutations are preferably found in CDR loops, which alter the Ab combining sites, but not the overall structure of the variable domain. FWR of CDR are usually resistant to and less tolerant of mutations. This study reports that most bnAbs require somatic mutations in the FWRs which provide flexibility, increasing Ab breadth and potency. To determine the consequence of FWR mutations the framework residues were reverted to the Ab's germline counterpart (FWR-GL) and binding and neutralizing properties were then evaluated. PGT128, which recognizes the base of the V3 loop, was among the 17 bnAbs which were used in studying the mutations in FWR. PGT128 was used in comparing the Ab framework amino acid replacement vs. interactive surface area on Ab.
Klein2013
(neutralization, structure, antibody lineage)
-
PGT128: Glycan shield of HIV Env protein helps to escape the Ab recognition. Several of the PGT BnAbs interact directly with the HIV glycan coat. Crystal structures of Fabs PGT127 and PGT128 showed that the high neutralizing potency was mediated by cross-linking Env trimers on the viral surface. PGT128 binds to Man8/9 glycans on gp120 and potently neutralize across the clades.
Pejchal2011
(glycosylation, structure, broad neutralizer)
-
PGT128: Glycan Asn332-targeting broadly cross-neutralizing (BCN) antibodies were studied in 2 C-clade infected women. The ASn332 glycan was absent on infecting virus, but the BCN epitope with Asn332 evolved within 6 months though immune escape from earlier antibodies. Plasma from the subject CAP177 neutralized 88% of a large multi-subtype panel of 225 heterologous viruses, whereas CAP 314 neutralized 46% of 41 heterologous viruses but failed to neutralize viruses that lack glycan at 332. Crystal structure revealed that PGT128 penetrates the glycan shield and target high mannose glycans at 302 and 332 to neutralize.
Moore2012
(neutralization, escape, structure)
-
PGT128: The use of computationally derived B cell clonal lineages as templates for HIV-1 immunogen design is discussed. PGT128 has been discussed in terms of immunogenic and functional characteristics of representative HIV-1 BnAbs and their reactions to antigens.
Haynes2012
(antibody interactions, memory cells, vaccine antigen design, review, antibody polyreactivity, broad neutralizer)
-
PGT128: HIV therapy by combinations of 5 bNAbs was tested in YU2-infected humanized mice. Penta-mix (PG16, 45-46W, 3BC176, PGT128 and 10-1074) was the most effective in controlling viraemia compared to tri-mix (PG16, 45-46, 3BC176) and monotherapy (Fig S9). Viral escape with PGT128 monotherapy was associated with mutations at residues 332 or 334, both of which abrogate the potential N-linked glycosylation site in V1/V2 loop.
Klein2012a
(escape, immunotherapy)
-
PGT128: Several antibodies including 10-1074 were isolated from B-cell clone encoding PGT121, from a clade A-infected African donor using YU-2 gp140 trimers as bait. These antibodies were segregated into PGT121-like (PGT121-123 and 9 members) and 10-1074-like (20 members) groups distinguished by sequence, binding affinity, carbohydrate recognition, neutralizing activity, the V3 loop binding and the role of glycans in epitope formation. PGT128 was used as a control in virus neutralization assay. Detail information on the binding and neutralization assays are described in the figures S2-S11.
Mouquet2012a
(glycosylation, binding affinity, broad neutralizer)
-
PGT128: Neutralizing antibody repertoires of 4 HIV-infected donors with remarkably broad and potent neutralizing responses were probed. 17 new monoclonal antibodies that neutralize broadly across clades were rescued. These MAbs were not polyreactive. All MAbs exhibited broad cross-clade neutralizing activity, but several showed exceptional potency. PGT128 neutralized 72% of 162 isolates from major HIV clades at IC50<50 μg/ml, which was lower than 93% by VRC01, but the median antibody concentration required to inhibit HIV activity by 50% or 90% (IC50 and IC90 values) was almost 10-fold lower (that is, more potent) that of PG9, VRC01 and PGV04, and 100-fold lower than that of b12, 2G12 and 4E10. PGT MAbs 121-123, 130, 131 and 135-137 bound to monomeric gp120 and competed with glycan-specific 2G12 MAb and all MAbs except PGT 135-137 also competed with a V3-loop-specific antibody and did not bind to gp120ΔV3, suggesting that their epitopes are in proximity to or contiguous with V3. Glycan array analysis revealed that PGT MAbs 125–128 and 130 bound specifically to both Man8GlcNAc2 and Man9GlcNAc2, whereas the remaining antibodies showed no detectable binding to high-mannose glycans. Alanine substitution analysis suggested that N-linked glycans at positions 332 and/or 301 were important for neutralization by PGT MAbs 125–128, 130 and 131, suggesting their direct involvement in epitope formation.
Walker2011
(antibody binding site, antibody generation, variant cross-reactivity, broad neutralizer)
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Hannah J. Barbian, Julie M. Decker, Frederic Bibollet-Ruche, Rachel P. Galimidi, Anthony P. West, Jr., Gerald H. Learn, Nicholas F. Parrish, Shilpa S. Iyer, Yingying Li, Craig S. Pace, Ruijiang Song, Yaoxing Huang, Thomas N. Denny, Hugo Mouquet, Loic Martin, Priyamvada Acharya, Baoshan Zhang, Peter D. Kwong, John R. Mascola, C. Theo Verrips, Nika M. Strokappe, Lucy Rutten, Laura E. McCoy, Robin A. Weiss, Corrine S. Brown, Raven Jackson, Guido Silvestri, Mark Connors, Dennis R. Burton, George M. Shaw, Michel C. Nussenzweig, Pamela J. Bjorkman, David D. Ho, Michael Farzan, and Beatrice H. Hahn. Neutralization Properties of Simian Immunodeficiency Viruses Infecting Chimpanzees and Gorillas. mBio, 6(2), 21 Apr 2015. PubMed ID: 25900654.
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Beauparlant2017
David Beauparlant, Peter Rusert, Carsten Magnus, Claus Kadelka, Jacqueline Weber, Therese Uhr, Osvaldo Zagordi, Corinna Oberle, Maria J. Duenas-Decamp, Paul R. Clapham, Karin J. Metzner, Huldrych F. Günthard, and Alexandra Trkola. Delineating CD4 Dependency of HIV-1: Adaptation to Infect Low Level CD4 Expressing Target Cells Widens Cellular Tropism But Severely Impacts on Envelope Functionality. PLoS Pathog., 13(3):e1006255, Mar 2017. PubMed ID: 28264054.
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Behrens2016
Anna-Janina Behrens, Snezana Vasiljevic, Laura K. Pritchard, David J. Harvey, Rajinder S. Andev, Stefanie A. Krumm, Weston B. Struwe, Albert Cupo, Abhinav Kumar, Nicole Zitzmann, Gemma E. Seabright, Holger B. Kramer, Daniel I. R. Spencer, Louise Royle, Jeong Hyun Lee, Per J. Klasse, Dennis R. Burton, Ian A. Wilson, Andrew B. Ward, Rogier W. Sanders, John P. Moore, Katie J. Doores, and Max Crispin. Composition and Antigenic Effects of Individual Glycan Sites of a Trimeric HIV-1 Envelope Glycoprotein. Cell Rep., 14(11):2695-2706, 22 Mar 2016. PubMed ID: 26972002.
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Berendam2021
Stella J. Berendam, Tiffany M. Styles, Papa K.. Morgan-Asiedu, DeAnna Tenney, Amit Kumar, Veronica Obregon-Perko, Katharine J. Bar, Kevin O. Saunders, Sampa Santra, Kristina De Paris, Georgia D. Tomaras, Ann Chahroudi, Sallie R. Permar, Rama R. Amara, and Genevieve G. Fouda. Systematic Assessment of Antiviral Potency, Breadth, and Synergy of Triple Broadly Neutralizing Antibody Combinations against Simian-Human Immunodeficiency Viruses. J. Virol., 95(3), 13 Jan 2021. PubMed ID: 33177194.
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Blattner2014
Claudia Blattner, Jeong Hyun Lee, Kwinten Sliepen, Ronald Derking, Emilia Falkowska, Alba Torrents de la Peña, Albert Cupo, Jean-Philippe Julien, Marit van Gils, Peter S. Lee, Wenjie Peng, James C. Paulson, Pascal Poignard, Dennis R. Burton, John P. Moore, Rogier W. Sanders, Ian A. Wilson, and Andrew B. Ward. Structural Delineation of a Quaternary, Cleavage-Dependent Epitope at the gp41-gp120 Interface on Intact HIV-1 Env Trimers. Immunity, 40(5):669-680, 15 May 2014. PubMed ID: 24768348.
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Mattia Bonsignori, S. Munir Alam, Hua-Xin Liao, Laurent Verkoczy, Georgia D. Tomaras, Barton F. Haynes, and M. Anthony Moody. HIV-1 Antibodies from Infection and Vaccination: Insights for Guiding Vaccine Design. Trends Microbiol., 20(11):532-539, Nov 2012. PubMed ID: 22981828.
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Bonsignori2017
Mattia Bonsignori, Edward F. Kreider, Daniela Fera, R. Ryan Meyerhoff, Todd Bradley, Kevin Wiehe, S. Munir Alam, Baptiste Aussedat, William E. Walkowicz, Kwan-Ki Hwang, Kevin O. Saunders, Ruijun Zhang, Morgan A. Gladden, Anthony Monroe, Amit Kumar, Shi-Mao Xia, Melissa Cooper, Mark K. Louder, Krisha McKee, Robert T. Bailer, Brendan W. Pier, Claudia A. Jette, Garnett Kelsoe, Wilton B. Williams, Lynn Morris, John Kappes, Kshitij Wagh, Gift Kamanga, Myron S. Cohen, Peter T. Hraber, David C. Montefiori, Ashley Trama, Hua-Xin Liao, Thomas B. Kepler, M. Anthony Moody, Feng Gao, Samuel J. Danishefsky, John R. Mascola, George M. Shaw, Beatrice H. Hahn, Stephen C. Harrison, Bette T. Korber, and Barton F. Haynes. Staged Induction of HIV-1 Glycan-Dependent Broadly Neutralizing Antibodies. Sci. Transl. Med., 9(381), 15 Mar 2017. PubMed ID: 28298420.
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Bricault2019
Christine A. Bricault, Karina Yusim, Michael S. Seaman, Hyejin Yoon, James Theiler, Elena E. Giorgi, Kshitij Wagh, Maxwell Theiler, Peter Hraber, Jennifer P. Macke, Edward F. Kreider, Gerald H. Learn, Beatrice H. Hahn, Johannes F. Scheid, James M. Kovacs, Jennifer L. Shields, Christy L. Lavine, Fadi Ghantous, Michael Rist, Madeleine G. Bayne, George H. Neubauer, Katherine McMahan, Hanqin Peng, Coraline Chéneau, Jennifer J. Jones, Jie Zeng, Christina Ochsenbauer, Joseph P. Nkolola, Kathryn E. Stephenson, Bing Chen, S. Gnanakaran, Mattia Bonsignori, LaTonya D. Williams, Barton F. Haynes, Nicole Doria-Rose, John R. Mascola, David C. Montefiori, Dan H. Barouch, and Bette Korber. HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design. Cell Host Microbe, 25(1):59-72.e8, 9 Jan 2019. PubMed ID: 30629920.
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Burton2012
Dennis R. Burton, Pascal Poignard, Robyn L. Stanfield, and Ian A. Wilson. Broadly Neutralizing Antibodies Present New Prospects to Counter Highly Antigenically Diverse Viruses. Science, 337(6091):183-186, 13 Jul 2012. PubMed ID: 22798606.
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Burton2016
Dennis R. Burton and Lars Hangartner. Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design. Annu. Rev. Immunol., 34:635-659, 20 May 2016. PubMed ID: 27168247.
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Cai2017
Yongfei Cai, Selen Karaca-Griffin, Jia Chen, Sai Tian, Nicholas Fredette, Christine E. Linton, Sophia Rits-Volloch, Jianming Lu, Kshitij Wagh, James Theiler, Bette Korber, Michael S. Seaman, Stephen C. Harrison, Andrea Carfi, and Bing Chen. Antigenicity-Defined Conformations of an Extremely Neutralization-Resistant HIV-1 Envelope Spike. Proc. Natl. Acad. Sci. U.S.A., 114(17):4477-4482, 25 Apr 2017. PubMed ID: 28396421.
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Cai2018
Hui Cai, Rou-Shu Zhang, Jared Orwenyo, John Giddens, Qiang Yang, Celia C. LaBranche, David C. Montefiori, and Lai-Xi Wang. Synthetic HIV V3 Glycopeptide Immunogen Carrying a N334 N-Glycan Induces Glycan-Dependent Antibodies with Promiscuous Site Recognition. J. Med. Chem., 61(22):10116-10125, 21 Nov 2018. PubMed ID: 30384610.
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Chen2015
Jia Chen, James M. Kovacs, Hanqin Peng, Sophia Rits-Volloch, Jianming Lu, Donghyun Park, Elise Zablowsky, Michael S. Seaman, and Bing Chen. Effect of the Cytoplasmic Domain on Antigenic Characteristics of HIV-1 Envelope Glycoprotein. Science, 349(6244):191-195, 10 Jul 2015. PubMed ID: 26113642.
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Chuang2017
Gwo-Yu Chuang, Hui Geng, Marie Pancera, Kai Xu, Cheng Cheng, Priyamvada Acharya, Michael Chambers, Aliaksandr Druz, Yaroslav Tsybovsky, Timothy G. Wanninger, Yongping Yang, Nicole A. Doria-Rose, Ivelin S. Georgiev, Jason Gorman, M. Gordon Joyce, Sijy O'Dell, Tongqing Zhou, Adrian B. McDermott, John R. Mascola, and Peter D. Kwong. Structure-Based Design of a Soluble Prefusion-Closed HIV-1 Env Trimer with Reduced CD4 Affinity and Improved Immunogenicity. J. Virol., 91(10), 15 May 2017. PubMed ID: 28275193.
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Chuang2019
Gwo-Yu Chuang, Jing Zhou, Priyamvada Acharya, Reda Rawi, Chen-Hsiang Shen, Zizhang Sheng, Baoshan Zhang, Tongqing Zhou, Robert T. Bailer, Venkata P. Dandey, Nicole A. Doria-Rose, Mark K. Louder, Krisha McKee, John R. Mascola, Lawrence Shapiro, and Peter D. Kwong. Structural Survey of Broadly Neutralizing Antibodies Targeting the HIV-1 Env Trimer Delineates Epitope Categories and Characteristics of Recognition. Structure, 27(1):196-206.e6, 2 Jan 2019. PubMed ID: 30471922.
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Crooks2015
Ema T. Crooks, Tommy Tong, Bimal Chakrabarti, Kristin Narayan, Ivelin S. Georgiev, Sergey Menis, Xiaoxing Huang, Daniel Kulp, Keiko Osawa, Janelle Muranaka, Guillaume Stewart-Jones, Joanne Destefano, Sijy O'Dell, Celia LaBranche, James E. Robinson, David C. Montefiori, Krisha McKee, Sean X. Du, Nicole Doria-Rose, Peter D. Kwong, John R. Mascola, Ping Zhu, William R. Schief, Richard T. Wyatt, Robert G. Whalen, and James M. Binley. Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site. PLoS Pathog, 11(5):e1004932, May 2015. PubMed ID: 26023780.
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Davis-Gardner2020
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Decamp2014
Allan deCamp, Peter Hraber, Robert T. Bailer, Michael S. Seaman, Christina Ochsenbauer, John Kappes, Raphael Gottardo, Paul Edlefsen, Steve Self, Haili Tang, Kelli Greene, Hongmei Gao, Xiaoju Daniell, Marcella Sarzotti-Kelsoe, Miroslaw K. Gorny, Susan Zolla-Pazner, Celia C. LaBranche, John R. Mascola, Bette T. Korber, and David C. Montefiori. Global Panel of HIV-1 Env Reference Strains for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies. J. Virol., 88(5):2489-2507, Mar 2014. PubMed ID: 24352443.
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Derking2015
Ronald Derking, Gabriel Ozorowski, Kwinten Sliepen, Anila Yasmeen, Albert Cupo, Jonathan L. Torres, Jean-Philippe Julien, Jeong Hyun Lee, Thijs van Montfort, Steven W. de Taeye, Mark Connors, Dennis R. Burton, Ian A. Wilson, Per-Johan Klasse, Andrew B. Ward, John P. Moore, and Rogier W. Sanders. Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer. PLoS Pathog, 11(3):e1004767, Mar 2015. PubMed ID: 25807248.
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Deshpande2016
Suprit Deshpande, Shilpa Patil, Rajesh Kumar, Tandile Hermanus, Kailapuri G. Murugavel, Aylur K. Srikrishnan, Suniti Solomon, Lynn Morris, and Jayanta Bhattacharya. HIV-1 Clade C Escapes Broadly Neutralizing Autologous Antibodies with N332 Glycan Specificity by Distinct Mechanisms. Retrovirology, 13(1):60, 30 Aug 2016. PubMed ID: 27576440.
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Doria-Rose2017
Nicole A. Doria-Rose, Han R. Altae-Tran, Ryan S. Roark, Stephen D. Schmidt, Matthew S. Sutton, Mark K. Louder, Gwo-Yu Chuang, Robert T. Bailer, Valerie Cortez, Rui Kong, Krisha McKee, Sijy O'Dell, Felicia Wang, Salim S. Abdool Karim, James M. Binley, Mark Connors, Barton F. Haynes, Malcolm A. Martin, David C. Montefiori, Lynn Morris, Julie Overbaugh, Peter D. Kwong, John R. Mascola, and Ivelin S. Georgiev. Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting. PLoS Pathog., 13(1):e1006148, Jan 2017. PubMed ID: 28052137.
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Dufloo2022
Jérémy Dufloo, Cyril Planchais, Stéphane Frémont, Valérie Lorin, Florence Guivel-Benhassine, Karl Stefic, Nicoletta Casartelli, Arnaud Echard, Philippe Roingeard, Hugo Mouquet, Olivier Schwartz, and Timothée Bruel. Broadly Neutralizing Anti-HIV-1 Antibodies Tether Viral Particles at the Surface of Infected Cells. Nat. Commun., 13(1):630, 2 Feb 2022. PubMed ID: 35110562.
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Escolano2021
Amelia Escolano, Harry .B Gristick, Rajeev Gautam, Andrew T. DeLaitsch, Morgan E. Abernathy, Zhi Yang, Haoqing Wang, Magnus A. G. Hoffmann, Yoshiaki Nishimura, Zijun Wang, Nicholas Koranda, Leesa M. Kakutani, Han Gao, Priyanthi N. P. Gnanapragasam, Henna Raina, Ana Gazumyan, Melissa Cipolla, Thiago Y. Oliveira, Victor Ramos, Darrell J. Irvine, Murillo Silva, Anthony P. West, Jr., Jennifer R. Keeffe, Christopher O. Barnes, Michael S. Seaman, Michel C. Nussenzweig, Malcolm A. Martin, and Pamela J. Bjorkman. Sequential Immunization of Macaques Elicits Heterologous Neutralizing Antibodies Targeting the V3-Glycan Patch of HIV-1 Env. Sci. Transl. Med., 13(621):eabk1533, 24 Nov 2021. PubMed ID: 34818054.
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Evans2014
Mark C. Evans, Pham Phung, Agnes C. Paquet, Anvi Parikh, Christos J. Petropoulos, Terri Wrin, and Mojgan Haddad. Predicting HIV-1 Broadly Neutralizing Antibody Epitope Networks Using Neutralization Titers and a Novel Computational Method. BMC Bioinformatics, 15:77, 19 Mar 2014. PubMed ID: 24646213.
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Falkowska2014
Emilia Falkowska, Khoa M. Le, Alejandra Ramos, Katie J. Doores, Jeong Hyun Lee, Claudia Blattner, Alejandro Ramirez, Ronald Derking, Marit J. van Gils, Chi-Hui Liang, Ryan Mcbride, Benjamin von Bredow, Sachin S. Shivatare, Chung-Yi Wu, Po-Ying Chan-Hui, Yan Liu, Ten Feizi, Michael B. Zwick, Wayne C. Koff, Michael S. Seaman, Kristine Swiderek, John P. Moore, David Evans, James C. Paulson, Chi-Huey Wong, Andrew B. Ward, Ian A. Wilson, Rogier W. Sanders, Pascal Poignard, and Dennis R. Burton. Broadly Neutralizing HIV Antibodies Define a Glycan-Dependent Epitope on the Prefusion Conformation of gp41 on Cleaved Envelope Trimers. Immunity, 40(5):657-668, 15 May 2014. PubMed ID: 24768347.
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Ferguson2013
Andrew L. Ferguson, Emilia Falkowska, Laura M. Walker, Michael S. Seaman, Dennis R. Burton, and Arup K. Chakraborty. Computational Prediction of Broadly Neutralizing HIV-1 Antibody Epitopes from Neutralization Activity Data. PLoS One, 8(12):e80562, 2013. PubMed ID: 24312481.
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Georgiev2013
Ivelin S. Georgiev, Nicole A. Doria-Rose, Tongqing Zhou, Young Do Kwon, Ryan P. Staupe, Stephanie Moquin, Gwo-Yu Chuang, Mark K. Louder, Stephen D. Schmidt, Han R. Altae-Tran, Robert T. Bailer, Krisha McKee, Martha Nason, Sijy O'Dell, Gilad Ofek, Marie Pancera, Sanjay Srivatsan, Lawrence Shapiro, Mark Connors, Stephen A. Migueles, Lynn Morris, Yoshiaki Nishimura, Malcolm A. Martin, John R. Mascola, and Peter D. Kwong. Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization. Science, 340(6133):751-756, 10 May 2013. PubMed ID: 23661761.
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Goo2012
Leslie Goo, Zahra Jalalian-Lechak, Barbra A. Richardson, and Julie Overbaugh. A Combination of Broadly Neutralizing HIV-1 Monoclonal Antibodies Targeting Distinct Epitopes Effectively Neutralizes Variants Found in Early Infection. J. Virol., 86(19):10857-10861, Oct 2012. PubMed ID: 22837204.
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Guenaga2015a
Javier Guenaga, Viktoriya Dubrovskaya, Natalia de Val, Shailendra K. Sharma, Barbara Carrette, Andrew B. Ward, and Richard T. Wyatt. Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers. J. Virol., 90(6):2806-2817, 30 Dec 2015. PubMed ID: 26719252.
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Guzzo2018
Christina Guzzo, Peng Zhang, Qingbo Liu, Alice L. Kwon, Ferzan Uddin, Alexandra I. Wells, Hana Schmeisser, Raffaello Cimbro, Jinghe Huang, Nicole Doria-Rose, Stephen D. Schmidt, Michael A. Dolan, Mark Connors, John R. Mascola, and Paolo Lusso. Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation. mBio, 9(6), 11 Dec 2018. PubMed ID: 30538178.
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Halper-Stromberg2016
Ariel Halper-Stromberg and Michel C Nussenzweig. Towards HIV-1 Remission: Potential Roles for Broadly Neutralizing Antibodies. J. Clin. Invest., 126(2):415-423, Feb 2016. PubMed ID: 26752643.
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Haynes2012
Barton F. Haynes, Garnett Kelsoe, Stephen C. Harrison, and Thomas B. Kepler. B-Cell-Lineage Immunogen Design in Vaccine Development with HIV-1 as a Case Study. Nat. Biotechnol., 30(5):423-433, May 2012. PubMed ID: 22565972.
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He2018
Linling He, Sonu Kumar, Joel D. Allen, Deli Huang, Xiaohe Lin, Colin J. Mann, Karen L. Saye-Francisco, Jeffrey Copps, Anita Sarkar, Gabrielle S. Blizard, Gabriel Ozorowski, Devin Sok, Max Crispin, Andrew B. Ward, David Nemazee, Dennis R. Burton, Ian A. Wilson, and Jiang Zhu. HIV-1 Vaccine Design through Minimizing Envelope Metastability. Sci. Adv., 4(11):eaau6769, Nov 2018. PubMed ID: 30474059.
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Henderson2019
Rory Henderson, Brian E. Watts, Hieu N. Ergin, Kara Anasti, Robert Parks, Shi-Mao Xia, Ashley Trama, Hua-Xin Liao, Kevin O. Saunders, Mattia Bonsignori, Kevin Wiehe, Barton F. Haynes, and S. Munir Alam. Selection of Immunoglobulin Elbow Region Mutations Impacts Interdomain Conformational Flexibility in HIV-1 Broadly Neutralizing Antibodies. Nat. Commun., 10(1):654, 8 Feb 2019. PubMed ID: 30737386.
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Hraber2014
Peter Hraber, Michael S. Seaman, Robert T. Bailer, John R. Mascola, David C. Montefiori, and Bette T. Korber. Prevalence of Broadly Neutralizing Antibody Responses during Chronic HIV-1 Infection. AIDS, 28(2):163-169, 14 Jan 2014. PubMed ID: 24361678.
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Hraber2017
Peter Hraber, Cecilia Rademeyer, Carolyn Williamson, Michael S. Seaman, Raphael Gottardo, Haili Tang, Kelli Greene, Hongmei Gao, Celia LaBranche, John R. Mascola, Lynn Morris, David C. Montefiori, and Bette Korber. Panels of HIV-1 Subtype C Env Reference Strains for Standardized Neutralization Assessments. J. Virol., 91(19), 1 Oct 2017. PubMed ID: 28747500.
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Hraber2018
Peter Hraber, Bette Korber, Kshitij Wagh, David Montefiori, and Mario Roederer. A Single, Continuous Metric To Define Tiered Serum Neutralization Potency against Hiv. eLife, 7, 19 Jan 2018. PubMed ID: 29350181.
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Hu2015
Joyce K. Hu, Jordan C. Crampton, Albert Cupo, Thomas Ketas, Marit J. van Gils, Kwinten Sliepen, Steven W. de Taeye, Devin Sok, Gabriel Ozorowski, Isaiah Deresa, Robyn Stanfield, Andrew B. Ward, Dennis R. Burton, Per Johan Klasse, Rogier W. Sanders, John P. Moore, and Shane Crotty. Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity. J. Virol., 89(20):10383-10398, Oct 2015. PubMed ID: 26246566.
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Huang2017a
Xun Huang, Qianqian Zhu, Xiaoxing Huang, Lifei Yang, Yufeng Song, Ping Zhu, and Paul Zhou. In Vivo Electroporation in DNA-VLP Prime-Boost Preferentially Enhances HIV-1 Envelope-Specific IgG2a, Neutralizing Antibody and CD8 T Cell Responses. Vaccine, 35(16):2042-2051, 11 Apr 2017. PubMed ID: 28318765.
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Hutchinson2019
Jennie M. Hutchinson, Kathryn A. Mesa, David L. Alexander, Bin Yu, Sara M. O'Rourke, Kay L. Limoli, Terri Wrin, Steven G. Deeks, and Phillip W. Berman. Unusual Cysteine Content in V1 Region of gp120 from an Elite Suppressor That Produces Broadly Neutralizing Antibodies. Front. Immunol., 10:1021, 2019. PubMed ID: 31156622.
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Kesavardhana2017
Sannula Kesavardhana, Raksha Das, Michael Citron, Rohini Datta, Linda Ecto, Nonavinakere Seetharam Srilatha, Daniel DiStefano, Ryan Swoyer, Joseph G. Joyce, Somnath Dutta, Celia C. LaBranche, David C. Montefiori, Jessica A. Flynn, and Raghavan Varadarajan. Structure-Based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies. J. Biol. Chem., 292(1):278-291, 6 Jan 2017. PubMed ID: 27879316.
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Klein2012a
Florian Klein, Ariel Halper-Stromberg, Joshua A. Horwitz, Henning Gruell, Johannes F. Scheid, Stylianos Bournazos, Hugo Mouquet, Linda A. Spatz, Ron Diskin, Alexander Abadir, Trinity Zang, Marcus Dorner, Eva Billerbeck, Rachael N. Labitt, Christian Gaebler, Paola M. Marcovecchio, Reha-Baris Incesu, Thomas R. Eisenreich, Paul D. Bieniasz, Michael S. Seaman, Pamela J. Bjorkman, Jeffrey V. Ravetch, Alexander Ploss, and Michel C. Nussenzweig. HIV Therapy by a Combination of Broadly Neutralizing Antibodies in Humanized Mice. Nature, 492(7427):118-122, 6 Dec 2012. PubMed ID: 23103874.
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Klein2013
Florian Klein, Ron Diskin, Johannes F. Scheid, Christian Gaebler, Hugo Mouquet, Ivelin S. Georgiev, Marie Pancera, Tongqing Zhou, Reha-Baris Incesu, Brooks Zhongzheng Fu, Priyanthi N. P. Gnanapragasam, Thiago Y. Oliveira, Michael S. Seaman, Peter D. Kwong, Pamela J. Bjorkman, and Michel C. Nussenzweig. Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization. Cell, 153(1):126-138, 28 Mar 2013. PubMed ID: 23540694.
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Kong2013
Leopold Kong, Jeong Hyun Lee, Katie J. Doores, Charles D. Murin, Jean-Philippe Julien, Ryan McBride, Yan Liu, Andre Marozsan, Albert Cupo, Per-Johan Klasse, Simon Hoffenberg, Michael Caulfield, C. Richter King, Yuanzi Hua, Khoa M. Le, Reza Khayat, Marc C. Deller, Thomas Clayton, Henry Tien, Ten Feizi, Rogier W. Sanders, James C. Paulson, John P. Moore, Robyn L. Stanfield, Dennis R. Burton, Andrew B. Ward, and Ian A. Wilson. Supersite of Immune Vulnerability on the Glycosylated Face of HIV-1 Envelope Glycoprotein gp120. Nat. Struct. Mol. Biol., 20(7):796-803, Jul 2013. PubMed ID: 23708606.
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Kong2015a
Leopold Kong, Alba Torrents de la Peña, Marc C. Deller, Fernando Garces, Kwinten Sliepen, Yuanzi Hua, Robyn L. Stanfield, Rogier W. Sanders, and Ian A. Wilson. Complete Epitopes for Vaccine Design Derived from a Crystal Structure of the Broadly Neutralizing Antibodies PGT128 and 8ANC195 in Complex with an HIV-1 Env trimer. Acta Crystallogr. D Biol. Crystallogr., 71(Pt 10):2099-2108, Oct 2015. PubMed ID: 26457433.
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Korber2017
Bette Korber, Peter Hraber, Kshitij Wagh, and Beatrice H. Hahn. Polyvalent Vaccine Approaches to Combat HIV-1 Diversity. Immunol. Rev., 275(1):230-244, Jan 2017. PubMed ID: 28133800.
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Krumm2016
Stefanie A. Krumm, Hajer Mohammed, Khoa M. Le, Max Crispin, Terri Wrin, Pascal Poignard, Dennis R. Burton, and Katie J. Doores. Mechanisms of Escape from the PGT128 Family of Anti-HIV Broadly Neutralizing Antibodies. Retrovirology, 13:8, 2 Feb 2016. PubMed ID: 26837192.
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Kwon2015
Young Do Kwon, Marie Pancera, Priyamvada Acharya, Ivelin S. Georgiev, Emma T. Crooks, Jason Gorman, M. Gordon Joyce, Miklos Guttman, Xiaochu Ma, Sandeep Narpala, Cinque Soto, Daniel S. Terry, Yongping Yang, Tongqing Zhou, Goran Ahlsen, Robert T. Bailer, Michael Chambers, Gwo-Yu Chuang, Nicole A. Doria-Rose, Aliaksandr Druz, Mark A. Hallen, Adam Harned, Tatsiana Kirys, Mark K. Louder, Sijy O'Dell, Gilad Ofek, Keiko Osawa, Madhu Prabhakaran, Mallika Sastry, Guillaume B. E. Stewart-Jones, Jonathan Stuckey, Paul V. Thomas, Tishina Tittley, Constance Williams, Baoshan Zhang, Hong Zhao, Zhou Zhou, Bruce R. Donald, Lawrence K. Lee, Susan Zolla-Pazner, Ulrich Baxa, Arne Schön, Ernesto Freire, Lawrence Shapiro, Kelly K. Lee, James Arthos, James B. Munro, Scott C. Blanchard, Walther Mothes, James M. Binley, Adrian B. McDermott, John R. Mascola, and Peter D. Kwong. Crystal Structure, Conformational Fixation and Entry-Related Interactions of Mature Ligand-Free HIV-1 Env. Nat. Struct. Mol. Biol., 22(7):522-531, Jul 2015. PubMed ID: 26098315.
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Kwong2012
Peter D. Kwong and John R. Mascola. Human Antibodies that Neutralize HIV-1: Identification, Structures, and B Cell Ontogenies. Immunity, 37(3):412-425, 21 Sep 2012. PubMed ID: 22999947.
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Kwong2013
Peter D. Kwong, John R. Mascola, and Gary J. Nabel. Broadly Neutralizing Antibodies and the Search for an HIV-1 Vaccine: The End of the Beginning. Nat. Rev. Immunol., 13(9):693-701, Sep 2013. PubMed ID: 23969737.
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Leaman2013
Daniel P. Leaman and Michael B. Zwick. Increased Functional Stability and Homogeneity of Viral Envelope Spikes through Directed Evolution. PLoS Pathog., 9(2):e1003184, Feb 2013. PubMed ID: 23468626.
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Lee2015a
Jeong Hyun Lee, Natalia de Val, Dmitry Lyumkis, and Andrew B. Ward. Model Building and Refinement of a Natively Glycosylated HIV-1 Env Protein by High-Resolution Cryoelectron Microscopy. Structure, 23(10):1943-1951, 6 Oct 2015. PubMed ID: 26388028.
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Liao2013a
Hongyan Liao, Jun-tao Guo, Miles D. Lange, Run Fan, Michael Zemlin, Kaihong Su, Yongjun Guan, and Zhixin Zhang. Contribution of V(H) Replacement Products to the Generation of Anti-HIV Antibodies. Clin. Immunol., 146(1):46-55, Jan 2013. PubMed ID: 23220404.
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Liu2015a
Mengfei Liu, Guang Yang, Kevin Wiehe, Nathan I. Nicely, Nathan A. Vandergrift, Wes Rountree, Mattia Bonsignori, S. Munir Alam, Jingyun Gao, Barton F. Haynes, and Garnett Kelsoe. Polyreactivity and Autoreactivity among HIV-1 Antibodies. J. Virol., 89(1):784-798, Jan 2015. PubMed ID: 25355869.
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Longo2016
Nancy S. Longo, Matthew S. Sutton, Andrea R. Shiakolas, Javier Guenaga, Marissa C. Jarosinski, Ivelin S. Georgiev, Krisha McKee, Robert T. Bailer, Mark K. Louder, Sijy O'Dell, Mark Connors, Richard T. Wyatt, John R. Mascola, and Nicole A. Doria-Rose. Multiple Antibody Lineages in One Donor Target the Glycan-V3 Supersite of the HIV-1 Envelope Glycoprotein and Display a Preference for Quaternary Binding. J. Virol., 90(23):10574-10586, 1 Dec 2016. PubMed ID: 27654288.
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Magnus2016
Carsten Magnus, Lucia Reh, and Alexandra Trkola. HIV-1 Resistance to Neutralizing Antibodies: Determination of Antibody Concentrations Leading to Escape Mutant Evolution. Virus Res., 218:57-70, 15 Jun 2016. PubMed ID: 26494166.
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Mannar2021
Dhiraj Mannar, Karoline Leopold, and Sriram Subramaniam. Glycan Reactive Anti-HIV-1 Antibodies bind the SARS-CoV-2 Spike Protein But Do Not Block Viral Entry. Sci. Rep., 11(1):12448, 14 Jun 2021. PubMed ID: 34127709.
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McCoy2015
Laura E. McCoy, Emilia Falkowska, Katie J. Doores, Khoa Le, Devin Sok, Marit J. van Gils, Zelda Euler, Judith A. Burger, Michael S. Seaman, Rogier W. Sanders, Hanneke Schuitemaker, Pascal Poignard, Terri Wrin, and Dennis R. Burton. Incomplete Neutralization and Deviation from Sigmoidal Neutralization Curves for HIV Broadly Neutralizing Monoclonal Antibodies. PLoS Pathog., 11(8):e1005110, Aug 2015. PubMed ID: 26267277.
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Mishra2020
Nitesh Mishra, Shaifali Sharma, Ayushman Dobhal, Sanjeev Kumar, Himanshi Chawla, Ravinder Singh, Bimal Kumar Das, Sushil Kumar Kabra, Rakesh Lodha, and Kalpana Luthra. A Rare Mutation in an Infant-Derived HIV-1 Envelope Glycoprotein Alters Interprotomer Stability and Susceptibility to Broadly Neutralizing Antibodies Targeting the Trimer Apex. J. Virol., 94(19), 15 Sep 2020. PubMed ID: 32669335.
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Mishra2020a
Nitesh Mishra, Shaifali Sharma, Ayushman Dobhal, Sanjeev Kumar, Himanshi Chawla, Ravinder Singh, Muzamil Ashraf Makhdoomi, Bimal Kumar Das, Rakesh Lodha, Sushil Kumar Kabra, and Kalpana Luthra. Broadly Neutralizing Plasma Antibodies Effective against Autologous Circulating Viruses in Infants with Multivariant HIV-1 Infection. Nat. Commun., 11(1):4409, 2 Sep 2020. PubMed ID: 32879304.
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Molinos-Albert2023
Luis M. Molinos-Albert, Eduard Baquero, Melanie Bouvin-Pley, Valerie Lorin, Caroline Charre, Cyril Planchais, Jordan D. Dimitrov, Valerie Monceaux, Matthijn Vos, Laurent Hocqueloux, Jean-Luc Berger, Michael S. Seaman, Martine Braibant, Veronique Avettand-Fenoel, Asier Saez-Cirion, and Hugo Mouquet. Anti-V1/V3-glycan broadly HIV-1 neutralizing antibodies in a post-treatment controller. Cell Host Microbe, 31(8):1275-1287e8 doi, Aug 2023. PubMed ID: 37433296
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Moore2012
Penny L. Moore, Elin S. Gray, C. Kurt Wibmer, Jinal N. Bhiman, Molati Nonyane, Daniel J. Sheward, Tandile Hermanus, Shringkhala Bajimaya, Nancy L. Tumba, Melissa-Rose Abrahams, Bronwen E. Lambson, Nthabeleng Ranchobe, Lihua Ping, Nobubelo Ngandu, Quarraisha Abdool Karim, Salim S. Abdool Karim, Ronald I. Swanstrom, Michael S. Seaman, Carolyn Williamson, and Lynn Morris. Evolution of an HIV Glycan-Dependent Broadly Neutralizing Antibody Epitope through Immune Escape. Nat. Med., 18(11):1688-1692, Nov 2012. PubMed ID: 23086475.
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Morgand2015
Marion Morgand, Mélanie Bouvin-Pley, Jean-Christophe Plantier, Alain Moreau, Elodie Alessandri, François Simon, Craig S. Pace, Marie Pancera, David D. Ho, Pascal Poignard, Pamela J. Bjorkman, Hugo Mouquet, Michel C. Nussenzweig, Peter D. Kwong, Daniel Baty, Patrick Chames, Martine Braibant, and Francis Barin. A V1V2 Neutralizing Epitope Is Conserved in Divergent Non-M Groups of HIV-1. J. Acquir. Immune Defic. Syndr., 21 Sep 2015. PubMed ID: 26413851.
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Mouquet2012a
Hugo Mouquet, Louise Scharf, Zelda Euler, Yan Liu, Caroline Eden, Johannes F. Scheid, Ariel Halper-Stromberg, Priyanthi N. P. Gnanapragasam, Daniel I. R. Spencer, Michael S. Seaman, Hanneke Schuitemaker, Ten Feizi, Michel C. Nussenzweig, and Pamela J. Bjorkman. Complex-Type N-Glycan Recognition by Potent Broadly Neutralizing HIV Antibodies. Proc. Natl. Acad. Sci. U.S.A, 109(47):E3268-E3277, 20 Nov 2012. PubMed ID: 23115339.
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Moyo2018
Thandeka Moyo, June Ereño-Orbea, Rajesh Abraham Jacob, Clara E. Pavillet, Samuel Mundia Kariuki, Emily N. Tangie, Jean-Philippe Julien, and Jeffrey R. Dorfman. Molecular Basis of Unusually High Neutralization Resistance in Tier 3 HIV-1 Strain 253-11. J. Virol., 92(14), 15 Jul 2018. PubMed ID: 29618644.
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Nogal2020
Bartek Nogal, Laura E. McCoy, Marit J. van Gils, Christopher A. Cottrell, James E. Voss, Raiees Andrabi, Matthias Pauthner, Chi-Hui Liang, Terrence Messmer, Rebecca Nedellec, Mia Shin, Hannah L. Turner, Gabriel Ozorowski, Rogier W. Sanders, Dennis R. Burton, and Andrew B. Ward. HIV Envelope Trimer-Elicited Autologous Neutralizing Antibodies Bind a Region Overlapping the N332 Glycan Supersite. Sci. Adv., 6(23):eaba0512, Jun 2020. PubMed ID: 32548265.
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Pancera2013a
Marie Pancera, Yongping Yang, Mark K. Louder, Jason Gorman, Gabriel Lu, Jason S. McLellan, Jonathan Stuckey, Jiang Zhu, Dennis R. Burton, Wayne C. Koff, John R. Mascola, and Peter D. Kwong. N332-Directed Broadly Neutralizing Antibodies Use Diverse Modes of HIV-1 Recognition: Inferences from Heavy-Light Chain Complementation of Function. PLoS One, 8(2):e55701, 2013. PubMed ID: 23431362.
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Pejchal2011
Robert Pejchal, Katie J. Doores, Laura M. Walker, Reza Khayat, Po-Ssu Huang, Sheng-Kai Wang, Robyn L. Stanfield, Jean-Philippe Julien, Alejandra Ramos, Max Crispin, Rafael Depetris, Umesh Katpally, Andre Marozsan, Albert Cupo, Sebastien Maloveste, Yan Liu, Ryan McBride, Yukishige Ito, Rogier W. Sanders, Cassandra Ogohara, James C. Paulson, Ten Feizi, Christopher N. Scanlan, Chi-Huey Wong, John P. Moore, William C. Olson, Andrew B. Ward, Pascal Poignard, William R. Schief, Dennis R. Burton, and Ian A. Wilson. A Potent and Broad Neutralizing Antibody Recognizes and Penetrates the HIV Glycan Shield. Science, 334(6059):1097-1103, 25 Nov 2011. PubMed ID: 21998254.
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Pinto2019
Dora Pinto, Craig Fenwick, Christophe Caillat, Chiara Silacci, Serafima Guseva, François Dehez, Christophe Chipot, Sonia Barbieri, Andrea Minola, David Jarrossay, Georgia D. Tomaras, Xiaoying Shen, Agostino Riva, Maciej Tarkowski, Olivier Schwartz, Timothée Bruel, Jérémy Dufloo, Michael S. Seaman, David C. Montefiori, Antonio Lanzavecchia, Davide Corti, Giuseppe Pantaleo, and Winfried Weissenhorn. Structural Basis for Broad HIV-1 Neutralization by the MPER-Specific Human Broadly Neutralizing Antibody LN01. Cell Host Microbe, 26(5):623-637.e8, 13 Nov 2019. PubMed ID: 31653484.
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Prigent2018
Julie Prigent, Annaëlle Jarossay, Cyril Planchais, Caroline Eden, Jérémy Dufloo, Ayrin Kök, Valérie Lorin, Oxana Vratskikh, Thérèse Couderc, Timothée Bruel, Olivier Schwartz, Michael S. Seaman, Ohlenschläger, Jordan D. Dimitrov, and Hugo Mouquet. Conformational Plasticity in Broadly Neutralizing HIV-1 Antibodies Triggers Polyreactivity. Cell Rep., 23(9):2568-2581, 29 May 2018. PubMed ID: 29847789.
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Qi2016
Yifei Qi, Sunhwan Jo, and Wonpil Im. Roles of Glycans in Interactions between gp120 and HIV Broadly Neutralizing Antibodies. Glycobiology, 26(3):251-260, Mar 2016. PubMed ID: 26537503.
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Rademeyer2016
Cecilia Rademeyer, Bette Korber, Michael S. Seaman, Elena E. Giorgi, Ruwayhida Thebus, Alexander Robles, Daniel J. Sheward, Kshitij Wagh, Jetta Garrity, Brittany R. Carey, Hongmei Gao, Kelli M. Greene, Haili Tang, Gama P. Bandawe, Jinny C. Marais, Thabo E. Diphoko, Peter Hraber, Nancy Tumba, Penny L. Moore, Glenda E. Gray, James Kublin, M. Juliana McElrath, Marion Vermeulen, Keren Middelkoop, Linda-Gail Bekker, Michael Hoelscher, Leonard Maboko, Joseph Makhema, Merlin L. Robb, Salim Abdool Karim, Quarraisha Abdool Karim, Jerome H. Kim, Beatrice H. Hahn, Feng Gao, Ronald Swanstrom, Lynn Morris, David C. Montefiori, and Carolyn Williamson. Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization. PLoS Pathog., 12(7):e1005742, Jul 2016. PubMed ID: 27434311.
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Reiss2022
E. I. M. M. Reiss, M. M. van Haaren, J. van Schooten, M. A. F. Claireaux, P. Maisonnasse, A. Antanasijevic, J. D. Allen, I. Bontjer, J. L. Torres, W.-H. Lee, G. Ozorowski, N. Vázquez Bernat, M. Kaduk, Y. Aldon, J. A. Burger, H. Chawla, A. Aartse, M. Tolazzi, H. Gao, P. Mundsperger, M. Crispin, D. C. Montefiori, G. B. Karlsson Hedestam, G. Scarlatti, A. B. Ward, R. Le Grand, R. Shattock, N. Dereuddre-Bosquet, R. W. Sanders, and M. J. van Gils. Fine-Mapping the Immunodominant Antibody Epitopes on Consensus Sequence-Based HIV-1 Envelope Trimer Vaccine Candidates. NPJ Vaccines, 7(1):152, 25 Nov 2022. PubMed ID: 36433972.
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Rosenberg2015
Yvonne Rosenberg, Markus Sack, David Montefiori, Celia Labranche, Mark Lewis, Lori Urban, Lingjun Mao, Rainer Fischer, and Xiaoming Jiang. Pharmacokinetics and Immunogenicity of Broadly Neutralizing HIV Monoclonal Antibodies in Macaques. PLoS One, 10(3):e0120451, 25 Mar 2015. PubMed ID: 25807114.
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Rusert2016
Peter Rusert, Roger D. Kouyos, Claus Kadelka, Hanna Ebner, Merle Schanz, Michael Huber, Dominique L. Braun, Nathanael Hozé, Alexandra Scherrer, Carsten Magnus, Jacqueline Weber, Therese Uhr, Valentina Cippa, Christian W. Thorball, Herbert Kuster, Matthias Cavassini, Enos Bernasconi, Matthias Hoffmann, Alexandra Calmy, Manuel Battegay, Andri Rauch, Sabine Yerly, Vincent Aubert, Thomas Klimkait, Jürg Böni, Jacques Fellay, Roland R. Regoes, Huldrych F. Günthard, Alexandra Trkola, and Swiss HIV Cohort Study. Determinants of HIV-1 Broadly Neutralizing Antibody Induction. Nat. Med., 22(11):1260-1267, Nov 2016. PubMed ID: 27668936.
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Sanders2013
Rogier W. Sanders, Ronald Derking, Albert Cupo, Jean-Philippe Julien, Anila Yasmeen, Natalia de Val, Helen J. Kim, Claudia Blattner, Alba Torrents de la Peña, Jacob Korzun, Michael Golabek, Kevin de los Reyes, Thomas J. Ketas, Marit J. van Gils, C. Richter King, Ian A. Wilson, Andrew B. Ward, P. J. Klasse, and John P. Moore. A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but not Non-Neutralizing Antibodies. PLoS Pathog., 9(9):e1003618, Sep 2013. PubMed ID: 24068931.
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Saunders2017
Kevin O. Saunders, Nathan I. Nicely, Kevin Wiehe, Mattia Bonsignori, R. Ryan Meyerhoff, Robert Parks, William E. Walkowicz, Baptiste Aussedat, Nelson R. Wu, Fangping Cai, Yusuf Vohra, Peter K. Park, Amanda Eaton, Eden P. Go, Laura L. Sutherland, Richard M. Scearce, Dan H. Barouch, Ruijun Zhang, Tarra Von Holle, R. Glenn Overman, Kara Anasti, Rogier W. Sanders, M. Anthony Moody, Thomas B. Kepler, Bette Korber, Heather Desaire, Sampa Santra, Norman L. Letvin, Gary J. Nabel, David C. Montefiori, Georgia D. Tomaras, Hua-Xin Liao, S. Munir Alam, Samuel J. Danishefsky, and Barton F. Haynes. Vaccine Elicitation of High Mannose-Dependent Neutralizing Antibodies against the V3-Glycan Broadly Neutralizing Epitope in Nonhuman Primates. Cell Rep., 18(9):2175-2188, 28 Feb 2017. PubMed ID: 28249163.
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Scheepers2015
Cathrine Scheepers, Ram K. Shrestha, Bronwen E. Lambson, Katherine J. L. Jackson, Imogen A. Wright, Dshanta Naicker, Mark Goosen, Leigh Berrie, Arshad Ismail, Nigel Garrett, Quarraisha Abdool Karim, Salim S. Abdool Karim, Penny L. Moore, Simon A. Travers, and Lynn Morris. Ability to Develop Broadly Neutralizing HIV-1 Antibodies Is Not Restricted by the Germline Ig Gene Repertoire. J. Immunol., 194(9):4371-4378, 1 May 2015. PubMed ID: 25825450.
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Schiffner2016
Torben Schiffner, Natalia de Val, Rebecca A. Russell, Steven W. de Taeye, Alba Torrents de la Peña, Gabriel Ozorowski, Helen J. Kim, Travis Nieusma, Florian Brod, Albert Cupo, Rogier W. Sanders, John P. Moore, Andrew B. Ward, and Quentin J. Sattentau. Chemical Cross-Linking Stabilizes Native-Like HIV-1 Envelope Glycoprotein Trimer Antigens. J. Virol., 90(2):813-828, 28 Oct 2015. PubMed ID: 26512083.
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Schiffner2018
Torben Schiffner, Jesper Pallesen, Rebecca A. Russell, Jonathan Dodd, Natalia de Val, Celia C. LaBranche, David Montefiori, Georgia D. Tomaras, Xiaoying Shen, Scarlett L. Harris, Amin E. Moghaddam, Oleksandr Kalyuzhniy, Rogier W. Sanders, Laura E. McCoy, John P. Moore, Andrew B. Ward, and Quentin J. Sattentau. Structural and Immunologic Correlates of Chemically Stabilized HIV-1 Envelope Glycoproteins. PLoS Pathog., 14(5):e1006986, May 2018. PubMed ID: 29746590.
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Anna Schorcht, Tom L. G. M. van den Kerkhof, Christopher A. Cottrell, Joel D. Allen, Jonathan L. Torres, Anna-Janina Behrens, Edith E. Schermer, Judith A. Burger, Steven W. de Taeye, Alba Torrents de la Peña, Ilja Bontjer, Stephanie Gumbs, Gabriel Ozorowski, Celia C. LaBranche, Natalia de Val, Anila Yasmeen, Per Johan Klasse, David C. Montefiori, John P. Moore, Hanneke Schuitemaker, Max Crispin, Marit J. van Gils, Andrew B. Ward, and Rogier W. Sanders. Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers. J. Virol., 94(24), 23 Nov 2020. PubMed ID: 32999024.
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Silver2019
Zachary A. Silver, Gordon M. Dickinson, Michael S. Seaman, and Ronald C. Desrosiers. A Highly Unusual V1 Region of Env in an Elite Controller of HIV Infection. J. Virol., 93(10), 15 May 2019. PubMed ID: 30842322.
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Kwinten Sliepen, Max Medina-Ramirez, Anila Yasmeen, John P. Moore, Per Johan Klasse, and Rogier W. Sanders. Binding of Inferred Germline Precursors of Broadly Neutralizing HIV-1 Antibodies to Native-Like Envelope Trimers. Virology, 486:116-120, Dec 2015. PubMed ID: 26433050.
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Kwinten Sliepen, Byung Woo Han, Ilja Bontjer, Petra Mooij, Fernando Garces, Anna-Janina Behrens, Kimmo Rantalainen, Sonu Kumar, Anita Sarkar, Philip J. M. Brouwer, Yuanzi Hua, Monica Tolazzi, Edith Schermer, Jonathan L. Torres, Gabriel Ozorowski, Patricia van der Woude, Alba Torrents de la Pena, Marielle J. van Breemen, Juan Miguel Camacho-Sanchez, Judith A. Burger, Max Medina-Ramirez, Nuria Gonzalez, Jose Alcami, Celia LaBranche, Gabriella Scarlatti, Marit J. van Gils, Max Crispin, David C. Montefiori, Andrew B. Ward, Gerrit Koopman, John P. Moore, Robin J. Shattock, Willy M. Bogers, Ian A. Wilson, and Rogier W. Sanders. Structure and immunogenicity of a stabilized HIV-1 envelope trimer based on a group-M consensus sequence. Nat Commun, 10(1):2355 doi, May 2019. PubMed ID: 31142746
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Sok2014a
Devin Sok, Katie J. Doores, Bryan Briney, Khoa M. Le, Karen L. Saye-Francisco, Alejandra Ramos, Daniel W. Kulp, Jean-Philippe Julien, Sergey Menis, Lalinda Wickramasinghe, Michael S. Seaman, William R. Schief, Ian A. Wilson, Pascal Poignard, and Dennis R. Burton. Promiscuous Glycan Site Recognition by Antibodies to the High-Mannose Patch of gp120 Broadens Neutralization of HIV. Sci. Transl. Med., 6(236):236ra63, 14 May 2014. PubMed ID: 24828077.
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Sok2016
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Wagh2016
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Walker2018
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Wang2019
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Webb2015
Nicholas E. Webb, David C. Montefiori, and Benhur Lee. Dose-Response Curve Slope Helps Predict Therapeutic Potency and Breadth of HIV Broadly Neutralizing Antibodies. Nat. Commun., 6:8443, 29 Sep 2015. PubMed ID: 26416571.
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Wen2018
Yingxia Wen, Hung V. Trinh, Christine E Linton, Chiara Tani, Nathalie Norais, DeeAnn Martinez-Guzman, Priyanka Ramesh, Yide Sun, Frank Situ, Selen Karaca-Griffin, Christopher Hamlin, Sayali Onkar, Sai Tian, Susan Hilt, Padma Malyala, Rushit Lodaya, Ning Li, Gillis Otten, Giuseppe Palladino, Kristian Friedrich, Yukti Aggarwal, Celia LaBranche, Ryan Duffy, Xiaoying Shen, Georgia D. Tomaras, David C. Montefiori, William Fulp, Raphael Gottardo, Brian Burke, Jeffrey B. Ulmer, Susan Zolla-Pazner, Hua-Xin Liao, Barton F. Haynes, Nelson L. Michael, Jerome H. Kim, Mangala Rao, Robert J. O'Connell, Andrea Carfi, and Susan W. Barnett. Generation and Characterization of a Bivalent Protein Boost for Future Clinical Trials: HIV-1 Subtypes CR01\_AE and B gp120 Antigens with a Potent Adjuvant. PLoS One, 13(4):e0194266, 2018. PubMed ID: 29698406.
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Wieczorek2023
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Displaying record number 2651
Download this epitope
record as JSON.
MAb ID |
PGT145 (PGT-145) |
HXB2 Location |
Env |
Env Epitope Map
|
Author Location |
gp160(126-196) |
Epitope |
|
Subtype |
AD |
Ab Type |
gp120 V2 // V2 glycan(V2g) // V2 apex |
Neutralizing |
P View neutralization details |
Contacts and Features |
View contacts and features |
Species
(Isotype)
|
human(IgG) |
Patient |
Donor 84 |
Immunogen |
HIV-1 infection |
Keywords |
acute/early infection, anti-idiotype, antibody binding site, antibody gene transfer, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autoantibody or autoimmunity, autologous responses, binding affinity, broad neutralizer, complement, computational prediction, contact residues, early treatment, effector function, elite controllers and/or long-term non-progressors, escape, glycosylation, HIV reservoir/latency/provirus, immunoprophylaxis, immunotherapy, mutation acquisition, neutralization, polyclonal antibodies, rate of progression, responses in children, review, SIV, structure, subtype comparisons, therapeutic vaccine, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity, viral fitness and/or reversion |
Notes
Showing 100 of
100 notes.
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PGT145: The study describes the generation, crystal structure, and immunogenic properties of a native-like Env SOSIP trimer based on a group M consensus (ConM) sequence. A crystal structure of ConM SOSIP.v7 trimer together with nAbs PGT124 and 35O22 revealed that ConM SOSIP.v7 is structurally similar to other Env trimers. In rabbits, the ConM SOSIP trimer induced serum nAbs that neutralized the autologous Tier 1A virus (ConM from 2004) and a related Tier 1B ConS virus (ConM from 2001). These responses target the trimer apex and were enhanced when the trimers were presented on ferritin nanoparticles. The neutralization of ConM and ConS pseudoviruses was tested against a large panel of nAbs and non-nAbs (2219, 2557, 3074, 3869, 447-52D, 830A, 654-30D, 1008-30D, 1570D, 729-30D, F105, 181D, 246D, 50-69D, sCD4, VRC01, 3BNC117, CH31, PG9, PG16, CH01, PGDM1400, PGT128, PGT121, 10-1074, PGT151, VRC43.01, 2G12, DH511.2_K3, 10E8, 2F5, 4E10); most nAbs were able to neutralize these pseudoviruses. Soluble ConM trimers were able to weakly activate B cells expressing PGT121 and PG16 BCRs but were inactive against those expressing VRC01 and PGT145. In contrast, at the same molar amount of trimers, the ConM SOSIP.v7-ferritin nanoparticles activated all 4 B cells efficiently. Binding of bnAbs 2G12 and PGT145 and non-nAbs F105 and 19b to ConM SOSIP.v7 trimer and SOSIP showed that the ferritin-bound trimer bound more avidly than the soluble trimer. This study shows that native-like HIV-1 Env trimers can be generated from consensus sequences, and such immunogens might be suitable vaccine components to prime and/or boost desirable nAb responses.
Sliepen2019
(neutralization, vaccine antigen design, binding affinity)
-
PGT145: Membrane-bound mRNA-encoded BG505-based Apex GT Env trimer vaccine candidates, which bind to inferred germline variants of bnAbs PCT64 and PG9, were developed through directed evolution and characterized. Soluble ApexGT2, ApexGT5 and BG505 SOSIP.MD39 (MD39, background for Apex constructs) all had generally similar antigenic profiles and bound mAb PGT145 at high levels. Of the 3, MD39 had slightly higher binding while ApexGT2 had slightly lower binding. Membrane-bound DNA-expressed MD39 had moderate binding to PGT145, while analogous ApexGT5, ApexGT5.Congly and ApexGT5.Gmax, as well as membrane-bound mRNA-encoded MD39, ApexGT5 and ApexGT5Congly all had minimal-low binding to PGT145.
Willis2022
(antibody binding site)
-
PGT145: Following the VRC018 clinical trial of the BG505 DS-SOSIP immunogen, donor N751 showed the highest BG505-reactive ELISA responses. B cells from this donor were sorted for binding to a novel BG505 trimer construct (BG505 glycan base); 8 clones were identified that bound to glycan-base BG505, and 2 were selected for characterization (2C06 and 2C09). The epitopes of 2C06.01 and 2C09.01 were similar to each other, and have substantial overlap with the epitope of VRC34.01, and lower overlap with two other FP-targeting mAbs, PGT151 and ACS202. Binding of mAbs to BG505 DS-SOSIP was compared with binding to the glycan base construct; some mAbs bound to both BG505 DS-SOSIP and glycan base (PGT145, VRC26.25, VRC01, PGT151, VRC34.01, and 2G12), some bound to neither (PG05, 447-52D, and 2557), and 4 base-binding mAbs bound to BG505 DS-SOSIP, but not to BG505 glycan base (1E6, 5H3, 3H2, and 9B9).
Wang2023
(binding affinity)
-
PGT145: A SHIV carrying a highly neutralization-sensitive Env (SHIVCNE40) was passaged in macaques. SHIVCNE40 developed enhanced replication kinetics associated with neutralization resistance against autologous serum, CD4-Ig, and several nAbs (17b, 3BNC117, N6, PGT145, PGT121, PGT128, 35O22, 2F5, 10E8). A gp41 substitution, E658K, was the major determinant for this resistance. Structural modeling and functional verification indicate that the substitution disrupts an intermolecular salt bridge with the neighboring protomer, thereby promoting fusion and facilitating immune evasion. This effect is applicable across many HIV-1 viruses of diverse subtypes. These results highlight the critical role of gp41 in shaping the neutralization profile and conformation of Env during viral adaptation. The unique intermolecular salt bridge could potentially be utilized for rational vaccine design involving more stable HIV-1 Env trimers.
Wang2019
(mutation acquisition, neutralization, structure)
-
PGT145: A panel of 30 contemporary subtype B pseudoviruses (PSVs) was generated. Neutralization sensitivities of these PSVs were compared with subtype B strains from earlier in the pandemic using 31 nAbs (PG9, PG16, PGT145, PGDM1400, CH02, CH03, CH04, 830A, PGT121, PGT126, PGT128, PGT130, 10-1074, 2192, 2219, 3074, 3869, 447-52D, b12, NIH45-46, VRC01, VRC03, 3BNC117, HJ16, sCD4, 10E8, 4E10, 2F5, 7H6, 2G12, 35O22). A significant reduction in Env neutralization sensitivity was observed for 27 out of 31 nAbs for the contemporary, as compared to earlier-decade subtype B PSVs. A decline in neutralization sensitivity was observed across all Env domains; the nAbs that were most potent early in the pandemic suffered the greatest decline in potency over time. A metaanalysis demonstrated this trend across multiple subtypes. As HIV-1 Env diversification continues, changes in Env antigenicity and neutralization sensitivity should continue to be evaluated to inform the development of improved vaccine and antibody products to prevent and treat HIV-1.
Wieczorek2023
(neutralization, viral fitness and/or reversion)
-
PGT145:This study identified a B cell lineage of bNAbs in an HIV-1 elite post-treatment controller (ePTC; donor: PTC-005002). Circulating viruses in PTC escaped bNAb pressure but remained sensitive to autologous neutralization by other Ab populations. PGT145 was used as a reference antibody for epitope mapping and binding profile of EPTC112.
Molinos-Albert2023
(binding affinity)
-
PGT145: This study analyzed Env sequences of early HIV-1 clonal variants from 31 individuals from the Amsterdam Cohort Studies with diverse levels of heterologous neutralization at 2-4 years post-seroconversion. A number of Env signatures coincided with neutralization development. These included a statistically shorter variable region 1 and a lower probability of glycosylation. Induction of neutralization was associated with a lower probability of glycosylation at position 332, which is involved in the epitopes of many bnAbs. 2G12 and PGT126 were tested for their ability to block infectivity by patient viruses with predicted glycosylation at N332; the NLS glycosylation motif was associated with resistance to these mAbs more often than the NIS glycosylation motif. Sequence Harmony software identified amino acid changes associated with the development of heterologous neutralization. These residues mapped to various Env subdomains, but in particular to the first and fourth variable region, as well as the underlying α2 helix of the third constant region. These findings imply that the development of heterologous neutralization might depend on specific characteristics of early Env. Env signatures that correlate with the induction of neutralization might be relevant for the design of effective HIV-1 vaccines. Primary virus isolates from 21 of the patients were assayed for neutralization by 11 well-known nAbs (b12, VRC01, 447-52D, 2G12, PGT121, PGT126, PG9, PG16, PGT145, 2F5, 4E10).
vandenKerkhof2013
(glycosylation, neutralization, vaccine antigen design, polyclonal antibodies)
-
PGT145: This study explored the basis of the neutralization resistance of tier 3 virus 253-11 (subtype CRF02_AG). Virus 253-11 was resistant to neutralization by 17b, b12, VRC03, F105, SCD4, CH12, Z13e1, PG16, PGT145, 2G12, PGT121, PGT126, PGT128, PGT130, 39F, F240, and 35O22; the virus was sensitive to 3BNC117, NIH45-46G54W, VRC01, 10E8, 2F5, 4E10, PG9, VRC26.26, 10-1074, and PGT151. Virus 253-11 was strikingly resistant to most tested antibodies that target V3/glycans, despite possessing key potential N-linked glycosylation sites, especially N301 and N332, needed for the recognition of this class of antibodies. The resistance of 253-11 was not associated with an unusually long V1/V2 loop, nor with polymorphisms in the V3 loop and N-linked glycosylation sites. The 253-11 MPER was rarely recognized by sera, but was more often recognized in a chimera consisting of a HIV-2 backbone with the 253-11 MPER, suggesting steric or kinetic hindrance of the MPER. Mutations in the 253-11 MPER previously reported to increase the lifetime of the prefusion Env conformation (Y681H, L669S), decreased the resistance of 253-11 to several mAbs, presumably destabilizing its otherwise stable, closed trimer structure. A crystal structure of a recombinant 253-11 SOSIP trimer revealed that the heptad repeat helices in gp41 are drawn in close proximity to the trimer axis and that gp120 protomers also showed a relatively compact form around the trimer axis.
Moyo2018
(neutralization, structure)
-
PGT145: This study assessed the ability of single bNAbs and triple bNAb combinations to mediate polyfunctional antiviral activity against a panel of cross-clade simian-human immunodeficiency viruses (SHIVs), which are commonly used as tools for validation of therapeutic strategies in nonhuman primate models. Most bnAbs assayed were capable of mediating both neutralizing and nonneutralizing effector functions (ADCC and ADCP) against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs was highly strain dependent. Several triple bNAb combinations were identified comprising of CD4 binding site-, V2-glycan-, and gp120-gp41 interface-targeting bNAbs that are capable of mediating synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. In assays using the transmitted/founder SHIV.C.CH505, there was a correlation between the neutralization potencies and nonneutralizing effector functions of bnAbs: PGT145 was positive for neutralization, ADCC, and binding to infected cells.
Berendam2021
(effector function, neutralization, binding affinity, broad neutralizer)
-
PGT145: Reduction in exposure of non-neutralizing Ab (nnAb) epitopes on native-like Env trimer immunogens results in bnAbs being elicited that have autologous tier 2 neutralization instead of tier 1. The design of trimer modifications to silence nnAb reactivity were directed towards (1) the V3 loop (2) epitopes exposed through CD4-induced conformational changes (CD4i epitopes) and (3) the exposed SOSIP trimer base that is usually buried within virus membrane. (1) In Steichen2016 2 Env variants of BG505 SOSIP.664 with reduced V3 nnAb-generating activity were created, one using mammalian display screens, BG505 MD39, and the other with an engineered disulfide bond, BG505 SOSIP.DS21. MD39's trimer design was improved by using the Rosetta Design platform and inserting 6 buried mutations to form BG505 Olio6, and both this trimer as well as the DS21 were shown to have reduced antigenicity for nnAb generation in a rabbit vaccine model. (2) To reduce CD4i epitope elicitation of nnAbs, saturation mutagenesis of Olio6 was performed, in search of the trimer that binds VRC01-class bnAbs but not CD4. BG505 Olio6.CD4KO containing the G473T mutation was identified. In addition, for the purposes of nucleic acid-based vaccine platform designs, the natural furin cleavage site between gp120 and gp41 was removed to abolish protease cleavage, by swapping the order of gp14 and gp120 in the gp160 gene, giving the trimer BG505 MD39.CP (circular permutation). (3) The exposed trimer base was masked with glycan in 3 under-glycosylated regions in order to direct bnAb responses to the distal regions (CD4bs, V2 apex, N332 superset) of the trimer instead, generating the GRSF (glycan resurfaced) MD39 and GRSF MD39.CP variants. Furthermore, variants with improved thermostability over MD39 were created, MD37 and MD64. All of these stabilizing mutations were transferred to diverse HIV isolates from different subtypes. Finally 3 subtype C (isolate 327c) trimers were assessed for binding to bnAbs, VRC01, PGT121, PGT151, PGT145, PG9 and to nnAbs, F105 and 17b - PGT145 binds all three as well as AD8 SOSIP, AD8 MD64, and BG505s foldon, Olio6, SOSIP.664 and Olio6 CD4KO.
Kulp2017
(antibody binding site, antibody generation, antibody interactions, assay or method development, autologous responses, vaccine antigen design, structure)
-
PGT145: Using subtype A BG505 Env structural information, improved variants of subtype B JRFL and subtype C 16055 Env native flexibly linked (NFL) trimers were generated. The trimer-derived (TD) residues that increased well-ordered, homogeneous, stable, and soluble trimers did not require positive or negative selection as previously needed [Guenaga2015, PLoS Pathos. 11(1):e1004570]. PG16, PGDM1400, PGT145 which are "trimer-preferring" bnAbs are known to target one site on the variable cap per spike and while PGT145 preferentially recognized 16055 NFL TD8 over JRFL NFL TD15, it also bound subtype B JRFL with a very high (nM) affinity.
Guenaga2015a
(antibody interactions, assay or method development, vaccine antigen design, structure)
-
PGT145: Most published structures of bnAbs, yet none of non- or poorly-neutralizing mAbs, were structurally compatible with a newly generated crystal structure of a mature ligand-free endoglycosidase H-treated BG505 SOSIP.664 Env trimer. Robust binding of the structurally incompatible V3- and CD4-bs targeting nAbs could be induced with CD4. A “DS” variant of BG505 SOSIP.664, containing a stabilizing disulfide bond between 201C and 433C mutations, was developed and appeared to represent an obligate intermediate in that it only bound a single CD4 and remained in a prefusion closed conformation. BnAb PGT145 had KD values of 4.38 and 7.22 nM, respectively, when binding to BG505 SOSIP.664 wildtype and DS variant.
Kwon2015
(vaccine antigen design, binding affinity, structure)
-
PGT145: Native, well-ordered, soluble mimetics of the Env trimer from subtypes B (JRFL) and C (16055) were obtained from genetically identical samples of heterogeneous mixture of disordered Env SOSIPs. Negative selection by non-nAbs was used to remove disordered oligomers, leaving well-ordered trimers that were able to bind sCD4, a panel of bnAbs that bind CD4bs, and PGT15 which is a bnAb that binds only cleavage-dependent, well-ordered, Env trimer. Several biophysical techniques were used to interrogate the structure of the purified subtype B and C trimers. Trimer antigenicity was assessed by bio-layer interferometry against F105-like non-neutralizing Abs, and some bnAbs in solution. Quaternary epitope-preferring and glycan-specific PGT145 does not bind open/disordered trimers well or recognize monomers, but recognizes these non-nAb negatively selected trimers.
Guenaga2015
(vaccine antigen design, subtype comparisons, structure)
-
PGT145: This paper comprehensively defined the effect of every viable single aa mutation in the ectodomain and transmembrane domain of BG505.T332N Env on binding by 9 individual bnAbs targeting 5 epitope classes (VRC01, 3BNC117, PGT121, 10-1074, PG9, PGT145, PGT151, VRC34.01, and 10E8), as well as by a mixture of 3BNC117 and 10-1074. Escape mutations mostly occurred in a small subset of structurally-defined contacts within <4 Å and at sites within 5-10 Å of the Ab. Escape from both V2-apex-targeting bnAbs, PG9 and PGT145, occurred through the elimination of the N160 glycan and/or positive charges from the epitope as well as mutations in trimer apex contact sites. For PGT145, escape was also facilitated through the introduction of charges and mutations at the trimer interface. Env sites with the largest cumulative mutational impact on PGT145 binding were R166, N160, K121, K169, and T162. See LANL Features and Contacts database for more details.
Dingens2019
(antibody binding site, escape, contact residues)
-
PGT145: Primary HIV-1 Envs were expressed as SHIVs, and responses from infected rhesus macaques showed patterns of Env-antibody coevolution similar to those in humans. This included conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions, and deletions leading to virus persistence. A total of 22 macaques were infected with one of the following: SHIV.CH505, SHIV.CH848, or SHIV.CAP256SU. Seven of the animals’ sera showed heterologous neutralization against tier 1A pseudoviruses: 2 were infected by SHIV.CH505 (RM5695 and RM6070), 2 by SHIV.CH848 (RM6163 and RM6167), and 3 by SHIV.CAP256SU (RM40591, RM42056 and RM6727). The remaining 15 animals showed either no or very limited, low titer neutralization of heterologous tier 2 viruses. Escape mutations from the macaque sera and mAbs closely resembled those of human mAb of the same binding type. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design. Four mAbs were isolated from RM5695 (infected with SHIV.CH505): RHA1.V2.01 - RHA1.V2.04. One (RHA1.V2.01), neutralized 49% of a 208-strain panel, and structural analysis revealed a V2-apex mode of recognition that resembles human bnAbs PGT145 or PCT64-35S. The structure of mAb RHA1.V2.01 in complex with the BG505 DS-SOSIP Env trimer, determined by cryo-EM, showed striking similarity to human V2 apex bnAbs PGT145 and PCT64-35S. In a hierarchical clustering analysis of the neutralization profiles of RHA1.V2.01 and other prototypic human V2 apex bNAbs measured against a 208-virus panel, RHA1.V2.01 grouped most closely with PCT64-35M.
Roark2021
(mutation acquisition, neutralization, vaccine antigen design, escape, structure)
-
PGT145: This study reports on bispecific antibodies in which one arm is a single-chain (scFv) form of a V2-glycan antibody (VRC26.25 or PGT145), and the other arm is a V3-glycan Fab (10-1074, PGT121, or PGT128). A linker was used consisting of 10 repeats of tetraglycine-serine (10GS); additionally, KIH (knob in hole) mutations were introduced for stabilization. Some of these bispecific antibodies are markedly more potent than their parental bNAbs, likely because they simultaneously engage both the V2-apex and V3-glycan epitopes of Env.
Davis-Gardner2020
(neutralization, broad neutralizer)
-
PGT145: This study aimed to define properties shared by transmitted viruses by comparing antigenic and functional properties of envelope glycoproteins of viral variants isolated during primary infection in 27 patients belonging to 8 transmission clusters. The neutralization of the 27 pseudotyped viruses was assayed with 8 human bnAbs targeting various regions of the virus. The infectious properties of the viruses was assessed by measuring their infectivity and sensitivity to entry inhibitors. Transmitted viruses from the same transmission chain shared many properties, including similar neutralization profiles, sensitivity to inhibitors, and infectivity. All transmitted viruses were CCR5-tropic, sensitive to maraviroc, and resistant to soluble forms of CD4, irrespective of cluster. They were also generally sensitive to bnAbs that target V3 (10-1074, PGT121), CD4bs (3BNC117, NIH45-46G54W), and MPER region (10E8), suggesting that the loss of these epitopes may affect a virus’s capacity to be transmitted. The viruses were somewhat less sensitive to bnAbs targeting the V1V2 region (PG9, PGT145) and gp120/gp41 interface (8ANC195). These data suggest that the transmission bottleneck is governed by selective forces.
Beretta2018
(neutralization, acute/early infection)
-
PGT145: This study examined whether HIV-1-specific bnAbs are capable of cross-neutralizing simian immunodeficiency viruses (SIVs) from chimpanzees (n=11) or western gorillas (n=1). BnAbs directed against the epitopes at the CD4 binding site (VRC01, VRC03, VRC-PG04, VRC-CH03, VRC-CH31, F105, b13, NIH45-46G54W, 45-46m2, 45-46m7), V3 (10-1074, PGT121, PGT128, PGT135, and 2G12), and gp41-gp120 interface (8ANC195, 35O22, PGT151, PGT152, PGT158) failed to neutralize SIVcpz and SIVgor strains. V2-directed bNabs (PG9, PG16, PGT145) as well as llama-derived heavy-chain only antibodies recognizing the CD4 binding site or gp41 epitopes (JM4, J3, 3E3, 2E7, 11F1F, Bi-2H10) were either completely inactive or neutralized only a fraction of SIVcpz strains. In contrast, neutralization of SIVcpz and SIVgor strains was achieved with low-nanomolar potency by one antibody targeting the MPER region of gp41 (10E8), as well as functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Igmim2, CD4-218.3-E51, CD4-218.3-E51-mim2), mono- and bispecific anti-human CD4 mAbs (iMab, PG9-iMab, PG16-iMab, LM52, LM52-PGT128), and CCR5 receptor mAbs (PRO140, PRO140-10E8). Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5, and neutralized SIVcpz in chimpanzee CD4+ T cells. These findings provide new insight into the protective capacity of anti-HIV-1 bnAbs and identify candidates for further development to combat SIV infection.
Barbian2015
(neutralization, SIV, binding affinity)
-
PGT145: HIV-1 and its SIV precursors share a bnAb epitope in Env V2 at the trimer apex. This study tested the immunogenicity of a chimpanzee SIV (SIVcpz) Env trimer. In mice expressing a human V2-apex bnAb heavy-chain precursor, trimer immunization induced V2-directed nAbs. Infection of macaques with chimeric simian-chimpanzee immunodeficiency viruses (SCIVs) elicited high-titer viremia, potent autologous neutralizing antibodies, rapid sequence escape in the canonical V2-apex epitope, and in some cases, low-titer heterologous plasma breadth mapping to the V2-apex. Antibody cloning from 2 macaques (T925 and T927) identified 7 lineages (53 mAbs) with long CDRH3 regions that cross-neutralize some primary HIV-1 strains with low potency. Electron microscopy of members of the two most cross-reactive lineages confirmed V2 targeting with an angle of approach distinct from prototypical V2-apex bNAbs; antibody binding either required or induced an occluded-open trimer. Probing with conformation-sensitive, nonneutralizing antibodies revealed that SCIV-expressed, but not wild-type SIVcpz Envs, as well as a subset of primary HIV-1 Envs, preferentially adopted a more open trimeric state. These results reveal the existence of a cryptic V2 epitope that is exposed in occluded-open SIVcpz and HIV-1 Env trimers and elicits cross-neutralizing responses of limited breadth and potency. This cryptic epitope, which in some Env backgrounds is immunodominant, needs to be considered in immunogen design. As part of the study, binding and neutralization assays used panels of nAbs (PG9, PG16, PGT145, PGDM1400, VRC26.25, CH01, BG1, VRC38.01), non-nAbs (697-D, 1393A, CH58, CAP228-3D, 3074, 447-52D, 17b, A32), and unmutated ancestors (PG9-RUA, PG16-RUA, VRC26-UCA, CH01-RUA).
Bibollet-Ruche2023
(neutralization, vaccine antigen design, vaccine-induced immune responses)
-
PGT145: Structural characterization of macaque vaccine-induced mAbs Ab1303 and Ab1573 revealed a CD4bs binding mechanism that requires an occluded-open Env trimer conformation, similar to what has been observed for mAb b12. BnAb PGT145 was used to capture and lock BG505 Env trimers into a closed, pre-fusion conformation which only bnAb IOMA, and not b12, Ab1303 or Ab1573, could bind.
Yang2022
(antibody binding site)
-
PGT145: A macaque sequential immunization protocol with increasingly native-like V3-glycan-targeting Env trimers multimerized onto virus-like particles elicited multiple on-target mAbs with heterologous, yet generally weak, neutralization activity and minimal protection in a subsequent intrarectal heterologous challenge with SHIVDH12-V3AD8. The priming immunogen was RC1-4fill (clade A/E, RC1 with 4 additional glycans), a low affinity Env trimer with additional glycans to facilitate V3-glycan targeting and mask BG505 glycan hole, while the boosting immunogens were 11MUTB-4fill (clade A/E), B41-5MUT or B41 wildtype (clade B), AMC011/Du422 (clade B/C), and consensus group M/consensus clade C Env trimers. In a RC1 binding assay, PGT145 Fab competed moderately with itself and bnAb PG16. PGT145 IgG binding to RC1 was also competed by 10-1074 Fab. Serum from the 8 immunized macaques collected after each immunization did not display RC1-binding competition with 3BC315.
Escolano2021
(antibody interactions, vaccine antigen design)
-
PGT145: HIV-1 bnAbs require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations. Probable mutations occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. The paper introduced the ARMADiLLO program, which estimates how probable a particular mAb mutation is, and thus the key improbable mutations were defined for a panel of 26 bnAbs. The number of improbable mutations ranged from 7 (PGT128) to 23 (VRC01 and 35O22); PGT145 had 12 improbable mutations out of 52 total AA mutations, and 0 indels. Single-amino acid reversion mutants were made for key improbable mutations of 3 bnAbs (CH235, VRC01, and BF520.1), and these mutant mAbs were tested for their neutralization ability. The study also noted that bnAbs that had relatively small numbers of improbable single somatic mutations had other unusual characteristics that were due to additional improbable events, such as indels (PGT128) or extraordinary CDR H3 lengths (VRC26.25).
Wiehe2018
(neutralization)
-
PGT145: A panel of 33 CRF02_AG pseudoviruses was generated from HIV-1-infected individuals during early stages of infection. Samples represented a 15-year period 1997-2012. These viruses were best neutralized by the CD4bs-directed bnAbs (VRC01, 3BNC117, NIH45-46G54W, and N6) and the MPER-directed bnAb 10E8 in terms of both potency and breadth. There was a higher resistance to bnAbs targeting the V1V2-glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Neutralization by 8ANC195 was also assayed. Combinations of antibodies were predicted by the CombiNaber tool to achieve full coverage across this subtype. There was increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the timespan sampled.
Stefic2019
(neutralization, acute/early infection, subtype comparisons)
-
PGT145: The authors review Fc effector functions, which cooperatively with Fab neutralization functions, could be used passively as immunotherapeutic or immunoprophylactic agents of HIV reservoir control or even infection prevention. One effector function, antibody-dependent complement-mediated lysis (ADCML), is seen with IgG1 and IgG3 anti-V1/V2 glycan bnAbs, PG9, PG16, PGT145; but not with 2F5, 4E10, 2G12, VRC01 and 3BNC117 unless they are delivered with anti-regulators of complement activation (RCA) antibodies. Another effector function, antibody-dependent cellular cytotoxicity (ADCC) can slow disease progression by NK-mediated degranulation of infected cells that are coated by bnAbs whose Fc region is recognized by the low affinity NK receptor, FcγRIIIA (or CD16). Strong ADCC was induced by NIH45-46, 3BNC117, 10-1074, PGT121 and 10E8, with intermediate activity for PG16 and VRC01, but no ADCC activation for 12A12, 8ANC195 and 4E10. A final effector function, antibody-dependent phagocytosis (ADP) also eliminates infected cells but through phagocytosis mediated by Fc portions of coating anti-HIV antibodies interacting with other FcγR (or FcαR) on the surface of granulocytes, monocytes or macrophages. This protective mode is less well studied but bnAbs like VRC01 have been engineered to increase phagocytosis by neutrophils. Protein engineering of bispecifics against the surface of infected or reservoir virus cells has potential in the future.
Danesh2020
(antibody interactions, assay or method development, complement, effector function, immunoprophylaxis, neutralization, immunotherapy, early treatment, review, broad neutralizer, HIV reservoir/latency/provirus)
-
PGT145: To understand early bnAb responses, 51 HIV-1 clade C infected infants were assayed for neutralization of a 12-virus multi-clade panel. Plasma bnAbs targeting V2-apex on Env were predominant in infant elite and broad neutralizers. In infant elite neutralizers, multi-variant infection was associated with plasma bnAbs targeting diverse autologous viruses. A panel of mAbs (PG9, PG16, PGT145, PGDM1400, VRC26.25, 10-1074, BG18, AIIMS-P01, PGT121, PGT128, PGT135, VRC01, N6, 3BNC117, PGT151, 35O22, 10E8, 4E10, F105, 17b, A32, 48d, b6, 447-52d) was assayed for their ability to neutralize Env clones from infant elite neutralizers; circulating viral variants in infant elite neutralizers were most susceptible to V2-apex bnAbs.
Mishra2020a
(neutralization, polyclonal antibodies)
-
PGT145: In vertically-infected infant AIIMS731, a rare HIV-1 mutation in hypervariable loop 2 (L184F) was studied. In patient sequences, this mutation was present in the majority of clones. A panel of 6 V2 bnAbs (PG9, PG16, PGT145, PGDM1400, CAP256.25, and CH01) was assayed for neutralization of 6 patient viral clones. The AIIMS731 viral variants segregated into 4 neutralization-sensitive and 2 resistant clones; sensitive clones carried 184F, while resistant clones carried the rare 184L mutation. A large panel of bnAbs targeting non-V2 epitopes was used to assess the neutralization of the 6 patient viral variants. The bnAb panel consisted of V3/N332 glycan supersite bnAbs (10-1074, BG18, AIIMS-P01, PGT121, PGT128, and PGT135), CD4bs bnAbs (VRC01, VRC03, VRC07-523LS, N6, 3BNC117, and NIH45-46 G54W), a silent face-targeting bnAb (PG05), fusion peptide and gp120-gp41 interface bnAbs (PGT151, 35O22, and N123-VRC34.01), and MPER bnAbs (10E8, 4E10, and 2F5). All of these bnAbs had similar neutralization efficiencies for all 6 clones, suggesting that the L184F mutation was specific for viral escape from neutralization by V2 apex bnAbs. A panel of non-neutralizing mAbs (V3 loop-targeting non-nAbs 447-52D and 19b, and CD4-induced non-nAbs 17b, A32, 48d, and b6), were also assessed; 2 of the variants (the same 2 susceptible to the V2 bnAbs) showed moderate neutralization by 447-52D, 19b, 17b, and 48d. The structure of ligand-free BG505 SOSIP trimer revealed that the side chain of L184 was outward facing and did not make significant intraprotomeric interactions, but upon mutating L184 to F184, a disruption of the accessible surface between the bulky side chain of F184 on one protomer and R165 on the neighboring protomer was seen. Thus, the L184F mutation resulted in increased susceptibility to neutralization by antibodies known to target the relatively more open conformation of Env on tier 1 viruses, suggesting that the rare L184F mutation allowed Env to sample more open states resembling the CD4-bound conformation where the CCR5 binding site is exposed.
Mishra2020
(neutralization, polyclonal antibodies)
-
PGT145: A plant-based expression system was used to produce different glycoforms of the bnAbs PG9, PG16, 10–1074, NIH45–46G54W, 10E8, PGT121, PGT128, PGT145, PGT135, and b12. Also produced were mutated forms (N92T) of VRC01 (mVRC01) and NIH45–46G54W (mNIH45–46G54W). The in vivo properties of these mAbs were assessed in macaques to distinguish those most likely to comprise or become a component of an affordable and efficacious immunotherapeutic cocktails. N-glycans within the VL domain impaired the plasma stability of plant-derived bnAbs. While PGT121 and b12 exhibited no immunogenicity in rhesus macaques, VRC01, 10-1074 and NIH45-46G54W elicited high titer anti-idiotypic antibodies. The results indicated that that specific mutations in certain bnAbs caused immunogenicity in macaques. Such immunogenicity in humans would potentially compromise their value for immunotherapy. CHO1-31 was used as a positive control in a neutralization assay.
Rosenberg2015
(anti-idiotype, neutralization, immunotherapy)
-
PGT145: Since cross-reactive antibodies can interfere in immunoassays, HIV-1 mAbs were tested for binding to the SARS-COV-2 spike (S) protein (SARS-COV-2 S cross-reactivity). The following 9 gp120-epitope binding HIV-1 mAbs are cross-reactive with COV-2 S: 2G12, PGT121, PGT126, PGT128, PGT145, PG9, PG16, 10-1074, and 35O22. CD4bs Abs VRC01 and VRC03 are not cross-reactive. Cross-reactivity of the 9 HIV-1 Abs was through glycoepitopes. Glycan-dependent, V3-loop-binding PGT126 and PGT128, as well as 2G12, were the strongest binders of COV-2 S and were found to be immunoreactive but incapable of neutralization or antibody-dependent enhancement (ADE).
Mannar2021
(antibody interactions, effector function, glycosylation, computational prediction, antibody polyreactivity)
-
PGT145: The crystal structure of Fab NC-Cow1 was determined. The NC-Cow1 structure was then determined in a quaternary complex with BG505 SOSIP.664, in which human Fabs PGT128 and 35022 were added to facilitate formation of diffraction-quality crystals. The exceptionally long (60 residues) CDR H3 of the heavy chain of NC-Cow1 forms a mini domain (knob) on an extended stalk that navigates through the dense glycan shield on Env to target a small footprint on the gp120 CD4bs with no contact of the other CDRs to the rest of the Env trimer. The 3D structure of NC-Cow1 was closely compared with that of PGT145.
Stanfield2020
(structure)
-
PGT145: In an effort to identify new Env immunogens able to elicit bNAbs, this study looked at Envs derived from rare individuals who possess bNAbs and are elite viral suppressors, hypothesizing that in at least some people the antibodies may mediate durable virus control. The Env proteins recovered from these individuals may more closely resemble the Envs that gave rise to bNAbs compared to the highly diverse viruses isolated from normal progressors. This study identified a treatment-naive elite suppressor, EN3 (patient record #4929), whose serum had broad neutralization. The Env sequences of EN3 had much fewer polymorphisms, compared to those of a normal progressor, EN1 (patient record #4928), who also had broad serum neutralization. This result confirmed other reports of slower virus evolution in elite suppressors. EN3 Envelope proteins were unusual in that most possessed two extra cysteines within an elongated V1 region. The impact of the extra cysteines on the binding to bNAbs, virus infectivity, and sensitivity to neutralization suggested that structural motifs in V1 can affect infectivity, and that rare viruses may be prevented from developing escape. As part of this study, the neutralization of pseudotype viruses for EN3 Env clones was assayed for several bNAbs (PG9, PG16, PGT145, PGT121, PGT128, VRC01, 4E10, and 35O22).
Hutchinson2019
(elite controllers and/or long-term non-progressors, neutralization, vaccine antigen design, polyclonal antibodies)
-
PGT145: Extensive structural and biochemical analyses demonstrated that PGT145 achieves recognition and neutralization by targeting quaternary structure of the cationic trimer apex required for CCR5/CSCR4 binding through long and unusually stabilized anionic β-hairpin HCDR3 loops. Analysis of generated cryoEM and X-ray Fab structures, BG505.Env.C2 alanine-scanning neutralization assays and glycan knockouts revealed that PGT145 represents a distinct class of apex bNAb that is dependent on N160, indirectly affected by N156 glycan and requires simultaneous recognition of peptide contacts from apex central residues of all 3 gp120 V1V2 loops. Logistic regression sequence analysis revealed that BG505 V2 amino acids important for neutralization included K121, R166, & T162 that directly contact PGT145; K171 that indirectly affect PGT145 via N160 & N156; and L125, I309, L175 & I326 that affect trimer stabilization via hydrophobic packing. Electrostatic pairwise interactions in HCDR3 were also required for neutralizing activity while mutations affecting other extensive electrostatic interactions reduced neutralization potency. Authors predict that PGT145 IgG binding in vivo would prevent CD4 binding through steric interference. 3BNC117-binding induced allosteric effects resulting in greater access to the apical binding site for PGT145.
Lee2017
(antibody binding site, antibody interactions, structure, broad neutralizer)
-
PGT145: Analyses of all PDB HIV1-Env trimer (prefusion, closed) structures fulfilling certain parameters of resolution were performed to classify them on the basis of (a) antibody class which was informed by parental B cells as well as structural recognition, and (b) Env residues defining recognized HIV epitopes. Structural features of the 206 HIV epitope and bNAb paratopes were correlated with functional properties of the breadth and potency of neutralization against a 208-strain panel. Broadly nAbs with >25% breadth of neutralization belonged to 20 classes of antibodies with a large number of protruding loops and high degree of somatic hypermutation (SHM). Analysis of recognized HIV epitopes placed the bNAbs into 6 categories (viz. V1V2, glycan-V3, CD4-binding site, silent face center, fusion peptide and subunit interface). The epitopes contained high numbers of independent sequence segments and glycosylated surface area. PGT145-Env formed a distinct group within the V1V2 category, Class PGT145, as the recognition site was an Ab loop insertion into a trimeric hole at the spike apex of Env. Data for PGT145 complexed to BG505 SOSIP.664 trimer was found in PDB ID: 5V8L.
Chuang2019
(antibody binding site, antibody interactions, binding affinity, antibody sequence, structure, antibody lineage, broad neutralizer)
-
PGT145: Soluble versions of HIV-1 Env trimers (sgp140 SOSIP.664) stabilized by a gp120-gp41 disulfide bond and a change (I559P) in gp41 have been structurally characterized. Cross-linking/mass spectrometry to evaluate the conformations of functional membrane Env and sgp140 SOSIP.664 has been reported. Differences were detected in the gp120 trimer association domain and C terminus and in the gp41 HR1 region which can guide the improvement of Env glycoprotein preparations and potentially increase their effectiveness as a vaccine. PGT145 broadly neutralized HIV-1AD8 full-length and cytoplasmic tail-deleted Envs.
Castillo-Menendez2019
(vaccine antigen design, structure)
-
PGT145: Lipid-based nanoparticles for the multivalent display of trimers have been shown to enhance humoral responses to trimer immunogens in the context of HIV vaccine development. After immunization with soluble MD39 SOSIP trimers (a stabilized version of BG505), trimer-conjugated liposomes improved both germinal center B cell and trimer-specific T follicular helper cell responses. In particular, MD39-liposomes showed high levels of binding by bNAbs such as V3 glycan specific PGT121, V1/V2 glycan specific PGT145, gp120/gp41 interface specific PGT151, CD4 binding site specific VRC01, and showed minimal binding by non-NAbs like CD4 binding site specific B6, and V3 specific 4025 or 39F.
Tokatlian2018
(vaccine antigen design, binding affinity)
-
PGT145: Without SOSIP changes, cleaved Env trimers disintegrate into their gp120 and gp41-ectodomain (gp41_ECTO) components. This study demonstrates that the gp41_ECTO component is the primary source of this Env metastability and that replacing wild-type gp41_ECTO with BG505 gp41_ECTO of the uncleaved prefusion-optimized design is a general and effective strategy for trimer stabilization. A panel of 11 bNAbs, including the V2 apex recognized by PGDM1400, PGT145, and PG16, was used to assess conserved neutralizing epitopes on the trimer surface, and the main result was that the substitution was found to significantly improve trimer binding to bNAbs VRC01, PGT151, and 35O22, with P values (paired t test) of 0.0229, 0.0269, and 0.0407, respectively.
He2018
(antibody interactions, glycosylation, vaccine antigen design)
-
PGT145: To reduce local V2 flexibility and improve the binding of V2-dependent bNAbs and germline precursor bNAbs, the authors designed BG505 SOSIP.664 trimer variants whose V1 and V2 domains were stabilized by introducing disulfide bonds either within the V2 loop or between the V1 and V2 loops. The resulting SOSIP trimer variants — E153C/K178C, E153C/K178C/G152E and I184C/E190C — have improved reactivity with V2 bNAbs and their inferred germline precursors and are more sensitive to neutralization by V2 bNAbs. The I184C/E190C mutant bound all the V2 bNAbs (PG9, PG16, PGT145, VRC26.09, and CH01) better than SOSIP.664.
deTaeye2019
(neutralization, vaccine antigen design, binding affinity)
-
PGT145: This study demonstrated that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens eliciting Ab responses with greater neutralization breadth. Data from four large virus panels were used to comprehensively map viral signatures associated with bNAb sensitivity, hypervariable region characteristics, and clade effects. The bNAb signatures defined for the V2 epitope region were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine which resulted in increased breadth of nAb responses compared with Env 459C alone. PGT145 was used for analyzing clade sensitivity and the V2Ab signature summaries (Table S1).
Bricault2019
(antibody binding site, neutralization, vaccine antigen design, computational prediction, broad neutralizer)
-
PGT145: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. PGT145, a prototype super-Ab, was isolated from direct functional screening of B cell clones. Antigenic region V2 apex (Table:1)
Walker2018
(antibody binding site, review, structure, broad neutralizer)
-
PGT145: The effects of 16 glycoengineering (GE) methods on the sensitivities of 293T cell-produced pseudoviruses (PVs) to a large panel of bNAbs were investigated. Some bNAbs were dramatically impacted. PG9 and CAP256.09 were up to ˜30-fold more potent against PVs produced with co-transfected α-2,6 sialyltransferase. PGT151 and PGT121 were more potent against PVs with terminal SA removed. 35O22 and CH01 were more potent against PV produced in GNT1-cells. The effects of GE on bNAbs VRC38.01, VRC13 and PGT145 were inconsistent between Env strains, suggesting context-specific glycan clashes. Overexpressing β-galactosyltransferase during PV production 'thinned' glycan coverage, by replacing complex glycans with hybrid glycans. This impacted PV sensitivity to some bNAbs. Maximum percent neutralization by excess bnAb was also improved by GE. Remarkably, some otherwise resistant PVs were rendered sensitive by GE. Germline-reverted versions of some bnAbs usually differed from their mature counterparts, showing glycan indifference or avoidance, suggesting that glycan binding is not germline-encoded but rather, it is gained during affinity maturation. Overall, these GE tools provided new ways to improve bnAb-trimer recognition that may be useful for informing the design of vaccine immunogens to try to elicit similar bnAbs.
Crooks2018
(vaccine antigen design, antibody lineage)
-
PGT145: A panel of bnAbs were studied to assess ongoing adaptation of the HIV-1 species to the humoral immunity of the human population. Resistance to neutralization is increasing over time, but concerns only the external glycoprotein gp120, not the MPER, suggesting a high selective pressure on gp120. Almost all the identified major neutralization epitopes of gp120 are affected by this antigenic drift, suggesting that gp120 as a whole has progressively evolved in less than 3 decades.
Bouvin-Pley2014
(neutralization)
-
PGT145: A rare glycan hole at the V2 apex is enriched in HIV isolates neutralized by inferred precursors of prototype V2-apex bNAbs. To investigate whether this feature could focus neutralizing responses onto the apex bnAb region, rabbits were immunized with soluble trimers adapted from these Envs. Potent autologous tier 2 neutralizing responses targeting basic residues in strand C of the V2 region, which forms the core epitope for V2-apex bnAbs, were observed. Neutralizing monoclonal antibodies (mAbs) derived from these animals display features promising for subsequent broadening of the response. Four human anti-V2 bnAbs (PG9, CH01, PGT145, and CAP256.09) were used as a basis of comparison.
Voss2017
(vaccine antigen design)
-
PGT145: This study describes the generation of CHO cell lines stably expressing the following vaccine Env Ags: CRF01_AE A244 Env gp120 protein (A244.AE) and 6240 Env gp120 protein (6240.B). The antigenic profiles of the molecules were assessed with a panel of well-characterized mAbs recognizing critical epitopes and glycosylation analysis confirming previously identified sites and revealing unknown sites at non-consensus motifs. A244.AE gp120 showed no measurable binding to PGT145 in ELISA EC50 and Surface Plasmon Resonance (SPR) assays.
Wen2018
(glycosylation, vaccine antigen design)
-
PGT145: Assays of poly- and autoreactivity demonstrated that broadly neutralizing NAbs are significantly more poly- and autoreactive than non-neutralizing NAbs. PGT145 is neither autoreactive nor polyreactive.
Liu2015a
(autoantibody or autoimmunity, antibody polyreactivity)
-
PGT145: Panels of C clade pseudoviruses were computationally downselected from the panel of 200 C clade viruses defined by Rademeyer et al. 2016. A 12-virus panel was defined for the purpose of screening sera from vaccinees. Panels of 50 and 100 viruses were defined as smaller sets for use in testing magnitude and breadth against C clade. Published neutralization data for 16 mAbs was taken from CATNAP for the computational selections: 10-1074, 10-1074V, PGT121, PGT128, VRC26.25, VRC26.08, PGDM1400, PG9, PGT145, VRC07-523, 10E8, VRC13, 3BNC117, VRC07, VRC01, 4E10.
Hraber2017
(assay or method development, neutralization)
-
PGT145: The immunologic effects of mutations in the Env cytoplasmic tail (CT) that included increased surface expression were explored using a vaccinia prime/protein boost protocol in mice. After vaccinia primes, CT- modified Envs induced up to 7-fold higher gp120-specific IgG, and after gp120 protein boosts, they elicited up to 16-fold greater Tier-1 HIV-1 neutralizing antibody titers. quaternary epitopes in the V1/V2 domain could not be probed using PGT145, as it doesn't bind to WT 89.6 or JRFL.
Hogan2018
(vaccine antigen design)
-
PGT145: SOSIP.664 trimer was modified at V3 positions 306 and 308 by Leucine substitution to create hydrophobic interactions with the tryptophan residue at position 316 and the V1V2 domain. These modifications stabilized the resulting SOSIP.v5.2 S306L R308L trimers. In vivo, the induction of V3 non-NAbs was significantly reduced compared with the SOSIP.v5.2 trimers. S306L plus R308L paired substitutions had no effect on the trimer reactivity of PGT145.
deTaeye2018
(broad neutralizer)
-
PGT145: DS-SOSIP.4mut (4mut) was identified as the most immunogenic and stable of 4 engineered, soluble, closed prefusion HIV-1 Env trimers. 4mut contained 4 mutations (M154, M300, M302 and L320) designed to form hydrophobic interactions between V1V1 and V3 loops. Both pre- and post-V3 negative selection, V2-apex-targeted bnAb PGT145 recognized 4mut, the other 3 designed trimers (DS-SOSIP.6mut containing 4mut mutations, Y177W and I420M, DS-SOSIP.I423F and DS-SOSIP.A316W), and related trimers DS-SOSIP and BG505 SOSIP.664. Each DS-SOSIP variant was able to elicit trimer-specific responses, comparable to BG505 SOSIP.664, in guinea pigs after 4 immunizations, but none elicited heterologous neutralizing activity. Crystal structures were generated for 4mut and 6mut.
Chuang2017
(vaccine antigen design, vaccine-induced immune responses)
-
PGT145: Three strategies were applied to perturb the structure of Env in order to make the protein more susceptible to neutralization: exposure to cold, Env-activating ligands, and a chaotropic agent. A panel of mAbs (E51, 48d, 17b, 3BNC176, 19b, 447-52D, 39F, b12, b6, PG16, PGT145, PGT126, 35O22, F240, 10E8, 7b2, 2G12) was used to test the neutralization resistance of a panel of subtype B and C pseudoviruses with and without these agents. Both cold and CD4 mimicking agents (CD4Ms) increased the sensitivity of some viruses. The chaotropic agent urea had little effect by itself, but could enhance the effects of cold or CD4Ms. Thus Env destabilizing agents can make Env more susceptible to neutralization and may hold promise as priming vaccine antigens.
Johnson2017
(vaccine antigen design)
-
PGT145: Env from of a highly neutralization-resistant isolate, CH120.6, was shown to be very stable and conformationally-homogeneous. Its gp140 trimer retains many antigenic properties of the intact Env, while its monomeric gp120 exposes more epitopes. Thus trimer organization and stability are important determinants for occluding epitopes and conferring resistance to antibodies. Among a panel of 21 mAbs, CH120.6 was resistant to neutralization by all non-neutralizing and strain-specific mAbs, regardless of the location of their epitopes. It was weakly neutralized by several broadly-neutralizing mAbs (VRC01, NIH45-46, 12A12, PG9, PG16, PGT128, 4E10, and 10E8), and well neutralized by only 2 (PGT145 and 10-1074).
Cai2017
(neutralization)
-
PGT145: The next generation of a computational neutralization fingerprinting (NFP) being used as a way to predict polyclonal Ab responses to HIV infection is presented. A new panel of 20 pseudoviruses, termed f61, was developed to aid in the assessment of experimental neutralization. This panel was used to assess 22 well-characterized bNAbs and mixtures thereof (HJ16, VRC01, 8ANC195, IGg1b12, PGT121, PGT128, PGT135, PG9, PGT151, 35O22, 10E8, 2F5, 4E10, VRC27, VRC-CH31, VRC-PG20, PG04, VRC23, 12A12, 3BNC117, PGT145, CH01). The new algorithms accurately predicted VRC01-like and PG9-like antibody specificities.
Doria-Rose2017
(neutralization, computational prediction)
-
PGT145: The isolation of trimers that mimic native Env by epitope-independent, biochemical methods is reported. Chromatography based approaches were used to isolate NL trimers from nonnative Env species, and the method was validated with SOSIP trimers from HIV-1 clades A and B. The resulting material was homogeneous (>95% pure), fully cleaved, and of the appropriate mol weight and size for SOSIP trimers. Since some isolated Envs, like BS208.b1 and KNH1144 T162A, did not present the glycan/quaternary structure-dependent epitope for PGT145 binding, it suggests that this method of isolation circumvents the limitations of mAb-dependdent affinity methods.
Verkerke2016
(vaccine antigen design, structure)
-
PGT145: This study performed cyclical permutation of the V1 loop of JRFL in order to develop better gp120 trimers to elicit neutralizing antibodies. Some mutated trimers showed improved binding to several mAbs, including VRC01, VRC03, VRC-PG04, PGT128, PGT145, PGDM1400, b6, and F105. Guinea pigs immunized with prospective trimers showed improved neutralization of a panel of HIV-1 pseudoviruses.
Kesavardhana2017
(vaccine antigen design, vaccine-induced immune responses)
-
PGT145: This study investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit NAbs. Rabbits were immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). N197 glycan- and residue 230- removal conferred sensitivity to Trimer VLP sera and DNA trimer sera respectively, showing for the first time that strain-specific holes in the "glycan fence" can allow the development of tier 2 NAbs to native spikes. All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. PGT145 was 1 of 2 reference PG9-like bNAbs - PG9 and PGT145.
Crooks2015
(glycosylation, neutralization)
-
PGT145: Env residue N197 on the BG505-SOSIP trimer was mutated to test the effect of its glycosylation on the binding kinetics of CD4BS and other mAbs. Removal of the glycan had little effect on the overall structure of the molecule. Its removal resulted in increased binding of CD4 and CD4BS antibodies (VRC01, VRC03, V3-3074), but little effect on bNAbs targeting other epitopes (PG9, PG16, PGT145, 17b, A32, 2G12, PGT121, PGT126). Two CD4BS-binding antibodies tested (b12, F105) had insufficient breadth to bind the BG505-SOSIP trimer. Removal of the N197 glycan may allow for the development of better SOSIP immunogens, particularly to elicit CD4BS-specific Abs.
Liang2016
(glycosylation, vaccine antigen design)
-
PGT145: This review classified and mapped the binding regions of 32 bNAbs isolated 2010-2016.
Wu2016
(review)
-
PGT145: This study produced Env SOSIP trimers for clades A (strain BG505), B (strain JR-FL), and G (strain X1193). Based on simulations, the MAb-trimer structures of all MAbs tested needed to accommodate at least one glycan, including both antibodies known to require specific glycans (PG9, PGT121, PGT135, 8ANC195, 35O22) and those that bind the CD4-binding site (b12, CH103, HJ16, VRC01, VRC13). A subset of monoclonal antibodies bound to glycan arrays assayed on glass slides (VRC26.09, PGT121, 2G12, PGT128, VRC13, PGT151, 35O22), while most of the antibodies did not have affinity for oligosaccharide in the context of a glycan array (PG9, PGT145, PGDM1400, PGT135, b12, CH103, HJ16, VRC16, VRC01, VRC-PG04, VRC-CH31, VRC-PG20, 3BNC60, 12A12, VRC18b, VRC23, VRC27, 1B2530, 8ANC131, 8ANC134, 8ANC195).
Stewart-Jones2016
(antibody binding site, glycosylation, structure)
-
PGT145: This review summarizes representative anti-HIV MAbs of the first generation (2G12, b12, 2F5, 4E10) and second generation (PG9, PG16, PGT145, VRC26.09, PGDM1400, PGT121, PGT124, PGT128, PGT135, 10-1074, VRC01, 3BNC117, CH103, PGT151, 35O22, 8ANC195, 10E8). Structures, epitopes, VDJ usage, CDR usage, and degree of somatic hypermutation are compared among these antibodies. The use of SOSIP trimers as immunogens to elicit B-cell responses is discussed.
Burton2016
(review, structure)
-
PGT145: HIV-1 bNAb eptiope networks were predicted using 4 algorithms informed by neutralization assays using 282 Env from multiclade viruses. Patch clusters of possible Ab epitope regions were tested for significant sensitivity by site-directed mutagenesis. Epitope (Ab binding site) networks of critical Env residues for 21 bNAb (b12, PG9, PG16, PGT121, PGT122, PGT123, PGT125, PGT126, PGT127, PGT128, PGT130, PGT131, PGT135, PGT136, PGT137, PGT141, PGT142, PGT143, PGT144, PGT145 and PGV04) were delineated and found to be located mostly in variable loops of gp120, particularly in V1/V2.
Evans2014
(antibody binding site, computational prediction)
-
PGT145: Two stable homogenous gp140 Env trimer spikes, Clade A 92UG037.8 Env and Clade C C97ZA012 Env, were identified. 293T cells stably transfected with either presented fully functional surface timers, 50% of which were uncleaved. A panel of neutralizing and non-neutralizing Abs were tested for binding to the trimers. V1/V2 glycan bNAbs PGT145 bound cell surface tightly whether the trimer contained its C-terminal or not, and was competed out by sCD4. It was able to neutralize the 92UG037.8 HIV-1 isolate.
Chen2015
(neutralization, binding affinity)
-
PGT145: Factors that independently affect bNAb induction and evolution were identified as viral load, length of untreated infection, and viral diversity. Black subjects induced bNAbs more than white subjects, but this did not correlate with type of Ab response. Fingerprint analyses of induced bNAbs showed strong subtype dependency, with subtype B inducing significantly higher levels of CD4bs Abs and non-subtype B inducing V2-glycan specific Abs. Of the 239 bNAb antibody inducers found from 4,484 HIV-1 infected subjects,the top 105 inducers' neutralization fingerprint and epitope specificity was determined by comparison to the following antibodies - PG9, PG16, PGDM1400, PGT145 (V2 glycan); PGT121, PGT128, PGT130 (V3 glycan); VRC01, PGV04 (CD4bs) and PGT151 (interface) and 2F5, 4E10, 10E8 (MPER).
Rusert2016
(neutralization, subtype comparisons, broad neutralizer)
-
PGT145: PGT145 was used to positively isolate a subtype B Env trimer immunogen, B41 SOSIP.664-D7324, that exists in two conformations, closed and partially open. bNAbs tested against the trimer were able to neutralize the B41 pseudovirus with a wide range of potencies. All tested non-NAbs did not neutralize B41 (IC50 >50µg/ml). V1/V2 glycan bNAb, PGT145, neutralized B41 psuedovirus and bound B41 trimer strongly.
Pugach2015
-
PGT145: The first generation of HIV trimer soluble immunogens, BG505 SOSIP.664 were tested in a mouse model for generation of nAb to neutralization-resistant circulating HIV strains. No such NAbs were induced, as mouse Abs targeted the bottom of soluble Env trimers, suggesting that the glycan shield of Env trimers is impenetrable to murine B cell receptors and that epitopes at the trimer base should be obscured in immunogen design in order to avoid non-nAb responses. Association and dissociation of known anti-trimer bNAbs (VRC01, PGT121, PGT128, PGT151, PGT135, PG9, 35O22, 3BC315 and PGT145) were found to be far greater than murine generated non-NAbs.
Hu2015
-
PGT145: A comprehensive antigenic map of the cleaved trimer BG505 SOSIP.664 was made by bNAb cross-competition. Epitope clusters at the CD4bs, quaternary V1/V2 glycan, N332-oligomannose patch and new gp120-gp41 interface and their interactions were delineated. Epitope overlap, proximal steric inhibition, allosteric inhibition or reorientation of glycans were seen in Ab cross-competition. Thus bNAb binding to trimers can affect surfaces beyond their epitopes. PGT145, PG16 and PG9, all V1/V2 glycan trimer apex bNAbs, were strongly, reciprocally competitive with one another. V3 glycan bNAbs PGT121, PGT122, PGT123 inhibited binding of PGT145 strongly, but in a non-reciprocal manner. Unexpectedly, PGT145 strongly and non-reciprocally competed 1NC9, 8ANC195 and to a lesser extent PGT151 and 35O22, most of them gp120-gp41 binding bNAbs.
Derking2015
(antibody interactions, neutralization, binding affinity, structure)
-
PGT145: Two clade C recombinant Env glycoprotein trimers, DU422 and ZM197M, with native-like structural and antigenic properties involving epitopes for all known classes of bNAbs, were produced and characterized. These Clade C trimers (10-15% of which are in a partially open form) were more like B41 Clade B trimers which have 50-75% trimers in the partially open configuration than like B505 Clade B trimers, almost 100% in the closed, prefusion state. The Clade C trimer ZM197M is strongly reactive to the quaternary-dependent, V1/V2 glycan trimer-apex bNAb, PGT145 but trimer DU442 and its pseudotyped virus are weakly reactive with PGT145.
Julien2015
(assay or method development, structure)
-
PGT145: Env trimer BG505 SOSIP.664 as well as the clade B trimer B41 SOSIP.664 were stabilized using a bifunctional aldehyde (glutaraldehye, GLA) or a heterobifunctional cross-linker, EDC/NHS with modest effects on antigenicity and barely any on biochemistry or structural morphology. ELISA, DSC and SPR were used to test recognition of the trimers by bNAbs, which was preserved and by weakly NAbs or non-NAbs, which was reduced. Cross-linking partially preserves quaternary morphology so that affinity chromatography by positive selection using quaternary epitope-specific bNAabs, and negative selection using non-NAbs, enriched antigenic characteristics of the trimers. Binding of V1/V2 apex-binding bNAb PGT145 to trimers was 3.7-fold reduced by trimer cross-linking.
Schiffner2016
(assay or method development, binding affinity, structure)
-
PGT145: HIV-1 escape from the N332-glycan dependent bNAb, PGT135, developed in an elite controller but without change to the PGT135-binding Env epitope itself. Instead an insertion increasing V1 length by up to 21 residues concomitant with an additional 1-3 glycans and 2-4 cysteines shields the epitope from PGT135. The majority of viruses tested developed a 14-fold resistance to PGT135 from month 7 to 11. In comparison, HIV-1 developed a 36 fold sensitivity to PGT145.
vandenKerkhof2016
(elite controllers and/or long-term non-progressors, neutralization, escape)
-
PGT145: The native-like, engineered trimer BG505 SOSIP.664 induced potent NAbs against conformational epitopes of neutralization-resistant Tier-2 viruses in rabbits and macaques, but induced cross-reactive NAbs against linear V3 epitopes of neutralization-sensitive Tier-1 viruses. A different trimer, B41 SOSIP.664 also induced strong autologous Tier-2 NAb responses in rabbits. Sera from 20 BG505 SOSIP.664-D7324 trimer-immunized rabbits were incapable of inhibiting PGT145 binding to V1/V2-glycan. 2/4 similarly trimer-immunized macaque sera however inhibited PGT145 binding by >50%.
Sanders2015
(antibody generation, neutralization, binding affinity, polyclonal antibodies)
-
PGT145: A new trimeric immunogen, BG505 SOSIP.664 gp140, was developed that bound and activated most known neutralizing antibodies but generally did not bind antibodies lacking neuralizing activity. This highly stable immunogen mimics the Env spike of subtype A transmitted/founder (T/F) HIV-1 strain, BG505. Anti-V1/V2 glycan bNAb PGT145, neutralized BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, and was shown to recognize and bind the immunogen too.
Sanders2013
(assay or method development, neutralization, binding affinity)
-
PGT145: This paper analyzed site-specific glycosylation of a soluble, recombinant trimer (BG505 SOSIP.664). This trimer mapped the extremes of simplicity and diversity of glycan processing at individual sites and revealed a mosaic of dense clusters of oligomannose glycans on the outer domain. Although individual sites usually minimally affect the global integrity of the glycan shield, they identified examples of how deleting some glycans can subtly influence neutralization by bNAbs that bind at distant sites. The network of bNAb-targeted glycans should be preserved on vaccine antigens. Neutralization profiles for V1V2 Ab, PG145, to multiple epitopes were determined. Removing the N156 or N160 or N197 glycans from either of the BG505 test viruses reduced the neutralization activities of PG145.
Behrens2016
(antibody binding site, glycosylation)
-
PGT145: The study detailed binding kinetics of the interaction between BG505 SOSIP.664 trimer or its variants (gp120 monomer; first study of disulfide-stabilized variant gp120-gp41ECTO protomer) and several mAbs, both neutralizing (VRC01, PGV04, PG9, PG16, PGT121, PGT122, PGT123, PGT145, PGT151, 2G12) and non-neutralizing (b6, b12, 14e, 19b, F240). V1V2 quarternary-dependent epitope-binding bNAb, PGT145, bound trimer best, did not bind protomer and BG505 gp120's monomer.
Yasmeen2014
(antibody binding site, assay or method development)
-
PGT145: Ten mAbs were isolated from a vertically-infected infant BF520 at 15 months of age. Ab BF520.1 neutralized pseudoviruses from clades A, B and C with a breadth of 58%, putting it in the same range as second-generation bNAbs derived from adults, but its potency was lower. BF520.1 was shown to target the base of the V3 loop at the N332 supersite. V1/V2 glycan-binding, second-generation mAb, PGT145 when compared had a geometric mean of IC50=0.23 µg/ml for 8/12 viruses it neutralized at a potency of 67%. The infant-derived antibodies had a lower rate of somatic hypermutation (SHM) and no indels compared to adult-derived anti-V3 mAbs. This study shows that bnAbs can develop without SHM or prolonged affinity maturation.
Simonich2016
(antibody binding site, neutralization, responses in children, structure)
-
PGT145: This study examined the neutralization of group N, O, and P primary isolates of HIV-1 by diverse antibodies. Cross-group neutralization was observed only with the bNAbs targeting the N160 glycan-V1/V2 site. Four group O isolates, 1 group N isolate, and the group P isolates were neutralized by PG9 and/or PG16 or PGT145 at low concentrations. None of the non-M primary isolates were neutralized by bNAbs targeting other regions, except 10E8, which weakly neutralized 2 group N isolates, and 35O22 which neutralized 1 group O isolate. Bispecific bNAbs (PG9-iMab and PG16-iMab) very efficiently neutralized all non-M isolates with IC50 below 1 ug/mL, except for 2 group O strains. Anti V1/V2 bNAb PGT145 was able to neutralize 1/16 tested non-M primary isolates at an IC50< 1 µg/ml, RBF168,P at 0.13 µg/ml.
Morgand2015
(neutralization, subtype comparisons)
-
PGT145: This study evaluated the binding of 15 inferred germline (gl) precursors of bNAbs that are directed to different epitope clusters, to 3 soluble native-like SOSIP.664 Env trimers - BG505, B41 and ZM197M. The trimers bound to some gl precursors, particularly those of V1V2-targeted Abs. These trimers may be useful for designing immunogens able to target gl precursors. V1/V2 apex-binding gl-PGT145 did not bind any trimers.
Sliepen2015
(binding affinity, antibody lineage)
-
PGT145: The study's goal was to produce modified SOSIP trimers that would reduce the exposure - and, by inference, the immunogenicity - of non-NAb epitopes such as V3. The binding of several modified SOSIP trimers was compared among 12 neutralizing (PG9, PG16, PGT145, PGT121, PGT126, 2G12, PGT135, VRC01, CH103, CD4, IgG2, PGT151, 35O22) and 3 non-neutralizing antibodies (14e, 19b, b6). The V3 non-NAbs 447-52D, 39F, 14e, and 19b bound less well to all A316W variant trimers compared to wild-type trimers. Mice and rabbits immunized with modified, stabilized SOSIP trimers developed fewer V3 Ab responses than those immunized with native trimers.
deTaeye2015
(antibody binding site)
-
PGT145: A large cross-sectional study of sera from 205 ART-naive patients infected with different HIV clades was tested against a panel of 219 cross-clade Env-pseudotyped viruses. Their neutralization was compared to the neutralization of 10 human bNAbs (10E8, 4E10, VRC01, PG9, PGT145, PGT128, 2F5, CH01, b12, 2G12) tested with a panel of 119 Env-pseudotyped viruses. Results from b12 and 2G12 suggested that these bnAbs may not be as broadly neutralizing as previously thought. PGT145 neutralized 76% of the 199 viruses tested.
Hraber2014
(neutralization)
-
PGT145: The study compared binding and neutralization of 4 V2 apex bnAbs (PG9, CH01, PGT145, and CAP256.VRC26.09). All recognized a core epitope on V1/V2 (the N-linked glycan at N160 and cysteine-linked lysine rich, HXB2:126-196), which includes residue N160 as well as N173. The lysine rich region on strand C of HIV-1 V2 that is key for binding to the nAb contains the sequence (168)KKQK(171). Inferred germline versions of three of the prototype bnAbs were able to neutralize specific Env isolates. Soluble Env derived from one of these isolates was shown to form a well-ordered Env trimer that could serve as an immunogen to initiate a V2-apex bnAb response. Escape from bnAb PGT145 was seen in patient Donor_584 by mutations K169S, Q170K and K171I.
Andrabi2015
(antibody binding site, neutralization, vaccine antigen design, escape, antibody lineage)
-
PGT145: Double, triple or quadruple combinations of fifteen bNAbs that target 4 distinct epitope regions: the CD4 binding site (3BNC117, VRC01, VRC07, VRC07-523, VRC13), the V3-glycan supersite (10–1074, 10-1074V, PGT121, PGT128), the V1/V2-glycan site (PG9, PGT145, PGDM1400, CAP256-VRC26.08, CAP256-VRC26.25), and the gp41 MPER epitope (10E8) were studied. Their neutralization potency and breadth were assayed against a panel of 200 acute/early subtype C strains, and compared to a novel, highly accurate predictive mathematical model (no-overlap Bliss Hill model, CombiNaber tool, LANL HIV Immunology database). These data were used to predict the best combinations of bNAbs for immunotherapy.
Wagh2016
(neutralization, immunotherapy)
-
PGT145: Guinea pigs were immunized with either BG505 Env trimer or a complex of BG505 together with the PGT145 FAb fragment. The hypothesis was that the antibody would stabilize BG505 in its prefusion closed conformation and limit the development of antibodies against V3. Both immunogens elicited similar levels of autologous NAbs, but the BG505-PGT145 complex elicited 100-fold lower responses to V3. This finding may represent an avenue toward reducing off-target immunogenicity while generating autologous NAbs.
Cheng2015
(therapeutic vaccine, vaccine antigen design)
-
PGT145: An atomic-level understanding of V1V2-directed bNAb recognition in a donor was used in the design of V1V2 scaffolds capable of interacting with quaternary-specific V1V2-directed bNAbs. The cocrystal structure of V1V2 with antibody CH03 from a second donor is reported and Env interactions of antibody CAP256-VRC26 from a third donor are modeled. V1V2-directed bNAbs used strand-strand interactions between a protruding Ab loop and a V1V2 strand but differed in their N-glycan recognition. Ontogeny analysis indicated that protruding loops develop early, and glycan interactions mature over time.PGT145 did not bind to the monomeric V1V2 scaffolds. The quaternary dependence might be one possible explanation for this lack of recognition.
Gorman2016
(glycosylation, structure, antibody lineage)
-
PGT145: The sequential development of three distinct bnAb responses within a single host, CAP257, over 4.5 years of infection has been described. It showed how escape from the first wave of Abs targeting V2 exposed a second site that was the stimulus for a new wave of glycan dependent bnAbs against the CD4 binding site. These data highlighted how Ab evolution in response to viral escape mutations served to broaden the host immune response to two epitopes. A third wave of neutralization targeting an undefined epitope that did not appear to overlap with the four known sites of vulnerability on the HIV-1 envelope has been reported. These data supported the design of templates for sequential immunization strategies.
Wibmer2013
(escape)
-
PGT145: Incomplete neutralization may decrease the ability of bnAbs to protect against HIV exposure. In order to determine the extent of non-sigmoidal slopes that plateau at <100% neutralization, a panel of 24 bnMAbs targeting different regions on Env was tested in a quantitative pseudovirus neutralization assay on a panel of 278 viral clones. All bNAbs had some viruses that they neutralized with a plateau <100%, but those targeting the V2 apex and MPER did so more often. All bnMAbs assayed had some viruses for which they had incomplete neutralization and non-sigmoidal neutralization curves. bNAbs were grouped into 3 groups based on their neutralization curves: group 1 antibodies neutralized more than 90% of susceptible viruses to >95% (PGT121-123, PGT125-128, PGT136, PGV04); group 2 was less effective, resulting in neutralization of 60-84% of susceptible viruses to >95% (b12, PGT130-131, PGT135, PGT137, PGT141-143, PGT145, 2G12, PG9); group 3 neutralized only 36-60% of susceptible viruses to >95% (PG16, PGT144, 2F5, 4E10).
McCoy2015
(neutralization)
-
PGT145: This study investigated the immunogenicity of three ΔV1V2 deleted variants of the HIV-1 Env protein. The mutant ΔV1V2.9.VK induced a prominent response directed to epitopes effectively bound and neutralized the ΔV1V2 Env virus. This Env variant efficiently neutralized tier 1 virus SF162.This did not result in broad neutralization of neutralization-resistant virus isolates. This Env variant efficiently neutralized tier 1 virus SF162.This did not result in broad neutralization of neutralization-resistant virus isolates. BG505 SOSIP.664 trimers bind very efficiently to quaternary structure dependent, broadly neutralizing PG9 against the V1V2 domain.
Bontjer2013
(vaccine antigen design, structure)
-
PGT145: Vectored Immuno Prophylaxis (VIP), involves passive immunization by viral vector-mediated delivery of genes encoding bnAbs for in vivo expression. Robust protection against virus infection was observed in preclinical settings when animals were given VIP to express monoclonal neutralizing Abs. This review article surveyed the status of antibody gene transfer, VIP experiments against HIV and its related virus conduced in humanized mice and macaque monkeys, and discuss the pros and cons of VIP and its opportunities and challenges towards clinical applications to control HIV/AIDS endemics.
Yang2014
(immunoprophylaxis, review, antibody gene transfer)
-
PGT145: A gp140 trimer mosaic construct (MosM) was produced based on M group sequences. MosM bound to CD4 as well as multiple bNAbs, including VRC01, 3BNC117, PGT121, PGT126, PGT145, PG9 and PG16. The immunogenicity of this construct, both alone and mixed together with a clade C Env protein vaccine, suggest a promising approach for improving NAb responses.
Nkolola2014
(vaccine antigen design)
-
PGT145: Computational prediction of bNAb epitopes from experimental neutralization activity data is presented. The approach relies on compressed sensing (CS) and mutual information (MI) methodologies and requires the sequences of the viral strains but does not require structural information. For PGT130, CS predicted 6 and MI predicted 3 positions, overlapping in positions 160, 166. Experimentally, PGT-145 binding was abolished by an alanine substitution at position 160, causing a >32,000 fold increase in the IC50 relative to wild type. 166 substitution resulted in 6.4 increases in IC50.
Ferguson2013
(computational prediction, broad neutralizer)
-
PGT145: Clade A Env sequence, BG505, was identified to bind to bNAbs representative of most of the known NAb classes. This sequence is the best natural sequence match (73%) to the MRCA sequence from 19 Env sequences derived from PG9 and PG16 MAbs' donor. A point mutation at position L111A of BG505 enabled more efficient production of a stable gp120 monomer, preserving the major neutralization epitopes. The antisera produced by this adjuvanted formulation of gp120 competed with bnAbs from 3 classes of non-overlapping epitopes. PGT145 showed very high neutralization titer against BG505 pseudovirus in a competitive binding assay as shown in Table 1.
Hoffenberg2013
(antibody interactions, glycosylation, neutralization)
-
PGT145: This is a review of identified bNAbs, including the ontogeny of B cells that give rise to these antibodies. Breadth and magnitude of neutralization, unique features and similar bNAbs are listed. PGT145 is a V1/V2-directed Ab, with breadth 60%, IC50 0.31 μg per ml, and its unique feature is its discontinuous conformational epitope. Similar MAbs include PGT141 and PGT144.
Kwong2013
(review)
-
PGT145: The conserved central region of gp120 V2 contains sulfated tyrosines (Tys173 and Tys177) that in the CD4-unbound prefusion state mediate intramolecular interaction between V2 and the conserved base of the third variable loop (V3), functionally mimicking sulfated tyrosines in CCR5 and anti-coreceptor-binding-site antibodies such as 412d. Enhancement of tyrosine sulfation decreased binding and neutralization of HIV-1 BaL by monomeric sCD4, 412d, and anti-V3 antibodies and increased recognition by the trimer-preferring antibodies PG9, PG16, CH01, and PGT145. Conversely, inhibition of tyrosine sulfation increased sensitivity to soluble CD4, 412d, and anti-V3 antibodies and diminished recognition by trimer-preferring antibodies. These results identify the sulfotyrosine-mediated V2-V3 interaction as a critical constraint that stabilizes the native HIV-1 envelope trimer and modulates its sensitivity to neutralization.
Cimbro2014
-
PGT145: "Neutralization fingerprints" for 30 neutralizing antibodies were determined using a panel of 34 diverse HIV-1 strains. 10 antibody clusters were defined: VRC01-like, PG9-like, PGT128-like, 2F5-like, 10E8-like and separate clusters for b12, CD4, 2G12, HJ16, 8ANC195. This mAb belongs to PG9-like cluster.
Georgiev2013
(neutralization)
-
PGT145: Although next-generation parallel sequencing techniques identify thousands of antibody somatic variants, the natural pairing between heavy and light chains is lost. This work suggests that it is possible to approximate them by comparing antibody heavy- and light-chain phylogenetic trees. Somatic variants of 10E8 from donor N152 and of antibodies PGT141-145 from donor 84 were studied. The heavy- and light-chain phylogenetic trees were remarkably similar in both cases.
Zhu2013
(antibody sequence)
-
PGT145: This study uncovered a potentially significant contribution of VH replacement products which are highly enriched in IgH genes for the generation of anti-HIV Abs including anti-gp41, anti-V3 loop, anti-gp120, CD4i and PGT Abs. IgH encoding PGT Abs are likely generated from multiple rounds of VH replacements. The details of PGT145 VH replacement products in IgH gene and mutations and amino acid sequence analysis are described in Table 1, Table 2 and Fig 4.
Liao2013a
(antibody sequence)
-
PGT145: Neutralization profiles of 7 bnAbs were analyzed against 45 Envs (A, C, D clades), obtained soon after infection (median 59 days). The transmitted variants have distinct characteristics compared to variants from chronic patients, such as shorter variable loops and fewer potential N-linked glycosylation sites (PNGS). PGT145 neutralized only 16% of these viruses.
Goo2012
(neutralization, rate of progression)
-
PGT145: Identification of broadly neutralizing antibodies, their epitopes on the HIV-1 spike, the molecular basis for their remarkable breadth, and the B cell ontogenies of their generation and maturation are reviewed. Ontogeny and structure-based classification is presented, based on MAb binding site, type (structural mode of recognition), class (related ontogenies in separate donors) and family (clonal lineage). This MAb's classification: gp120 V1V2 site, type not yet determined, PGt145 class, PGT145 family.
Kwong2012
(review, structure, broad neutralizer)
-
PGT145: This review discusses how analysis of infection and vaccine candidate-induced antibodies and their genes may guide vaccine design. This MAb is listed as V1/V2 conformational epitope bnAb, isolated after 2009 by neutralization screening of cultured, unselected IgG+ memory B cells.
Bonsignori2012b
(vaccine antigen design, vaccine-induced immune responses, review)
-
PGT145: PG9 and PG9-like V1V2-directed MAbs, that require an N-linked glycan at Env 160, were analyzed for gain-of-function mutations. 21 PG9-resistant HIV-1 isolates were analyzed by mutagenesis and neutralization assays. E to K mutations at positions 168, 169, 171 led to the most dramatic improvements on sensitivity to these MAbs (PG9, PG16, CH01, CH04, PGT141, PGT145).
Doria-RoseNA2012
(escape)
-
PGT145: Glycan Asn332-targeting broadly cross-neutralizing (BCN) antibodies were studied in 2 C-clade infected women. The ASn332 glycan was absent on infecting virus, but the BCN epitope with Asn332 evolved within 6 months though immune escape from earlier antibodies. Plasma from the subject CAP177 neutralized 88% of a large multi-subtype panel of 225 heterologous viruses, whereas CAP 314 neutralized 46% of 41 heterologous viruses but failed to neutralize viruses that lack glycan at 332. PGT145 was referred to have second BCN Ab epitopes at AA 156 and 160 in addition to 332.
Moore2012
(neutralization, escape)
-
PGT145: Vaccination efficacy of RV144 is described. The authors proposed that RV144 induced antibodies against Env V1/V2. The relationship between vaccine status and V1/V2 sequence have been characterized. The estimated cumulative HIV-1 incidence curve in the vaccine and placebo groups showed immunogenicity for K169 and 1181X genotypes and no immunogenicity for the opposite residues. PGT145 was discussed as the quaternary-structure-preferring (QSP) antibody and mutations at positions 169 and 181 were associated with significant alteration in neutralization.
Rolland2012
(vaccine-induced immune responses)
-
PGT145: Several antibodies including 10-1074 were isolated from B-cell clone encoding PGT121, from a clade A-infected African donor using YU-2 gp140 trimers as bait. These antibodies were segregated into PGT121-like (PGT121-123 and 9 members) and 10-1074-like (20 members) groups distinguished by sequence, binding affinity, carbohydrate recognition, neutralizing activity, the V3 loop binding and the role of glycans in epitope formation. PGT145 was used as a control in virus neutralization assay. Detail information on the binding and neutralization assays are described in the figures S2-S11.
Mouquet2012a
(glycosylation, neutralization, binding affinity)
-
PGT145: MAbs PG9, PG16, CH04, PGT145 and 2909 showed anionic protruding CDR H3s, most of which were tyrosine sulphated. All also displayed β-hairpins and, although these varied substantially in orientation relative to the rest of the combining site, all appeared capable of penetrating an N-linked glycan shield to reach a cationic protein surface.
McLellan2011
(structure)
-
PGT145: Neutralizing antibody repertoires of 4 HIV-infected donors with remarkably broad and potent neutralizing responses were probed. 17 new monoclonal antibodies that neutralize broadly across clades were rescued. These MAbs were not polyreactive. All MAbs exhibited broad cross-clade neutralizing activity, but several showed exceptional potency. PGT145 neutralized 78% of 162 isolates from major HIV clades at IC50<50 μg/ml. PGT 141–145 MAbs exhibited a strong preference for membrane-bound, trimeric HIV Env, suggesting that these MAbs broadly bound to quaternary epitopes similar to those of PG9 and PG16. This hypothesis was confirmed by competition studies, N160K sensitivity and an inability to neutralize JR-CSF pseudoviruses expressing homogenous Man9GlcNAc2 glycans.
Walker2011
(antibody binding site, antibody generation, variant cross-reactivity, broad neutralizer)
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Beretta2018
Maxime Beretta, Alain Moreau, Mélanie Bouvin-Pley, Asma Essat, Cécile Goujard, Marie-Laure Chaix, Stéphane Hue, Laurence Meyer, Francis Barin, Martine Braibant, and ANRS 06 Primo Cohort. Phenotypic Properties of Envelope Glycoproteins of Transmitted HIV-1 Variants from Patients Belonging to Transmission Chains. AIDS, 32(14):1917-1926, 10 Sep 2018. PubMed ID: 29927786.
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Bibollet-Ruche2023
Frederic Bibollet-Ruche, Ronnie M. Russell, Wenge Ding, Weimin Liu, Yingying Li, Kshitij Wagh, Daniel Wrapp, Rumi Habib, Ashwin N. Skelly, Ryan S. Roark, Scott Sherrill-Mix, Shuyi Wang, Juliette Rando, Emily Lindemuth, Kendra Cruickshank, Younghoon Park, Rachel Baum, John W. Carey, Andrew Jesse Connell, Hui Li, Elena E. Giorgi, Ge S. Song, Shilei Ding, Andrés Finzi, Amanda Newman, Giovanna E. Hernandez, Emily Machiele, Derek W. Cain, Katayoun Mansouri, Mark G. Lewis, David C. Montefiori, Kevin J. Wiehe, S. Munir Alam, I-Ting Teng, Peter D. Kwong, Raiees Andrabi, Laurent Verkoczy, Dennis R. Burton, Bette T. Korber, Kevin O. Saunders, Barton F. Haynes, Robert J. Edwards, George M. Shaw, and Beatrice H. Hahn. A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies.. mBio, 14(1):e0337022, 28 Feb 2023. PubMed ID: 36629414.
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Bonsignori2012b
Mattia Bonsignori, S. Munir Alam, Hua-Xin Liao, Laurent Verkoczy, Georgia D. Tomaras, Barton F. Haynes, and M. Anthony Moody. HIV-1 Antibodies from Infection and Vaccination: Insights for Guiding Vaccine Design. Trends Microbiol., 20(11):532-539, Nov 2012. PubMed ID: 22981828.
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Bontjer2013
Ilja Bontjer, Mark Melchers, Tommy Tong, Thijs van Montfort, Dirk Eggink, David Montefiori, William C. Olson, John P. Moore, James M. Binley, Ben Berkhout, and Rogier W. Sanders. Comparative Immunogenicity of Evolved V1V2-Deleted HIV-1 Envelope Glycoprotein Trimers. PLoS One, 8(6):e67484, 26 Jun 2013. PubMed ID: 23840716.
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Bouvin-Pley2014
M. Bouvin-Pley, M. Morgand, L. Meyer, C. Goujard, A. Moreau, H. Mouquet, M. Nussenzweig, C. Pace, D. Ho, P. J. Bjorkman, D. Baty, P. Chames, M. Pancera, P. D. Kwong, P. Poignard, F. Barin, and M. Braibant. Drift of the HIV-1 Envelope Glycoprotein gp120 Toward Increased Neutralization Resistance over the Course of the Epidemic: A Comprehensive Study Using the Most Potent and Broadly Neutralizing Monoclonal Antibodies. J. Virol., 88(23):13910-13917, Dec 2014. PubMed ID: 25231299.
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Bricault2019
Christine A. Bricault, Karina Yusim, Michael S. Seaman, Hyejin Yoon, James Theiler, Elena E. Giorgi, Kshitij Wagh, Maxwell Theiler, Peter Hraber, Jennifer P. Macke, Edward F. Kreider, Gerald H. Learn, Beatrice H. Hahn, Johannes F. Scheid, James M. Kovacs, Jennifer L. Shields, Christy L. Lavine, Fadi Ghantous, Michael Rist, Madeleine G. Bayne, George H. Neubauer, Katherine McMahan, Hanqin Peng, Coraline Chéneau, Jennifer J. Jones, Jie Zeng, Christina Ochsenbauer, Joseph P. Nkolola, Kathryn E. Stephenson, Bing Chen, S. Gnanakaran, Mattia Bonsignori, LaTonya D. Williams, Barton F. Haynes, Nicole Doria-Rose, John R. Mascola, David C. Montefiori, Dan H. Barouch, and Bette Korber. HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design. Cell Host Microbe, 25(1):59-72.e8, 9 Jan 2019. PubMed ID: 30629920.
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Burton2016
Dennis R. Burton and Lars Hangartner. Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design. Annu. Rev. Immunol., 34:635-659, 20 May 2016. PubMed ID: 27168247.
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Cai2017
Yongfei Cai, Selen Karaca-Griffin, Jia Chen, Sai Tian, Nicholas Fredette, Christine E. Linton, Sophia Rits-Volloch, Jianming Lu, Kshitij Wagh, James Theiler, Bette Korber, Michael S. Seaman, Stephen C. Harrison, Andrea Carfi, and Bing Chen. Antigenicity-Defined Conformations of an Extremely Neutralization-Resistant HIV-1 Envelope Spike. Proc. Natl. Acad. Sci. U.S.A., 114(17):4477-4482, 25 Apr 2017. PubMed ID: 28396421.
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Castillo-Menendez2019
Luis R. Castillo-Menendez, Hanh T. Nguyen, and Joseph Sodroski. Conformational Differences between Functional Human Immunodeficiency Virus Envelope Glycoprotein Trimers and Stabilized Soluble Trimers. J. Virol., 93(3), 1 Feb 2019. PubMed ID: 30429345.
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Chen2015
Jia Chen, James M. Kovacs, Hanqin Peng, Sophia Rits-Volloch, Jianming Lu, Donghyun Park, Elise Zablowsky, Michael S. Seaman, and Bing Chen. Effect of the Cytoplasmic Domain on Antigenic Characteristics of HIV-1 Envelope Glycoprotein. Science, 349(6244):191-195, 10 Jul 2015. PubMed ID: 26113642.
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Cheng2015
Cheng Cheng, Marie Pancera, Adam Bossert, Stephen D. Schmidt, Rita. Chen, Xuejun Chen, Aliaksandr Druz, Sandeep Narpala, Nicole A. Doria-Rose, Adrian B. McDermott, Peter D. Kwong, and John R. Mascola. Immunogenicity of a Prefusion HIV-1 Envelope Trimer in Complex with a Quaternary-Structure-Specific Antibody. J. Virol., 90(6):2740-2755, 30 Dec 2015. PubMed ID: 26719262.
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Chuang2017
Gwo-Yu Chuang, Hui Geng, Marie Pancera, Kai Xu, Cheng Cheng, Priyamvada Acharya, Michael Chambers, Aliaksandr Druz, Yaroslav Tsybovsky, Timothy G. Wanninger, Yongping Yang, Nicole A. Doria-Rose, Ivelin S. Georgiev, Jason Gorman, M. Gordon Joyce, Sijy O'Dell, Tongqing Zhou, Adrian B. McDermott, John R. Mascola, and Peter D. Kwong. Structure-Based Design of a Soluble Prefusion-Closed HIV-1 Env Trimer with Reduced CD4 Affinity and Improved Immunogenicity. J. Virol., 91(10), 15 May 2017. PubMed ID: 28275193.
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Chuang2019
Gwo-Yu Chuang, Jing Zhou, Priyamvada Acharya, Reda Rawi, Chen-Hsiang Shen, Zizhang Sheng, Baoshan Zhang, Tongqing Zhou, Robert T. Bailer, Venkata P. Dandey, Nicole A. Doria-Rose, Mark K. Louder, Krisha McKee, John R. Mascola, Lawrence Shapiro, and Peter D. Kwong. Structural Survey of Broadly Neutralizing Antibodies Targeting the HIV-1 Env Trimer Delineates Epitope Categories and Characteristics of Recognition. Structure, 27(1):196-206.e6, 2 Jan 2019. PubMed ID: 30471922.
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Cimbro2014
Raffaello Cimbro, Thomas R. Gallant, Michael A. Dolan, Christina Guzzo, Peng Zhang, Yin Lin, Huiyi Miao, Donald Van Ryk, James Arthos, Inna Gorshkova, Patrick H. Brown, Darrell E. Hurt, and Paolo Lusso. Tyrosine Sulfation in the Second Variable Loop (V2) of HIV-1 gp120 Stabilizes V2-V3 Interaction and Modulates Neutralization Sensitivity. Proc. Natl. Acad. Sci. U.S.A., 111(8):3152-3157, 25 Feb 2014. PubMed ID: 24569807.
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Crooks2015
Ema T. Crooks, Tommy Tong, Bimal Chakrabarti, Kristin Narayan, Ivelin S. Georgiev, Sergey Menis, Xiaoxing Huang, Daniel Kulp, Keiko Osawa, Janelle Muranaka, Guillaume Stewart-Jones, Joanne Destefano, Sijy O'Dell, Celia LaBranche, James E. Robinson, David C. Montefiori, Krisha McKee, Sean X. Du, Nicole Doria-Rose, Peter D. Kwong, John R. Mascola, Ping Zhu, William R. Schief, Richard T. Wyatt, Robert G. Whalen, and James M. Binley. Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site. PLoS Pathog, 11(5):e1004932, May 2015. PubMed ID: 26023780.
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Crooks2018
Ema T. Crooks, Samantha L. Grimley, Michelle Cully, Keiko Osawa, Gillian Dekkers, Kevin Saunders, Sebastian Ramisch, Sergey Menis, William R. Schief, Nicole Doria-Rose, Barton Haynes, Ben Murrell, Evan Mitchel Cale, Amarendra Pegu, John R. Mascola, Gestur Vidarsson, and James M. Binley. Glycoengineering HIV-1 Env Creates `Supercharged' and `Hybrid' Glycans to Increase Neutralizing Antibody Potency, Breadth and Saturation. PLoS Pathog., 14(5):e1007024, May 2018. PubMed ID: 29718999.
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Danesh2020
Ali Danesh, Yanqin Ren, and R. Brad Jones. Roles of Fragment Crystallizable-Mediated Effector Functions in Broadly Neutralizing Antibody Activity against HIV. Curr. Opin. HIV AIDS, 15(5):316-323, Sep 2020. PubMed ID: 32732552.
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Davis-Gardner2020
Meredith E. Davis-Gardner, Barnett Alfant, Jesse A. Weber, Matthew R. Gardner, and Michael Farzan. A Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies. mBio, 11(1), 14 Jan 2020. PubMed ID: 31937648.
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Derking2015
Ronald Derking, Gabriel Ozorowski, Kwinten Sliepen, Anila Yasmeen, Albert Cupo, Jonathan L. Torres, Jean-Philippe Julien, Jeong Hyun Lee, Thijs van Montfort, Steven W. de Taeye, Mark Connors, Dennis R. Burton, Ian A. Wilson, Per-Johan Klasse, Andrew B. Ward, John P. Moore, and Rogier W. Sanders. Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer. PLoS Pathog, 11(3):e1004767, Mar 2015. PubMed ID: 25807248.
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deTaeye2015
Steven W. de Taeye, Gabriel Ozorowski, Alba Torrents de la Peña, Miklos Guttman, Jean-Philippe Julien, Tom L. G. M. van den Kerkhof, Judith A. Burger, Laura K. Pritchard, Pavel Pugach, Anila Yasmeen, Jordan Crampton, Joyce Hu, Ilja Bontjer, Jonathan L. Torres, Heather Arendt, Joanne DeStefano, Wayne C. Koff, Hanneke Schuitemaker, Dirk Eggink, Ben Berkhout, Hansi Dean, Celia LaBranche, Shane Crotty, Max Crispin, David C. Montefiori, P. J. Klasse, Kelly K. Lee, John P. Moore, Ian A. Wilson, Andrew B. Ward, and Rogier W. Sanders. Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-Neutralizing Epitopes. Cell, 163(7):1702-1715, 17 Dec 2015. PubMed ID: 26687358.
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deTaeye2018
Steven W. de Taeye, Alba Torrents de la Peña, Andrea Vecchione, Enzo Scutigliani, Kwinten Sliepen, Judith A. Burger, Patricia van der Woude, Anna Schorcht, Edith E. Schermer, Marit J. van Gils, Celia C. LaBranche, David C. Montefiori, Ian A. Wilson, John P. Moore, Andrew B. Ward, and Rogier W. Sanders. Stabilization of the gp120 V3 Loop through Hydrophobic Interactions Reduces the Immunodominant V3-Directed Non-Neutralizing Response to HIV-1 Envelope Trimers. J. Biol. Chem., 293(5):1688-1701, 2 Feb 2018. PubMed ID: 29222332.
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deTaeye2019
Steven W. de Taeye, Eden P. Go, Kwinten Sliepen, Alba Torrents de la Peña, Kimberly Badal, Max Medina-Ramírez, Wen-Hsin Lee, Heather Desaire, Ian A. Wilson, John P. Moore, Andrew B. Ward, and Rogier W. Sanders. Stabilization of the V2 Loop Improves the Presentation of V2 Loop-Associated Broadly Neutralizing Antibody Epitopes on HIV-1 Envelope Trimers. J. Biol. Chem., 294(14):5616-5631, 5 Apr 2019. PubMed ID: 30728245.
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Dingens2019
Adam S. Dingens, Dana Arenz, Haidyn Weight, Julie Overbaugh, and Jesse D. Bloom. An Antigenic Atlas of HIV-1 Escape from Broadly Neutralizing Antibodies Distinguishes Functional and Structural Epitopes. Immunity, 50(2):520-532.e3, 19 Feb 2019. PubMed ID: 30709739.
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Doria-Rose2017
Nicole A. Doria-Rose, Han R. Altae-Tran, Ryan S. Roark, Stephen D. Schmidt, Matthew S. Sutton, Mark K. Louder, Gwo-Yu Chuang, Robert T. Bailer, Valerie Cortez, Rui Kong, Krisha McKee, Sijy O'Dell, Felicia Wang, Salim S. Abdool Karim, James M. Binley, Mark Connors, Barton F. Haynes, Malcolm A. Martin, David C. Montefiori, Lynn Morris, Julie Overbaugh, Peter D. Kwong, John R. Mascola, and Ivelin S. Georgiev. Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting. PLoS Pathog., 13(1):e1006148, Jan 2017. PubMed ID: 28052137.
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Doria-RoseNA2012
Nicole A. Doria-Rose, Ivelin Georgiev, Sijy O'Dell, Gwo-Yu Chuang, Ryan P. Staupe, Jason S. McLellan, Jason Gorman, Marie Pancera, Mattia Bonsignori, Barton F. Haynes, Dennis R. Burton, Wayne C. Koff, Peter D. Kwong, and John R. Mascola. A Short Segment of the HIV-1 gp120 V1/V2 Region Is a Major Determinant of Resistance to V1/V2 Neutralizing Antibodies. J. Virol., Aug 2012. PubMed ID: 22623764.
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Escolano2021
Amelia Escolano, Harry .B Gristick, Rajeev Gautam, Andrew T. DeLaitsch, Morgan E. Abernathy, Zhi Yang, Haoqing Wang, Magnus A. G. Hoffmann, Yoshiaki Nishimura, Zijun Wang, Nicholas Koranda, Leesa M. Kakutani, Han Gao, Priyanthi N. P. Gnanapragasam, Henna Raina, Ana Gazumyan, Melissa Cipolla, Thiago Y. Oliveira, Victor Ramos, Darrell J. Irvine, Murillo Silva, Anthony P. West, Jr., Jennifer R. Keeffe, Christopher O. Barnes, Michael S. Seaman, Michel C. Nussenzweig, Malcolm A. Martin, and Pamela J. Bjorkman. Sequential Immunization of Macaques Elicits Heterologous Neutralizing Antibodies Targeting the V3-Glycan Patch of HIV-1 Env. Sci. Transl. Med., 13(621):eabk1533, 24 Nov 2021. PubMed ID: 34818054.
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Evans2014
Mark C. Evans, Pham Phung, Agnes C. Paquet, Anvi Parikh, Christos J. Petropoulos, Terri Wrin, and Mojgan Haddad. Predicting HIV-1 Broadly Neutralizing Antibody Epitope Networks Using Neutralization Titers and a Novel Computational Method. BMC Bioinformatics, 15:77, 19 Mar 2014. PubMed ID: 24646213.
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Ferguson2013
Andrew L. Ferguson, Emilia Falkowska, Laura M. Walker, Michael S. Seaman, Dennis R. Burton, and Arup K. Chakraborty. Computational Prediction of Broadly Neutralizing HIV-1 Antibody Epitopes from Neutralization Activity Data. PLoS One, 8(12):e80562, 2013. PubMed ID: 24312481.
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Georgiev2013
Ivelin S. Georgiev, Nicole A. Doria-Rose, Tongqing Zhou, Young Do Kwon, Ryan P. Staupe, Stephanie Moquin, Gwo-Yu Chuang, Mark K. Louder, Stephen D. Schmidt, Han R. Altae-Tran, Robert T. Bailer, Krisha McKee, Martha Nason, Sijy O'Dell, Gilad Ofek, Marie Pancera, Sanjay Srivatsan, Lawrence Shapiro, Mark Connors, Stephen A. Migueles, Lynn Morris, Yoshiaki Nishimura, Malcolm A. Martin, John R. Mascola, and Peter D. Kwong. Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization. Science, 340(6133):751-756, 10 May 2013. PubMed ID: 23661761.
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Goo2012
Leslie Goo, Zahra Jalalian-Lechak, Barbra A. Richardson, and Julie Overbaugh. A Combination of Broadly Neutralizing HIV-1 Monoclonal Antibodies Targeting Distinct Epitopes Effectively Neutralizes Variants Found in Early Infection. J. Virol., 86(19):10857-10861, Oct 2012. PubMed ID: 22837204.
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Gorman2016
Jason Gorman, Cinque Soto, Max M. Yang, Thaddeus M. Davenport, Miklos Guttman, Robert T. Bailer, Michael Chambers, Gwo-Yu Chuang, Brandon J. DeKosky, Nicole A. Doria-Rose, Aliaksandr Druz, Michael J. Ernandes, Ivelin S. Georgiev, Marissa C. Jarosinski, M. Gordon Joyce, Thomas M. Lemmin, Sherman Leung, Mark K. Louder, Jonathan R. McDaniel, Sandeep Narpala, Marie Pancera, Jonathan Stuckey, Xueling Wu, Yongping Yang, Baoshan Zhang, Tongqing Zhou, NISC Comparative Sequencing Program, James C. Mullikin, Ulrich Baxa, George Georgiou, Adrian B. McDermott, Mattia Bonsignori, Barton F. Haynes, Penny L. Moore, Lynn Morris, Kelly K. Lee, Lawrence Shapiro, John R. Mascola, and Peter D. Kwong. Structures of HIV-1 Env V1V2 with Broadly Neutralizing Antibodies Reveal Commonalities That Enable Vaccine Design. Nat. Struct. Mol. Biol., 23(1):81-90, Jan 2016. PubMed ID: 26689967.
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Guenaga2015
Javier Guenaga, Natalia de Val, Karen Tran, Yu Feng, Karen Satchwell, Andrew B. Ward, and Richard T. Wyatt. Well-Ordered Trimeric HIV-1 Subtype B and C Soluble Spike Mimetics Generated by Negative Selection Display Native-Like Properties. PLoS Pathog., 11(1):e1004570, Jan 2015. PubMed ID: 25569572.
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Guenaga2015a
Javier Guenaga, Viktoriya Dubrovskaya, Natalia de Val, Shailendra K. Sharma, Barbara Carrette, Andrew B. Ward, and Richard T. Wyatt. Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers. J. Virol., 90(6):2806-2817, 30 Dec 2015. PubMed ID: 26719252.
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He2018
Linling He, Sonu Kumar, Joel D. Allen, Deli Huang, Xiaohe Lin, Colin J. Mann, Karen L. Saye-Francisco, Jeffrey Copps, Anita Sarkar, Gabrielle S. Blizard, Gabriel Ozorowski, Devin Sok, Max Crispin, Andrew B. Ward, David Nemazee, Dennis R. Burton, Ian A. Wilson, and Jiang Zhu. HIV-1 Vaccine Design through Minimizing Envelope Metastability. Sci. Adv., 4(11):eaau6769, Nov 2018. PubMed ID: 30474059.
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Hoffenberg2013
Simon Hoffenberg, Rebecca Powell, Alexei Carpov, Denise Wagner, Aaron Wilson, Sergei Kosakovsky Pond, Ross Lindsay, Heather Arendt, Joanne DeStefano, Sanjay Phogat, Pascal Poignard, Steven P. Fling, Melissa Simek, Celia LaBranche, David Montefiori, Terri Wrin, Pham Phung, Dennis Burton, Wayne Koff, C. Richter King, Christopher L. Parks, and Michael J. Caulfield. Identification of an HIV-1 Clade A Envelope That Exhibits Broad Antigenicity and Neutralization Sensitivity and Elicits Antibodies Targeting Three Distinct Epitopes. J. Virol., 87(10):5372-5383, May 2013. PubMed ID: 23468492.
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Hogan2018
Michael J. Hogan, Angela Conde-Motter, Andrea P. O. Jordan, Lifei Yang, Brad Cleveland, Wenjin Guo, Josephine Romano, Houping Ni, Norbert Pardi, Celia C. LaBranche, David C. Montefiori, Shiu-Lok Hu, James A. Hoxie, and Drew Weissman. Increased Surface Expression of HIV-1 Envelope Is Associated with Improved Antibody Response in Vaccinia Prime/Protein Boost Immunization. Virology, 514:106-117, 15 Jan 2018. PubMed ID: 29175625.
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Hraber2014
Peter Hraber, Michael S. Seaman, Robert T. Bailer, John R. Mascola, David C. Montefiori, and Bette T. Korber. Prevalence of Broadly Neutralizing Antibody Responses during Chronic HIV-1 Infection. AIDS, 28(2):163-169, 14 Jan 2014. PubMed ID: 24361678.
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Hraber2017
Peter Hraber, Cecilia Rademeyer, Carolyn Williamson, Michael S. Seaman, Raphael Gottardo, Haili Tang, Kelli Greene, Hongmei Gao, Celia LaBranche, John R. Mascola, Lynn Morris, David C. Montefiori, and Bette Korber. Panels of HIV-1 Subtype C Env Reference Strains for Standardized Neutralization Assessments. J. Virol., 91(19), 1 Oct 2017. PubMed ID: 28747500.
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Hu2015
Joyce K. Hu, Jordan C. Crampton, Albert Cupo, Thomas Ketas, Marit J. van Gils, Kwinten Sliepen, Steven W. de Taeye, Devin Sok, Gabriel Ozorowski, Isaiah Deresa, Robyn Stanfield, Andrew B. Ward, Dennis R. Burton, Per Johan Klasse, Rogier W. Sanders, John P. Moore, and Shane Crotty. Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity. J. Virol., 89(20):10383-10398, Oct 2015. PubMed ID: 26246566.
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Hutchinson2019
Jennie M. Hutchinson, Kathryn A. Mesa, David L. Alexander, Bin Yu, Sara M. O'Rourke, Kay L. Limoli, Terri Wrin, Steven G. Deeks, and Phillip W. Berman. Unusual Cysteine Content in V1 Region of gp120 from an Elite Suppressor That Produces Broadly Neutralizing Antibodies. Front. Immunol., 10:1021, 2019. PubMed ID: 31156622.
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Wiehe2018
Kevin Wiehe, Todd Bradley, R. Ryan Meyerhoff, Connor Hart, Wilton B. Williams, David Easterhoff, William J. Faison, Thomas B. Kepler, Kevin O. Saunders, S. Munir Alam, Mattia Bonsignori, and Barton F. Haynes. Functional Relevance of Improbable Antibody Mutations for HIV Broadly Neutralizing Antibody Development. Cell Host Microbe, 23(6):759-765.e6, 13 Jun 2018. PubMed ID: 29861171.
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Willis2022
Jordan R. Willis, Zachary T. Berndsen, Krystal M. Ma, Jon M. Steichen, Torben Schiffner, Elise Landais, Alessia Liguori, Oleksandr Kalyuzhniy, Joel D. Allen, Sabyasachi Baboo, Oluwarotimi Omorodion, Jolene K. Diedrich, Xiaozhen Hu, Erik Georgeson, Nicole Phelps, Saman Eskandarzadeh, Bettina Groschel, Michael Kubitz, Yumiko Adachi, Tina-Marie Mullin, Nushin B. Alavi, Samantha Falcone, Sunny Himansu, Andrea Carfi, Ian A. Wilson, John R. Yates III, James C. Paulson, Max Crispin, Andrew B. Ward, and William R. Schief. Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors. Immunity, 55(11):2149-2167e9 doi, Nov 2022. PubMed ID: 36179689
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Wu2016
Xueling Wu and Xiang-Peng Kong. Antigenic Landscape of the HIV-1 Envelope and New Immunological Concepts Defined by HIV-1 Broadly Neutralizing Antibodies. Curr. Opin. Immunol., 42:56-64, Oct 2016. PubMed ID: 27289425.
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Yang2014
Lili Yang and Pin Wang. Passive Immunization against HIV/AIDS by Antibody Gene Transfer. Viruses, 6(2):428-447, Feb 2014. PubMed ID: 24473340.
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Yang2022
Zhi Yang, Kim-Marie A. Dam, Michael D. Bridges, Magnus A. G. Hoffmann, Andrew T. DeLaitsch, Harry B. Gristick, Amelia Escolano, Rajeev Gautam, Malcolm A. Martin, Michel C. Nussenzweig, Wayne L. Hubbell, and Pamela J. Bjorkman. Neutralizing Antibodies Induced in Immunized Macaques Recognize the CD4-Binding Site on an Occluded-Open HIV-1 Envelope Trimer. Nat. Commun., 13(1):732, 8 Feb 2022. PubMed ID: 35136084.
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Yasmeen2014
Anila Yasmeen, Rajesh Ringe, Ronald Derking, Albert Cupo, Jean-Philippe Julien, Dennis R. Burton, Andrew B. Ward, Ian A. Wilson, Rogier W. Sanders, John P. Moore, and Per Johan Klasse. Differential Binding of Neutralizing and Non-Neutralizing Antibodies to Native-Like Soluble HIV-1 Env Trimers, Uncleaved Env Proteins, and Monomeric Subunits. Retrovirology, 11:41, 2014. PubMed ID: 24884783.
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Zhu2013
Jiang Zhu, Gilad Ofek, Yongping Yang, Baoshan Zhang, Mark K. Louder, Gabriel Lu, Krisha McKee, Marie Pancera, Jeff Skinner, Zhenhai Zhang, Robert Parks, Joshua Eudailey, Krissey E. Lloyd, Julie Blinn, S. Munir Alam, Barton F. Haynes, Melissa Simek, Dennis R. Burton, Wayne C. Koff, NISC Comparative Sequencing Program, James C. Mullikin, John R. Mascola, Lawrence Shapiro, and Peter D. Kwong. Mining the Antibodyome for HIV-1-Neutralizing Antibodies with Next-Generation Sequencing and Phylogenetic Pairing of Heavy/Light Chains. Proc. Natl. Acad. Sci. U.S.A., 110(16):6470-6475, 16 Apr 2013. PubMed ID: 23536288.
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Sliepen2019
Kwinten Sliepen, Byung Woo Han, Ilja Bontjer, Petra Mooij, Fernando Garces, Anna-Janina Behrens, Kimmo Rantalainen, Sonu Kumar, Anita Sarkar, Philip J. M. Brouwer, Yuanzi Hua, Monica Tolazzi, Edith Schermer, Jonathan L. Torres, Gabriel Ozorowski, Patricia van der Woude, Alba Torrents de la Pena, Marielle J. van Breemen, Juan Miguel Camacho-Sanchez, Judith A. Burger, Max Medina-Ramirez, Nuria Gonzalez, Jose Alcami, Celia LaBranche, Gabriella Scarlatti, Marit J. van Gils, Max Crispin, David C. Montefiori, Andrew B. Ward, Gerrit Koopman, John P. Moore, Robin J. Shattock, Willy M. Bogers, Ian A. Wilson, and Rogier W. Sanders. Structure and immunogenicity of a stabilized HIV-1 envelope trimer based on a group-M consensus sequence. Nat Commun, 10(1):2355 doi, May 2019. PubMed ID: 31142746
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Displaying record number 3201
Download this epitope
record as JSON.
MAb ID |
PGDM1400 |
HXB2 Location |
Env |
Env Epitope Map
|
Author Location |
|
Epitope |
|
Subtype |
C |
Ab Type |
gp120 V2 // V2 glycan(V2g) // V2 apex |
Neutralizing |
P (tier 2) View neutralization details |
Contacts and Features |
View contacts and features |
Species
(Isotype)
|
human(IgG) |
Patient |
Donor 84 |
Immunogen |
HIV-1 infection |
Country |
Rwanda |
Keywords |
antibody binding site, antibody generation, antibody interactions, antibody lineage, antibody sequence, assay or method development, autologous responses, binding affinity, bispecific/trispecific, broad neutralizer, computational prediction, effector function, escape, glycosylation, HAART, ART, HIV reservoir/latency/provirus, immunoprophylaxis, immunotherapy, kinetics, mutation acquisition, neutralization, polyclonal antibodies, review, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses, viral fitness and/or reversion |
Notes
Showing 46 of
46 notes.
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PGDM1400: N6/PGDM1400-10E8v4, a trispecific bnAb with variable domains from 3 different Abs (CD4bs-targeting N6 on a monospecific Ab arm, and V2-glycan-targeting PGDM1400 plus MPER-targeting 10E8v4 on a bispecific arm) demonstrated potent, yet transient, in vivo anti-viral activity in 6 SHIVBG505-infected naive Indian rhesus macaques. While viral mutants without the N160 glycan critical for neutralization by mAb PGDM1400 became dominant in 3 macaques, no N6/PGDM1400-10E8v4-resistant mutants were detected. At 1 year post-treatment, SHIV-specific CD4+ and CD8+ T cell responses were observed and CD8+ T cell depletion resulted in transient increases in plasma VL. N6/PGDM1400-10E8v4 suppressed viral outgrowth in ex vivo CD4+ T cells from 5 of 5 different viremic donors cultured with uninfected CD4+ T cells. Similar levels of viral replication suppression was also observed with N6 bnAb in cells from 3 of 5 donors, while generally only minimal or transient effects were observed with PDGM1400 and 10E8v4 bnAbs. PGDM1400 demonstrated ADCC and ADCP, but not ADCML, Fc-mediated effector functions.
Pegu2022
(effector function, bispecific/trispecific)
-
PGDM1400: This article reviews how B cell receptor sequence analyses and repertoires can be used in vaccine stratagem. Overall, multiple immunogens and their interactions driving bnAb development to generate Abs with special genetic characteristics of V gene restriction, long CDRH3 (for example, PGDM1400 has CDRH3 lengths of >34aa with is > 2x longer than the average of 15aa in naive and memory B cell receptor repertoires) and high load SHM are the current effective strategy being used.
Kreer2020
(antibody generation, neutralization, review, antibody sequence, broad neutralizer)
-
PGDM1400: The study describes the generation, crystal structure, and immunogenic properties of a native-like Env SOSIP trimer based on a group M consensus (ConM) sequence. A crystal structure of ConM SOSIP.v7 trimer together with nAbs PGT124 and 35O22 revealed that ConM SOSIP.v7 is structurally similar to other Env trimers. In rabbits, the ConM SOSIP trimer induced serum nAbs that neutralized the autologous Tier 1A virus (ConM from 2004) and a related Tier 1B ConS virus (ConM from 2001). These responses target the trimer apex and were enhanced when the trimers were presented on ferritin nanoparticles. The neutralization of ConM and ConS pseudoviruses was tested against a large panel of nAbs and non-nAbs (2219, 2557, 3074, 3869, 447-52D, 830A, 654-30D, 1008-30D, 1570D, 729-30D, F105, 181D, 246D, 50-69D, sCD4, VRC01, 3BNC117, CH31, PG9, PG16, CH01, PGDM1400, PGT128, PGT121, 10-1074, PGT151, VRC43.01, 2G12, DH511.2_K3, 10E8, 2F5, 4E10); most nAbs were able to neutralize these pseudoviruses. Soluble ConM trimers were able to weakly activate B cells expressing PGT121 and PG16 BCRs but were inactive against those expressing VRC01 and PGT145. In contrast, at the same molar amount of trimers, the ConM SOSIP.v7-ferritin nanoparticles activated all 4 B cells efficiently. Binding of bnAbs 2G12 and PGT145 and non-nAbs F105 and 19b to ConM SOSIP.v7 trimer and SOSIP showed that the ferritin-bound trimer bound more avidly than the soluble trimer. This study shows that native-like HIV-1 Env trimers can be generated from consensus sequences, and such immunogens might be suitable vaccine components to prime and/or boost desirable nAb responses.
Sliepen2019
(neutralization, vaccine antigen design)
-
PGDM1400: Membrane-bound BG505-based ApexGT Env trimer vaccine candidates, which bind to inferred germline variants of bnAbs PCT64 and PG9, were developed through directed evolution and characterized. PCT64 and PG9/PG16 lineages were identified to have the highest and most consistent frequencies of precursors in 14 HIV-unexposed donors among 5 V2-apex-targeting bnAb classes which also included PGT141-145/PGDM1400-1414, CH01-CH04 and CAP256-VRC26 lineages. PGT141-145/PGDM1400-1414 heavy chain (HC) precursors were found in only 6/14 donors with a median frequency of 0.17 precursors per million BCRs.
Willis2022
(antibody lineage)
-
PGDM1400: A panel of 30 contemporary subtype B pseudoviruses (PSVs) was generated. Neutralization sensitivities of these PSVs were compared with subtype B strains from earlier in the pandemic using 31 nAbs (PG9, PG16, PGT145, PGDM1400, CH02, CH03, CH04, 830A, PGT121, PGT126, PGT128, PGT130, 10-1074, 2192, 2219, 3074, 3869, 447-52D, b12, NIH45-46, VRC01, VRC03, 3BNC117, HJ16, sCD4, 10E8, 4E10, 2F5, 7H6, 2G12, 35O22). A significant reduction in Env neutralization sensitivity was observed for 27 out of 31 nAbs for the contemporary, as compared to earlier-decade subtype B PSVs. A decline in neutralization sensitivity was observed across all Env domains; the nAbs that were most potent early in the pandemic suffered the greatest decline in potency over time. A metaanalysis demonstrated this trend across multiple subtypes. As HIV-1 Env diversification continues, changes in Env antigenicity and neutralization sensitivity should continue to be evaluated to inform the development of improved vaccine and antibody products to prevent and treat HIV-1.
Wieczorek2023
(neutralization, viral fitness and/or reversion)
-
PGDM1400:This study identified a B cell lineage of bNAbs in an HIV-1 elite post-treatment controller (ePTC; donor: PTC-005002). Circulating viruses in PTC escaped bNAb pressure but remained sensitive to autologous neutralization by other Ab populations. PGDM1400 was used as a reference anti-V1/V2 Ab.
Molinos-Albert2023
(binding affinity)
-
PGDM1400: A panel of 58 mAbs was cloned from a rhesus macaque immunized with envelope glycoprotein immunogens developed from HIV-1 clade B-infected human donor VC10014. Neutralizing mAbs predominantly targeted linear epitopes in the V3 region in the cradle orientation (V3C), with others targeting the V3 ladle orientation (V3L), the CD4 binding site, C1, C4, or gp41. Nonneutralizing mAbs bound C1, C5, or undetermined gp120 conformational epitopes. Neutralization potency strongly correlated with the magnitude of binding to infected primary macaque splenocytes and to the level of ADCC, but did not correlate with ADCP. MAbs were traced to 23 of 72 functional IgHV germline alleles. Neutralizing V3C mAbs displayed minimal nucleotide SHM in the H chain V region (3.77%), indicating that relatively little affinity maturation was needed to achieve in-clade neutralization breadth. This study underscores the polyfunctional nature of vaccine-elicited tier 2-neutralizing V3 Abs and demonstrates partial reproduction of a human donor’s Ab response through nonhuman primate vaccination. Several previously-isolated mAbs were used in binding assays: b12, VRC01, N6, 3BNC117, 2558, 2219, 1006-15D, 447-52D, 10-1074, 830A, 2F5, F240, PGDM1400, 2219.
Spencer2021
(vaccine antigen design, binding affinity)
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PGDM1400: This study assessed the ability of single bNAbs and triple bNAb combinations to mediate polyfunctional antiviral activity against a panel of cross-clade simian-human immunodeficiency viruses (SHIVs), which are commonly used as tools for validation of therapeutic strategies in nonhuman primate models. Most bnAbs assayed were capable of mediating both neutralizing and nonneutralizing effector functions (ADCC and ADCP) against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs was highly strain dependent. Several triple bNAb combinations were identified comprising of CD4 binding site-, V2-glycan-, and gp120-gp41 interface-targeting bNAbs that are capable of mediating synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. In assays using the transmitted/founder SHIV.C.CH505, there was a correlation between the neutralization potencies and nonneutralizing effector functions of bnAbs: PGDM1400 was positive for neutralization, ADCC, and binding to infected cells.
Berendam2021
(effector function, neutralization, binding affinity, broad neutralizer)
-
PGDM1400: The human apoferritin light chain forms a spherical nanocage, and this was fused to single-chain Fab (scFab) plus Fabs from well-studied bnAbs. The resulting multispecific, multiaffinity antibodies were termed multabodies (MB). T-01 MB included Fabs of PGDM1400, 10E8v4, and N49P7, while T-02 MB was similarly engineered from PGDM1400, 10E8v4, and iMab. Following further engineering of the apoferritin to allow dimerization of the entire molecules, alternate versions (T-01 MB.v2 and T-2 MB.v2) were developed. The most potent, T-01 MB.v2, demonstrated a median IC50 value of 0.0009 μg/mL and 100% neutralization coverage (at a 4 μg/mL cutoff) when assayed on a panel of 118 HIV-1 pseudoviruses, a 32-fold enhancement in viral neutralization potency compared to a mixture of its constituent bnAbs. The pharmacokinetics and bioavailability of the multabodies were comparable to the parental mAbs.
Rujas2022
(neutralization, broad neutralizer)
-
PGDM1400: The VRC01 Antibody Mediated Prevention (AMP) vaccine trials (2016-2020) showed that passively administered bnAbs could prevent HIV-1 acquisition of bnAb-sensitive viruses. Viruses isolated from AMP participants who acquired infection during the study were used to make a panel of 218 HIV-1 pseudoviruses. The majority of viruses identified were clade B and C, with clades A, D, F, G and recombinants present at lower frequencies. BnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10–1074 and 10E8v4) were tested for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998–2010), the AMP clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best antibody mixture against clade C viruses, and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. The AMP placebo virus panel represents a resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs.
Mkhize2023
(assay or method development, neutralization, immunotherapy)
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PGDM1400: Using subtype A BG505 Env structural information, improved variants of subtype B JRFL and subtype C 16055 Env native flexibly linked (NFL) trimers were generated. The trimer-derived (TD) residues that increased well-ordered, homogeneous, stable, and soluble trimers did not require positive or negative selection as previously needed [Guenaga2015, PLoS Pathos. 11(1):e1004570]. PG16, PGDM1400, PGT145 which are "trimer-preferring" bnAbs are known to target one site on the variable cap per spike and while PGDM1400 preferentially recognized 16055 NFL TD8 over JRFL NFL TD15, it also bound subtype C 16055 with a very high (nM) affinity.
Guenaga2015a
(antibody interactions, assay or method development, vaccine antigen design, structure)
-
PGDM1400: Primary HIV-1 Envs were expressed as SHIVs, and responses from infected rhesus macaques showed patterns of Env-antibody coevolution similar to those in humans. This included conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions, and deletions leading to virus persistence. One macaque mAb (RHA1.V2.01), neutralized 49% of a 208-strain panel, and structural analysis revealed a V2-apex mode of recognition that resembles human bnAbs PGT145 or PCT64-35S. Signature sites were analyzed for RHA1.V2.01 and 7 V2 bnAbs (PCT64-34M, PGDM1400, PG9, CH01, PGT145, VRC26.08, VRC26.25).
Roark2021
(mutation acquisition, neutralization, vaccine antigen design, escape)
-
PGDM1400: A recombinant native-like Env SOSIP trimer, AMC009, was developed based on viral founder sequences of elite neutralizer H18877. The subtype B AMC009 Env was defined as a Tier 2 virus based on a neutralization assay against well known nAbs (VRC01, 3BNC117, CH31, CH01, PG9, PG16, PGDM1400, 10-1074, PGT128, PGT121, PGT151, VRC34.01, 2G12, 2F5, 4E10, DH511.2.K3_4, 10E8, and the mAb mixture CH01-31).The AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bnAb epitopes. Its overall structure was similar to that of BG505 SOSIP.664, and it resembled one from another elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, AMC009 trimers did not induce autologous neutralizing antibody responses efficiently, while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous tier 2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009, and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the nAb activity from rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers.
Schorcht2020
(neutralization, vaccine-induced immune responses, structure)
-
PGDM1400: The study looked at the neutralization of subtype C Env sequences from 9 South African individuals followed longitudinally. A total of 43 Env sequences were cloned and assayed for neutralization by 12 bnAbs of various binding types (VRC07-LS, N6.LS, VRC01, PGT151, 10-1074 and PGT121, 10E8, 3BNC117, CAP256.VRC26.25, 4E10, PGDM1400, and N123-VRC34.01). Features associated with resistance to bNAbs were higher potential glycosylation sites, relatively longer V1 and V4 domains, and known signature mutations. The study found significant variability in the breadth and potency of bnAbs against circulating HIV-1 subtype C envelopes. In particular, VRC07-LS, N6.LS, VRC01, PGT151, 10-1074, and PGT121 display broad activity against subtype C variants. The results suggest that these 6 bnAbs are potent antibodies that should be considered for future antibody therapy and treatment studies targeting HIV-1 subtype C.
Mandizvo2022
(glycosylation, mutation acquisition, neutralization, immunotherapy)
-
PGDM1400: HIV-1 and its SIV precursors share a bnAb epitope in Env V2 at the trimer apex. This study tested the immunogenicity of a chimpanzee SIV (SIVcpz) Env trimer. In mice expressing a human V2-apex bnAb heavy-chain precursor, trimer immunization induced V2-directed nAbs. Infection of macaques with chimeric simian-chimpanzee immunodeficiency viruses (SCIVs) elicited high-titer viremia, potent autologous neutralizing antibodies, rapid sequence escape in the canonical V2-apex epitope, and in some cases, low-titer heterologous plasma breadth mapping to the V2-apex. Antibody cloning from 2 macaques (T925 and T927) identified 7 lineages (53 mAbs) with long CDRH3 regions that cross-neutralize some primary HIV-1 strains with low potency. Electron microscopy of members of the two most cross-reactive lineages confirmed V2 targeting with an angle of approach distinct from prototypical V2-apex bNAbs; antibody binding either required or induced an occluded-open trimer. Probing with conformation-sensitive, nonneutralizing antibodies revealed that SCIV-expressed, but not wild-type SIVcpz Envs, as well as a subset of primary HIV-1 Envs, preferentially adopted a more open trimeric state. These results reveal the existence of a cryptic V2 epitope that is exposed in occluded-open SIVcpz and HIV-1 Env trimers and elicits cross-neutralizing responses of limited breadth and potency. This cryptic epitope, which in some Env backgrounds is immunodominant, needs to be considered in immunogen design. As part of the study, binding and neutralization assays used panels of nAbs (PG9, PG16, PGT145, PGDM1400, VRC26.25, CH01, BG1, VRC38.01), non-nAbs (697-D, 1393A, CH58, CAP228-3D, 3074, 447-52D, 17b, A32), and unmutated ancestors (PG9-RUA, PG16-RUA, VRC26-UCA, CH01-RUA).
Bibollet-Ruche2023
(neutralization, vaccine antigen design, vaccine-induced immune responses)
-
PGDM1400: HIV-1 bnAbs require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations. Probable mutations occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. The paper introduced the ARMADiLLO program, which estimates how probable a particular mAb mutation is, and thus the key improbable mutations were defined for a panel of 26 bnAbs. The number of improbable mutations ranged from 7 (PGT128) to 23 (VRC01 and 35O22); PGDM1400 had 14 improbable mutations out of 67 total AA mutations, and 0 indels. Single-amino acid reversion mutants were made for key improbable mutations of 3 bnAbs (CH235, VRC01, and BF520.1), and these mutant mAbs were tested for their neutralization ability. The study also noted that bnAbs that had relatively small numbers of improbable single somatic mutations had other unusual characteristics that were due to additional improbable events, such as indels (PGT128) or extraordinary CDR H3 lengths (VRC26.25).
Wiehe2018
(neutralization)
-
PGDM1400: The study assessed the breadths and potencies of 14 bnAbs against 36 viruses reactivated from peripheral blood CD4+ T cells from ARV-treated HIV-infected individuals by using paired neutralization and infected cell binding assays. Infected cell binding correlated with virus neutralization for 10 of 14 antibodies (VRC01, VRC07-523, 3BNC117, N6, PGT121, 10-1074, PGDM1400, PG9, 10E8, and 10E8v4-V5R-100cF). For example, the correlation for 3BNC117 had r=0.82 and P<0.0001. Heterogeneity was observed, however, with a lack of significant correlation for 2G12, CAP256.VRC26.25, 2F5, and 4E10. The study also performed paired infected cell binding and ADCC assays by using two reservoir virus isolates in combination with 9 bNAbs, and the results were consistent with previous studies indicating that infected cell binding is moderately predictive of ADCC activity for bNAbs with matched Fc domains. These data provide guidance on the selection of antibodies for clinical trials.
Ren2018
(effector function, neutralization, binding affinity, HIV reservoir/latency/provirus)
-
PGDM1400: The study found variations in the neutralization susceptibility of 71 Indian clade C viruses to 4 bnAbs (VRC01, VRC26.25, PGDM1400 and PGT121). Based on the neutralization data, the resistance signatures of the 4 bnAbs were determined. Using the CombiNAber tool, two possible combinations of three bnAbs (VRC01/VRC26.25/PGT121 and PGDM1400/VRC26.25/PGT121) were predicted to have 100% neutralization of the panel of Indian clade C viruses.
Mullick2021
(antibody interactions, neutralization)
-
PGDM1400: To understand early bnAb responses, 51 HIV-1 clade C infected infants were assayed for neutralization of a 12-virus multi-clade panel. Plasma bnAbs targeting V2-apex on Env were predominant in infant elite and broad neutralizers. In infant elite neutralizers, multi-variant infection was associated with plasma bnAbs targeting diverse autologous viruses. A panel of mAbs (PG9, PG16, PGT145, PGDM1400, VRC26.25, 10-1074, BG18, AIIMS-P01, PGT121, PGT128, PGT135, VRC01, N6, 3BNC117, PGT151, 35O22, 10E8, 4E10, F105, 17b, A32, 48d, b6, 447-52d) was assayed for their ability to neutralize Env clones from infant elite neutralizers; circulating viral variants in infant elite neutralizers were most susceptible to V2-apex bnAbs.
Mishra2020a
(neutralization, polyclonal antibodies)
-
PGDM1400: In vertically-infected infant AIIMS731, a rare HIV-1 mutation in hypervariable loop 2 (L184F) was studied. In patient sequences, this mutation was present in the majority of clones. A panel of 6 V2 bnAbs (PG9, PG16, PGT145, PGDM1400, CAP256.25, and CH01) was assayed for neutralization of 6 patient viral clones. The AIIMS731 viral variants segregated into 4 neutralization-sensitive and 2 resistant clones; sensitive clones carried 184F, while resistant clones carried the rare 184L mutation. A large panel of bnAbs targeting non-V2 epitopes was used to assess the neutralization of the 6 patient viral variants. The bnAb panel consisted of V3/N332 glycan supersite bnAbs (10-1074, BG18, AIIMS-P01, PGT121, PGT128, and PGT135), CD4bs bnAbs (VRC01, VRC03, VRC07-523LS, N6, 3BNC117, and NIH45-46 G54W), a silent face-targeting bnAb (PG05), fusion peptide and gp120-gp41 interface bnAbs (PGT151, 35O22, and N123-VRC34.01), and MPER bnAbs (10E8, 4E10, and 2F5). All of these bnAbs had similar neutralization efficiencies for all 6 clones, suggesting that the L184F mutation was specific for viral escape from neutralization by V2 apex bnAbs. A panel of non-neutralizing mAbs (V3 loop-targeting non-nAbs 447-52D and 19b, and CD4-induced non-nAbs 17b, A32, 48d, and b6), were also assessed; 2 of the variants (the same 2 susceptible to the V2 bnAbs) showed moderate neutralization by 447-52D, 19b, 17b, and 48d. The structure of ligand-free BG505 SOSIP trimer revealed that the side chain of L184 was outward facing and did not make significant intraprotomeric interactions, but upon mutating L184 to F184, a disruption of the accessible surface between the bulky side chain of F184 on one protomer and R165 on the neighboring protomer was seen. Thus, the L184F mutation resulted in increased susceptibility to neutralization by antibodies known to target the relatively more open conformation of Env on tier 1 viruses, suggesting that the rare L184F mutation allowed Env to sample more open states resembling the CD4-bound conformation where the CCR5 binding site is exposed.
Mishra2020
(neutralization, polyclonal antibodies)
-
PGDM1400: This report characterizes an additional antiviral activity of some bnAbs to block HIV-1 release by tethering viral particles at the surface of infected cells in vitro in a bivalency-dependent manner. After cultivation of infected primary CD4+ T cells with individual bnAbs, supernatant p24 levels were negatively correlated with cell-associated Gag levels, Env binding and neutralization potency while cell-associated Gag levels and Env binding positively correlated with each other and individually with neutralization potency. The capacity to mediate this tethering activity varied among different classes of mAbs: 0/3 non-neutralizing mAbs, 1/5 bnAbs targeting the MPER or gp120/gp41 interface and 9/9 of the bnAbs targeting the V3 and V1/V1 loops or the CD4bs demonstrated this activity against at least 1/3 diverse viral strains (AD8, CH058 and vKB18). Five of these latter 9 bnAbs, including bnAb 10-1074 which had the most potent effect observed in study when cultivated with vKB18-infected CD4+ T cells, displayed tethering activity against all 3 strains. Surface aggregation of mature virions and bnAb 10-1074 was observed in CH058-infected primary CD4+ T cells and CHME macrophage-like cells. V2-targeting bnAb PGDM1400 displayed tethering activity against 2 of 3 HIV-1 strains (AD8 and vKB18).
Dufloo2022
(binding affinity)
-
PGDM1400: This is the first report of a triple combination bnAb (PGDM1400, PGT121, and VRC07-523LS) therapeutic clinical trial in HIV-1-infected humans. Three subjects received this triple combination therapy, which was well-tolerated, and completed the trial. An additional subject, 683-7312, received double bnAb therapy (PGDM1400 and PGT121). After bnAb administration, all 4 subjects had an initial decrease from baseline viral loads and then rebounded. Subject 693-2215 showed resistance to PGDM1400 and PGT121 at baseline. The loss of a potential N-linked glycosylation site at residue 160, known to be a key Env glycan contact for V2 apex bnAbs, mediated PGDM1400 viral escape for 3 of these 4 subjects (693-1969, 693-7989, and 693-7312). The trial also established, for the first time, the safety, tolerability and pharmacokinetics of PGDM1400 alone, or in combination with PGT121, in adults without HIV. The median PGDM1400 elimination half-life estimate for the groups without HIV was 20.77 days when given alone and 17.4 days when co-administered with PGT121, and 11 days for the groups with HIV when co-administered with PGT121 and VRC07-523LS.
Julg2022
(antibody interactions, neutralization, escape, kinetics, immunotherapy, broad neutralizer)
-
PGDM1400: Analyses of all PDB HIV1-Env trimer (prefusion, closed) structures fulfilling certain parameters of resolution were performed to classify them on the basis of (a) antibody class which was informed by parental B cells as well as structural recognition, and (b) Env residues defining recognized HIV epitopes. Structural features of the 206 HIV epitope and bNAb paratopes were correlated with functional properties of the breadth and potency of neutralization against a 208-strain panel. Broadly nAbs with >25% breadth of neutralization belonged to 20 classes of antibodies with a large number of protruding loops and high degree of somatic hypermutation (SHM). Analysis of recognized HIV epitopes placed the bNAbs into 6 categories (viz. V1V2, glycan-V3, CD4-binding site, silent face center, fusion peptide and subunit interface). The epitopes contained high numbers of independent sequence segments and glycosylated surface area. PGDM1400 neutralization data was used as comparison in these studies.
Chuang2019
(antibody binding site, antibody interactions, neutralization, binding affinity, antibody sequence, structure, antibody lineage, broad neutralizer)
-
PGDM1400: This review focuses on the potential for bNAbs to induce HIV-1 remission, either alone or in combination with latency reversing agents, therapeutic vaccines, or other novel therapeutics. Ongoing human trials aimed at HIV therapy or remission are utilizing the following antibodies, alone or in combination: VRC01, VRC01-LS, VRC07-523-LS, 3BNC117, 10-1074, 10-1074-LS, PGT121, PGDM1400, 10E8.4-iMab, and SAR441236 (trispecific VRC01/PGDM1400-10E8v4). Ongoing non-human primate studies aimed to target, control, or potentially eliminate the viral reservoir are utilizing the following antibodies, alone or in combination: 3BNC117, 10-1074, N6-LS, PGT121, and the GS9721 variant of PGT121.
Hsu2021
(antibody interactions, immunotherapy, review, HIV reservoir/latency/provirus)
-
PGDM1400: A series of mutants was produced in the CAP256-VRC26.25 heavy chain for the purpose of avoiding the previously-identified proteolytic cleavage at position K100m. Neutralization of the mutants was tested, and the cleavage-resistant variant that showed the greatest potency was K100mA. In addition to the K100mA mutation, an LS mutation was added to the Fc portion of the heavy chain, as this change has been shown to improve the half-life of antibodies used for passive administration without affecting neutralization potency. The resulting construct was named CAP256V2LS. The pharmacokinetics of CAP256V2LS were assessed in macaques and mice, and it showed a profile similar to other antibodies used for immunotherapy. The antibody lacked autoreactivity. Structural analysis of wild-type CAP256-VRC26.25 showed that the K100m residue is not involved in interaction with the Env trimer. Neutralization data for PGDM1400-LS, and previously-published neutralization data for PGDM1400, were used for comparison purposes.
Zhang2022
(neutralization, immunotherapy, broad neutralizer)
-
PGDM1400: The mAb CAP256-VRC26.25 was engineered with the Fc-LS mutation to increase its half-life, and this modified mAb was named CAP256-VRC26.25-LS. Two mAbs (CAP256-VRC26.25-LS and PGDM1400) were assessed against a novel SHIV challenge stock, SHIV-325c. This SHIV was created in order to be more susceptible to neutralization than other SHIV stocks, in order better model human HIV infection in macaques. Macaques received an infusion of either CAP256-VRC26.25-LS or PGDM1400 prior to challenge with SHIV-325c. PGDM1400 was fully protective at an intermediate dose, whereas CAP256-VRC26.25-LS was fully protective even at the lowest dose given.
Julg2017a
(immunoprophylaxis, neutralization, immunotherapy, broad neutralizer)
-
PGDM1400: In 8 ART-treated patients, latent viruses were induced by a viral outgrowth assay and assayed for their sensitivity to neutralization by 8 broadly neutralizing antibodies (VRC01, VRC07-523, 3BNC117, PGT121, 10-1074, PGDM1400, VRC26.25, 10E8v4-V5F-100cF). The patients' inducible reservoir of autologous viruses was generally refractory to neutralization, and higher Env diversity correlated with greater resistance to neutralization.
Wilson2021
(autologous responses, neutralization, HAART, ART, HIV reservoir/latency/provirus)
-
PGDM1400: In this clinical trial, administration of PGT121 was well tolerated in both HIV-uninfected and HIV-infected individuals. PGT121 potently and transiently inhibited HIV-1 replication in viremic individuals who had PGT121-sensitive viruses at enrollment. There were several distinct viral evolutionary patterns associated with the emergence of PGT121 resistance and viral rebound. These pathways included single point mutations, multiple point mutations, and viral recombination that led to increased resistance. Loss of D325 and the glycan at N332 were specifically associated with resistance in multiple patients. In some patients, resistance to PGT121 was accompanied by resistance to other bNAbs (10-1074, PGDM1400, or 3BNC117), as measured by neutralization assays.
Stephenson2021
(glycosylation, mutation acquisition, neutralization, immunotherapy)
-
PGDM1400: Extensive structural and biochemical analyses demonstrated that PGT145 achieves recognition and neutralization by targeting quaternary structure of the cationic trimer apex with long and unusually stabilized anionic β-hairpin HCDR3 loops. In neutralization assays of BG505.Env.C2 alanine-scanning mutants and analysis of inter-CDR stabilizing interactions in X-ray Fab structures, PGDM1400 had similar results as PGT145 consistent with the proposed binding mechanism.
Lee2017
(antibody binding site, neutralization)
-
PGDM1400: A novel CD4bs bnAb, 1-18, is identified with breadth (97% against a 119-strain multiclade panel) and potency exceeding (IC50 = 0.048 µg/mL) most VH1-46 and VH1-2 class bnAbs like 3BNC117, VRC01, N6, 8ANC131, 10-1074, PGT151, PGT121, 8ANC195, PG16 and PGDM1400. 1-18 effectively restricts viral escape better than bnAbs 3BNC117 and VRC01. As with VRC01-like Abs, 1-18 targets the CD4bs but it recognizes the epitope differently. Neutralizing activity against VRC01 Ab-class escapes is maintained by 1-18. In humanized mice infected by strain HIV-1YU2, viral suppression is also maintained by 1-18. VH1-46-derived B cell clone 4.1 from patient IDC561 produced potent, broadly active mAbs. Subclone 4.1 is characterized by a 6 aa CDRH1 insertion lengthening it from 8 to 14 aa and produces bNAbs 1-18 and 1-55. Cryo-EM at 2.5A of 1-18 in complex with BG505SOSIP.664 suggests their insertion increases inter-protomer contacts by a negatively charged DDDPYTDDD motif, resulting in an enlargement of the buried surface on HIV-1 gp120. Variations in glycosylation is thought to confer higher neutralizing activity on 1-18 over 1-55.
Schommers2020
(neutralization)
-
PGDM1400: Without SOSIP changes, cleaved Env trimers disintegrate into their gp120 and gp41-ectodomain (gp41_ECTO) components. This study demonstrates that the gp41_ECTO component is the primary source of this Env metastability and that replacing wild-type gp41_ECTO with BG505 gp41_ECTO of the uncleaved prefusion-optimized design is a general and effective strategy for trimer stabilization. A panel of 11 bNAbs, including the V2 apex recognized by PGDM1400, PGT145, and PG16, was used to assess conserved neutralizing epitopes on the trimer surface, and the main result was that the substitution was found to significantly improve trimer binding to bNAbs VRC01, PGT151, and 35O22, with P values (paired t test) of 0.0229, 0.0269, and 0.0407, respectively.
He2018
(antibody interactions, glycosylation, vaccine antigen design)
-
PGDM1400: To reduce local V2 flexibility and improve the binding of V2-dependent bNAbs and germline precursor bNAbs, the authors designed BG505 SOSIP.664 trimer variants whose V1 and V2 domains were stabilized by introducing disulfide bonds either within the V2 loop or between the V1 and V2 loops. The resulting SOSIP trimer variants — E153C/K178C, E153C/K178C/G152E and I184C/E190C — have improved reactivity with V2 bNAbs and their inferred germline precursors and are more sensitive to neutralization by V2 bNAbs. I184C/E190C was more sensitive to neutralization by V2 bNAbs compared with BG505 (by 5-fold for PG9, 3-fold for PG16, 6-fold for CH01, and 3-fold for PGDM1400).
deTaeye2019
(neutralization, vaccine antigen design, binding affinity)
-
PGDM1400: This study demonstrated that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens eliciting Ab responses with greater neutralization breadth. Data from four large virus panels were used to comprehensively map viral signatures associated with bNAb sensitivity, hypervariable region characteristics, and clade effects. The bNAb signatures defined for the V2 epitope region were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine which resulted in increased breadth of nAb responses compared with Env 459C alone. PGDM1400 was used for analyzing clade sensitivity.
Bricault2019
(antibody binding site, neutralization, vaccine antigen design, computational prediction, broad neutralizer)
-
PGDM1400: The authors describe single-component molecules they designed that incorporate two (bispecific) or three (trispecific) bNAbs that recognize HIV Env exclusively, a bispecific CrossmAb targeting two epitopes on the major HIV coreceptor, CCR5, and bi- and trispecifics that cross-target both Env and CCR5. These newly designed molecules displayed exceptional breadth, neutralizing 98 to 100% of a 109-virus panel, as well as additivity and potency compared to those of the individual parental control IgGs. They constructed a bi-specific PGDM1400fv-PRO-140fv to simultaneously target epitopes on HIV Env and CCR5, 8 different versions of tri-specific 10E8Fab-PGT121fv-PGDM1400fv, 3 different versions of tri-specific 10E8Fab-PGT121fv-PGDM1400fv.V8, a tri-specific PRO-140Fab-PGDM1400fv-PGT121fv, and, finally, the most potent of all tri-specific, 10E8Fab-PGDM1400fv-PRO-140fv, with a median IC50 of 0.007 µg/ml.
Khan2018
(neutralization, bispecific/trispecific)
-
PGDM1400: In vitro neutralization data against 25 subtype A, 100 C, and 20 D pseudoviruses of 8 bNAbs (3BNC117, N6, VRC01, VRC07-523LS, CAP256-VRC26.25, PGDM1400, 10–1074, PGT121) and 2 bispecific Abs under clinical development (10E8-iMAb, 3BNC117-PGT135) was studied to assess the antibodies’ potential to prevent infection by dominant HIV-1 subtypes in sub-Saharan Africa. In vivo protection of these Abs and their 2-Ab combination was predicted using a function of in vitro neutralization based on data from a macaque simian-human immunodeficiency virus (SHIV) challenge study. Conclusions were that 1. bNAb combinations outperform individual bNAbs 2. Different bNAb combinations were optimal against different HIV subtypes 3. Bispecific 10E8-iMAb outperformed all combinations, and 4. 10E8-iMAb in combination with other conventional Abs was predicted to be the best combination against HIV-infection. Ab N6 in combination with PGDM1400 was the best Ab combination against subtype A. In the case of bispecific Ab combinations - for subtype A 10E8-iMAb with VRC07-523LS or N6 or PGDM1400 were best.
Wagh2018
(neutralization, computational prediction, immunotherapy)
-
PGDM1400: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. Recombinant native-like HIV Env trimers have enabled the identification of PGDM1400, a potent ‘PG9-class’ bNAb. Antigenic region V2 apex (Table:1). This Ab is in Phase I clinical trial (Table 2).
Walker2018
(antibody binding site, review, broad neutralizer)
-
PGDM1400: Panels of C clade pseudoviruses were computationally downselected from the panel of 200 C clade viruses defined by Rademeyer et al. 2016. A 12-virus panel was defined for the purpose of screening sera from vaccinees. Panels of 50 and 100 viruses were defined as smaller sets for use in testing magnitude and breadth against C clade. Published neutralization data for 16 mAbs was taken from CATNAP for the computational selections: 10-1074, 10-1074V, PGT121, PGT128, VRC26.25, VRC26.08, PGDM1400, PG9, PGT145, VRC07-523, 10E8, VRC13, 3BNC117, VRC07, VRC01, 4E10.
Hraber2017
(assay or method development, neutralization)
-
PGDM1400: In 33 individuals (14 uninfected and 19 HIV-1-infected), intravenous infusion of 10-1074 was well tolerated. In infected individuals with sensitive strains, 10-1074 decreased viremia, but escape variants and viral rebound occurred within a few weeks. Escape variants were also resistant to V3 antibody PGT121, but remained sensitive to antibodies targeting other epitopes (3BNC117, VRC01 or PGDM1400). Loss of the PNGS at position N332 or 324G(D/N)IR327 mutation was associated with resistance to 10-1074 and PGT121.
Caskey2017
(immunotherapy)
-
PGDM1400: This study performed cyclical permutation of the V1 loop of JRFL in order to develop better gp120 trimers to elicit neutralizing antibodies. Some mutated trimers showed improved binding to several mAbs, including VRC01, VRC03, VRC-PG04, PGT128, PGT145, PGDM1400, b6, and F105. Guinea pigs immunized with prospective trimers showed improved neutralization of a panel of HIV-1 pseudoviruses.
Kesavardhana2017
(vaccine antigen design, vaccine-induced immune responses)
-
PGDM1400: This study produced Env SOSIP trimers for clades A (strain BG505), B (strain JR-FL), and G (strain X1193). Based on simulations, the MAb-trimer structures of all MAbs tested needed to accommodate at least one glycan, including both antibodies known to require specific glycans (PG9, PGT121, PGT135, 8ANC195, 35O22) and those that bind the CD4-binding site (b12, CH103, HJ16, VRC01, VRC13). A subset of monoclonal antibodies bound to glycan arrays assayed on glass slides (VRC26.09, PGT121, 2G12, PGT128, VRC13, PGT151, 35O22), while most of the antibodies did not have affinity for oligosaccharide in the context of a glycan array (PG9, PGT145, PGDM1400, PGT135, b12, CH103, HJ16, VRC16, VRC01, VRC-PG04, VRC-CH31, VRC-PG20, 3BNC60, 12A12, VRC18b, VRC23, VRC27, 1B2530, 8ANC131, 8ANC134, 8ANC195).
Stewart-Jones2016
(antibody binding site, glycosylation, structure)
-
PGDM1400: This review summarizes representative anti-HIV MAbs of the first generation (2G12, b12, 2F5, 4E10) and second generation (PG9, PG16, PGT145, VRC26.09, PGDM1400, PGT121, PGT124, PGT128, PGT135, 10-1074, VRC01, 3BNC117, CH103, PGT151, 35O22, 8ANC195, 10E8). Structures, epitopes, VDJ usage, CDR usage, and degree of somatic hypermutation are compared among these antibodies. The use of SOSIP trimers as immunogens to elicit B-cell responses is discussed.
Burton2016
(review, structure)
-
PGDM1400: Factors that independently affect bNAb induction and evolution were identified as viral load, length of untreated infection, and viral diversity. Black subjects induced bNAbs more than white subjects, but this did not correlate with type of Ab response. Fingerprint analyses of induced bNAbs showed strong subtype dependency, with subtype B inducing significantly higher levels of CD4bs Abs and non-subtype B inducing V2-glycan specific Abs. Of the 239 bNAb antibody inducers found from 4,484 HIV-1 infected subjects,the top 105 inducers' neutralization fingerprint and epitope specificity was determined by comparison to the following antibodies - PG9, PG16, PGDM1400, PGT145 (V2 glycan); PGT121, PGT128, PGT130 (V3 glycan); VRC01, PGV04 (CD4bs) and PGT151 (interface) and 2F5, 4E10, 10E8 (MPER).
Rusert2016
(neutralization, subtype comparisons, broad neutralizer)
-
PGDM1400: Env trimer BG505 SOSIP.664 as well as the clade B trimer B41 SOSIP.664 were stabilized using a bifunctional aldehyde (glutaraldehye, GLA) or a heterobifunctional cross-linker, EDC/NHS with modest effects on antigenicity and barely any on biochemistry or structural morphology. ELISA, DSC and SPR were used to test recognition of the trimers by bNAbs, which was preserved and by weakly NAbs or non-NAbs, which was reduced. Cross-linking partially preserves quaternary morphology so that affinity chromatography by positive selection using quaternary epitope-specific bNAabs, and negative selection using non-NAbs, enriched antigenic characteristics of the trimers. Binding of V1/V2 apex-binding bNAb PGDM1400 to trimers was 2.8-fold reduced by trimer cross-linking.
Schiffner2016
(assay or method development, binding affinity, structure)
-
PGDM1400: This review discusses the application of bNAbs for HIV treatment and eradication, focusing on bnAbs that target key epitopes, specifically: 2G12, 2F5, 4E10, VRC01, 3BNC117, PGT121, VRC26.08, VRC26.09, PGDM1400, and 10-1074. PGDM1400 was mentioned as an example of a mAb with exceptionally high breadth of neutralization across global isolates.
Stephenson2016
(immunotherapy, review)
-
PGDM1400: Double, triple or quadruple combinations of fifteen bNAbs that target 4 distinct epitope regions: the CD4 binding site (3BNC117, VRC01, VRC07, VRC07-523, VRC13), the V3-glycan supersite (10–1074, 10-1074V, PGT121, PGT128), the V1/V2-glycan site (PG9, PGT145, PGDM1400, CAP256-VRC26.08, CAP256-VRC26.25), and the gp41 MPER epitope (10E8) were studied. Their neutralization potency and breadth were assayed against a panel of 200 acute/early subtype C strains, and compared to a novel, highly accurate predictive mathematical model (no-overlap Bliss Hill model, CombiNaber tool, LANL HIV Immunology database). These data were used to predict the best combinations of bNAbs for immunotherapy.
Wagh2016
(neutralization, immunotherapy)
-
PGDM1400: A soluble recombinant BG505 SOSIP.664 gp140 HIV trimer apex was used to select for IgG+ memory B cells. Single B-cell sorted samples were from the same donor (and same timepoint) from which the trimer-specific bNAbs PGT141–145 were previously isolated. 13 highly divergent, somatic variants of PGT145 family were isolated, named PGDM1400-1412 (other germline clonal antibodies were also selected, but not chosen for study). Though of the same family, PGDM NAbs are highly (49-67%) sequence divergent from PGT bNAbs. Neutralization breadth and potency between PDGM NAbs spanned a huge range. All PGDM1400-1412 NAbs were N160 glycan-dependent for neutralization. Pathway used rather than degree of somatic hypermutation impacted neutralization breadth for PGDM family NAbs. Newly isolated bNAb, PGDM1400, had exceptionally broad (83%) and potent (median IC50 = 0.003 µg/ml) cross-clade neutralization coverage against a 77-virus cross-clade panel, higher than the most potent PGT bNAbs (PGT121, PGT128, PGT151). Combined with PGT121, PGDM1400 breadth of neutralization reaches 96% with median potency of IC50 = 0.007 µg/ml when tested against a 106-virus panel. Maximum Percent Neutralization (MPN) levels were similar to PGT121, but greater than PGT151. Tyr100F sulfation of PGDM1400 stabilizes its kinked β-hairpin and a triad of Asp residues provides an anionic tip to its CDRH3. PGDM1400 binds Env trimer with a stoichiometry of 1. BG505 SOSIP.664 gp140 is now a proven tool for isolation of quarternary-dependent NAbs.
Sok2014
(antibody binding site, antibody generation, antibody sequence, structure, broad neutralizer)
References
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Sok2014
Devin Sok, Marit J. van Gils, Matthias Pauthner, Jean-Philippe Julien, Karen L. Saye-Francisco, Jessica Hsueh, Bryan Briney, Jeong Hyun Lee, Khoa M. Le, Peter S. Lee, Yuanzi Hua, Michael S. Seaman, John P. Moore, Andrew B. Ward, Ian A. Wilson, Rogier W. Sanders, and Dennis R. Burton. Recombinant HIV Envelope Trimer Selects for Quaternary-Dependent Antibodies Targeting the Trimer Apex. Proc. Natl. Acad. Sci. U.S.A., 111(49):17624-17629, 9 Dec 2014. PubMed ID: 25422458.
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Berendam2021
Stella J. Berendam, Tiffany M. Styles, Papa K.. Morgan-Asiedu, DeAnna Tenney, Amit Kumar, Veronica Obregon-Perko, Katharine J. Bar, Kevin O. Saunders, Sampa Santra, Kristina De Paris, Georgia D. Tomaras, Ann Chahroudi, Sallie R. Permar, Rama R. Amara, and Genevieve G. Fouda. Systematic Assessment of Antiviral Potency, Breadth, and Synergy of Triple Broadly Neutralizing Antibody Combinations against Simian-Human Immunodeficiency Viruses. J. Virol., 95(3), 13 Jan 2021. PubMed ID: 33177194.
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Frederic Bibollet-Ruche, Ronnie M. Russell, Wenge Ding, Weimin Liu, Yingying Li, Kshitij Wagh, Daniel Wrapp, Rumi Habib, Ashwin N. Skelly, Ryan S. Roark, Scott Sherrill-Mix, Shuyi Wang, Juliette Rando, Emily Lindemuth, Kendra Cruickshank, Younghoon Park, Rachel Baum, John W. Carey, Andrew Jesse Connell, Hui Li, Elena E. Giorgi, Ge S. Song, Shilei Ding, Andrés Finzi, Amanda Newman, Giovanna E. Hernandez, Emily Machiele, Derek W. Cain, Katayoun Mansouri, Mark G. Lewis, David C. Montefiori, Kevin J. Wiehe, S. Munir Alam, I-Ting Teng, Peter D. Kwong, Raiees Andrabi, Laurent Verkoczy, Dennis R. Burton, Bette T. Korber, Kevin O. Saunders, Barton F. Haynes, Robert J. Edwards, George M. Shaw, and Beatrice H. Hahn. A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies.. mBio, 14(1):e0337022, 28 Feb 2023. PubMed ID: 36629414.
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Bricault2019
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Burton2016
Dennis R. Burton and Lars Hangartner. Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design. Annu. Rev. Immunol., 34:635-659, 20 May 2016. PubMed ID: 27168247.
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Caskey2017
Marina Caskey, Till Schoofs, Henning Gruell, Allison Settler, Theodora Karagounis, Edward F. Kreider, Ben Murrell, Nico Pfeifer, Lilian Nogueira, Thiago Y. Oliveira, Gerald H. Learn, Yehuda Z. Cohen, Clara Lehmann, Daniel Gillor, Irina Shimeliovich, Cecilia Unson-O'Brien, Daniela Weiland, Alexander Robles, Tim Kummerle, Christoph Wyen, Rebeka Levin, Maggi Witmer-Pack, Kemal Eren, Caroline Ignacio, Szilard Kiss, Anthony P. West, Jr., Hugo Mouquet, Barry S. Zingman, Roy M. Gulick, Tibor Keler, Pamela J. Bjorkman, Michael S. Seaman, Beatrice H. Hahn, Gerd Fätkenheuer, Sarah J. Schlesinger, Michel C. Nussenzweig, and Florian Klein. Antibody 10-1074 Suppresses Viremia in HIV-1-Infected Individuals. Nat. Med., 23(2):185-191, Feb 2017. PubMed ID: 28092665.
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Chuang2019
Gwo-Yu Chuang, Jing Zhou, Priyamvada Acharya, Reda Rawi, Chen-Hsiang Shen, Zizhang Sheng, Baoshan Zhang, Tongqing Zhou, Robert T. Bailer, Venkata P. Dandey, Nicole A. Doria-Rose, Mark K. Louder, Krisha McKee, John R. Mascola, Lawrence Shapiro, and Peter D. Kwong. Structural Survey of Broadly Neutralizing Antibodies Targeting the HIV-1 Env Trimer Delineates Epitope Categories and Characteristics of Recognition. Structure, 27(1):196-206.e6, 2 Jan 2019. PubMed ID: 30471922.
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deTaeye2019
Steven W. de Taeye, Eden P. Go, Kwinten Sliepen, Alba Torrents de la Peña, Kimberly Badal, Max Medina-Ramírez, Wen-Hsin Lee, Heather Desaire, Ian A. Wilson, John P. Moore, Andrew B. Ward, and Rogier W. Sanders. Stabilization of the V2 Loop Improves the Presentation of V2 Loop-Associated Broadly Neutralizing Antibody Epitopes on HIV-1 Envelope Trimers. J. Biol. Chem., 294(14):5616-5631, 5 Apr 2019. PubMed ID: 30728245.
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Dufloo2022
Jérémy Dufloo, Cyril Planchais, Stéphane Frémont, Valérie Lorin, Florence Guivel-Benhassine, Karl Stefic, Nicoletta Casartelli, Arnaud Echard, Philippe Roingeard, Hugo Mouquet, Olivier Schwartz, and Timothée Bruel. Broadly Neutralizing Anti-HIV-1 Antibodies Tether Viral Particles at the Surface of Infected Cells. Nat. Commun., 13(1):630, 2 Feb 2022. PubMed ID: 35110562.
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Javier Guenaga, Viktoriya Dubrovskaya, Natalia de Val, Shailendra K. Sharma, Barbara Carrette, Andrew B. Ward, and Richard T. Wyatt. Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers. J. Virol., 90(6):2806-2817, 30 Dec 2015. PubMed ID: 26719252.
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He2018
Linling He, Sonu Kumar, Joel D. Allen, Deli Huang, Xiaohe Lin, Colin J. Mann, Karen L. Saye-Francisco, Jeffrey Copps, Anita Sarkar, Gabrielle S. Blizard, Gabriel Ozorowski, Devin Sok, Max Crispin, Andrew B. Ward, David Nemazee, Dennis R. Burton, Ian A. Wilson, and Jiang Zhu. HIV-1 Vaccine Design through Minimizing Envelope Metastability. Sci. Adv., 4(11):eaau6769, Nov 2018. PubMed ID: 30474059.
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Hraber2017
Peter Hraber, Cecilia Rademeyer, Carolyn Williamson, Michael S. Seaman, Raphael Gottardo, Haili Tang, Kelli Greene, Hongmei Gao, Celia LaBranche, John R. Mascola, Lynn Morris, David C. Montefiori, and Bette Korber. Panels of HIV-1 Subtype C Env Reference Strains for Standardized Neutralization Assessments. J. Virol., 91(19), 1 Oct 2017. PubMed ID: 28747500.
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Hsu2021
Denise C. Hsu, John W. Mellors, and Sandhya Vasan. Can Broadly Neutralizing HIV-1 Antibodies Help Achieve an ART-Free Remission? Front. Immunol., 12:710044, 2021. PubMed ID: 34322136.
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Julg2017a
Boris Julg, Lawrence J. Tartaglia, Brandon F. Keele, Kshitij Wagh, Amarendra Pegu, Devin Sok, Peter Abbink, Stephen D. Schmidt, Keyun Wang, Xuejun Chen, M. Gordon Joyce, Ivelin S. Georgiev, Misook Choe, Peter D. Kwong, Nicole A. Doria-Rose, Khoa Le, Mark K. Louder, Robert T. Bailer, Penny L. Moore, Bette Korber, Michael S. Seaman, Salim S. Abdool Karim, Lynn Morris, Richard A. Koup, John R. Mascola, Dennis R. Burton, and Dan H. Barouch. Broadly Neutralizing Antibodies Targeting the HIV-1 Envelope V2 Apex Confer Protection against a Clade C SHIV Challenge. Sci. Transl. Med., 9(406), 6 Sep 2017. PubMed ID: 28878010.
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Julg2022
Boris Julg, Kathryn E. Stephenson, Kshitij Wagh, Sabrina C. Tan, Rebecca Zash, Stephen Walsh, Jessica Ansel, Diane Kanjilal, Joseph Nkolola, Victoria E. K. Walker-Sperling, Jasper Ophel, Katherine Yanosick, Erica N. Borducchi, Lori Maxfield, Peter Abbink, Lauren Peter, Nicole L. Yates, Martina S. Wesley, Tom Hassell, Huub C. Gelderblom, Allen deCamp, Bryan T Mayer, Alicia Sato, Monica W. Gerber, Elena E. Giorgi, Lucio Gama, Richard A. Koup, John R. Mascola, Ana Monczor, Sofia Lupo, Charlotte-Paige Rolle, Roberto Arduino, Edwin DeJesus, Georgia D. Tomaras, Michael S. Seaman, Bette Korber, and Dan H. Barouch. Safety and Antiviral Activity of Triple Combination Broadly Neutralizing Monoclonal Antibody Therapy against HIV-1: A Phase 1 Clinical Trial. Nat. Med., 28(6):1288-1296, Jun 2022. PubMed ID: 35551291.
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Kesavardhana2017
Sannula Kesavardhana, Raksha Das, Michael Citron, Rohini Datta, Linda Ecto, Nonavinakere Seetharam Srilatha, Daniel DiStefano, Ryan Swoyer, Joseph G. Joyce, Somnath Dutta, Celia C. LaBranche, David C. Montefiori, Jessica A. Flynn, and Raghavan Varadarajan. Structure-Based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies. J. Biol. Chem., 292(1):278-291, 6 Jan 2017. PubMed ID: 27879316.
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Khan2018
Salar N. Khan, Devin Sok, Karen Tran, Arlette Movsesyan, Viktoriya Dubrovskaya, Dennis R. Burton, and Richard T. Wyatt. Targeting the HIV-1 Spike and Coreceptor with Bi- and Trispecific Antibodies for Single-Component Broad Inhibition of Entry. J. Virol., 92(18), 15 Sep 2018. PubMed ID: 29976677.
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Kreer2020
Christoph Kreer, Henning Gruell, Thierry Mora, Aleksandra M. Walczak, and Florian Klein. Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies. Vaccines (Basel), 8(1):13 doi, Jan 2020. PubMed ID: 31906351
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Lee2017
Jeong Hyun Lee, Raiees Andrabi, Ching-Yao Su, Anila Yasmeen, Jean-Philippe Julien, Leopold Kong, Nicholas C. Wu, Ryan McBride, Devin Sok, Matthias Pauthner, Christopher A. Cottrell, Travis Nieusma, Claudia Blattner, James C. Paulson, Per Johan Klasse, Ian A. Wilson, Dennis R. Burton, and Andrew B. Ward. A Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope Trimer Apex via a Long, Rigidified, and Anionic beta-Hairpin Structure. Immunity, 46(4):690-702, 18 Apr 2017. PubMed ID: 28423342.
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Mandizvo2022
Tawanda Mandizvo, Nombali Gumede, Bongiwe Ndlovu, Siphiwe Ndlovu, Jaclyn K. Mann, Denis R. Chopera, Lanish Singh, Krista L. Dong, Bruce D. Walker, Zaza M. Ndhlovu, Christy L. Lavine, Michael S. Seaman, Kamini Gounder, and Thumbi Ndung'u. Subtle Longitudinal Alterations in Env Sequence Potentiate Differences in Sensitivity to Broadly Neutralizing Antibodies following Acute HIV-1 Subtype C Infection. J. Virol., 96(24):e0127022, 21 Dec 2022. PubMed ID: 36453881.
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Mishra2020
Nitesh Mishra, Shaifali Sharma, Ayushman Dobhal, Sanjeev Kumar, Himanshi Chawla, Ravinder Singh, Bimal Kumar Das, Sushil Kumar Kabra, Rakesh Lodha, and Kalpana Luthra. A Rare Mutation in an Infant-Derived HIV-1 Envelope Glycoprotein Alters Interprotomer Stability and Susceptibility to Broadly Neutralizing Antibodies Targeting the Trimer Apex. J. Virol., 94(19), 15 Sep 2020. PubMed ID: 32669335.
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Mishra2020a
Nitesh Mishra, Shaifali Sharma, Ayushman Dobhal, Sanjeev Kumar, Himanshi Chawla, Ravinder Singh, Muzamil Ashraf Makhdoomi, Bimal Kumar Das, Rakesh Lodha, Sushil Kumar Kabra, and Kalpana Luthra. Broadly Neutralizing Plasma Antibodies Effective against Autologous Circulating Viruses in Infants with Multivariant HIV-1 Infection. Nat. Commun., 11(1):4409, 2 Sep 2020. PubMed ID: 32879304.
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Mkhize2023
Nonhlanhla N. Mkhize, Anna E. J. Yssel, Haajira Kaldine, Rebecca T. van Dorsten, Amanda S. Woodward Davis, Nicolas Beaume, David Matten, Bronwen Lambson, Tandile Modise, Prudence Kgagudi, Talita York, Dylan H. Westfall, Elena E. Giorgi, Bette Korber, Colin Anthony, Rutendo E. Mapengo, Valerie Bekker, Elizabeth Domin, Amanda Eaton, Wenjie Deng, Allan DeCamp, Yunda Huang, Peter B . Gilbert, Asanda Gwashu-Nyangiwe, Ruwayhida Thebus, Nonkululeko Ndabambi, Dieter Mielke, Nyaradzo Mgodi, Shelly Karuna, Srilatha Edupuganti, Michael S. Seaman, Lawrence Corey, Myron S. Cohen, John Hural, M. Juliana McElrath, James I. Mullins, David Montefiori, Penny L. Moore, Carolyn Williamson, and Lynn Morris. Neutralization Profiles of HIV-1 Viruses from the VRC01 Antibody Mediated Prevention (AMP) Trials. PLoS Pathog., 19(6):e1011469, Jun 2023. PubMed ID: 37384759.
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Molinos-Albert2023
Luis M. Molinos-Albert, Eduard Baquero, Melanie Bouvin-Pley, Valerie Lorin, Caroline Charre, Cyril Planchais, Jordan D. Dimitrov, Valerie Monceaux, Matthijn Vos, Laurent Hocqueloux, Jean-Luc Berger, Michael S. Seaman, Martine Braibant, Veronique Avettand-Fenoel, Asier Saez-Cirion, and Hugo Mouquet. Anti-V1/V3-glycan broadly HIV-1 neutralizing antibodies in a post-treatment controller. Cell Host Microbe, 31(8):1275-1287e8 doi, Aug 2023. PubMed ID: 37433296
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Mullick2021
Ranajoy Mullick, Jyoti Sutar, Nitin Hingankar, Suprit Deshpande, Madhuri Thakar, Seema Sahay, Rajesh P. Ringe, Sampurna Mukhopadhyay, Ajit Patil, Shubhangi Bichare, Kailapuri G. Murugavel, Aylur K. Srikrishnan, Rajat Goyal, Devin Sok, and Jayanta Bhattacharya. Neutralization Diversity of HIV-1 Indian Subtype C Envelopes Obtained from Cross Sectional and Followed up Individuals against Broadly Neutralizing Monoclonal Antibodies Having Distinct gp120 Specificities. Retrovirology, 18(1):12, 14 May 2021. PubMed ID: 33990195.
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Pegu2022
Amarendra Pegu, Ling Xu, Megan E. DeMouth, Giulia Fabozzi, Kylie March, Cassandra G. Almasri, Michelle D. Cully, Keyun Wang, Eun Sung Yang, Joana Dias, Christine M. Fennessey, Jason Hataye, Ronnie R. Wei, Ercole Rao, Joseph P. Casazza, Wanwisa Promsote, Mangaiarkarasi Asokan, Krisha McKee, Stephen D. Schmidt, Xuejun Chen, Cuiping Liu, Wei Shi, Hui Geng, Kathryn E. Foulds, Shing-Fen Kao, Amy Noe, Hui Li, George M. Shaw, Tongqing Zhou, Constantinos Petrovas, John-Paul Todd, Brandon F. Keele, Jeffrey D. Lifson, Nicole A. Doria-Rose, Richard A. Koup, Zhi-Yong Yang, Gary J. Nabel, and John R. Mascola. Potent Anti-Viral Activity of a Trispecific HIV Neutralizing Antibody in SHIV-Infected Monkeys. Cell Rep., 38(1):110199, 4 Jan 2022. PubMed ID: 34986348.
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Ren2018
Yanqin Ren, Maria Korom, Ronald Truong, Dora Chan, Szu-Han Huang, Colin C. Kovacs, Erika Benko, Jeffrey T. Safrit, John Lee, Hermes Garbán, Richard Apps, Harris Goldstein, Rebecca M. Lynch, and R. Brad Jones. Susceptibility to Neutralization by Broadly Neutralizing Antibodies Generally Correlates with Infected Cell Binding for a Panel of Clade B HIV Reactivated from Latent Reservoirs. J. Virol., 92(23), 1 Dec 2018. PubMed ID: 30209173.
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Roark2021
Ryan S. Roark, Hui Li, Wilton B. Williams, Hema Chug, Rosemarie D. Mason, Jason Gorman, Shuyi Wang, Fang-Hua Lee, Juliette Rando, Mattia Bonsignori, Kwan-Ki Hwang, Kevin O. Saunders, Kevin Wiehe, M. Anthony Moody, Peter T. Hraber, Kshitij Wagh, Elena E. Giorgi, Ronnie M. Russell, Frederic Bibollet-Ruche, Weimin Liu, Jesse Connell, Andrew G. Smith, Julia DeVoto, Alexander I. Murphy, Jessica Smith, Wenge Ding, Chengyan Zhao, Neha Chohan, Maho Okumura, Christina Rosario, Yu Ding, Emily Lindemuth, Anya M. Bauer, Katharine J. Bar, David Ambrozak, Cara W. Chao, Gwo-Yu Chuang, Hui Geng, Bob C. Lin, Mark K. Louder, Richard Nguyen, Baoshan Zhang, Mark G. Lewis, Donald D. Raymond, Nicole A. Doria-Rose, Chaim A. Schramm, Daniel C. Douek, Mario Roederer, Thomas B. Kepler, Garnett Kelsoe, John R. Mascola, Peter D. Kwong, Bette T. Korber, Stephen C. Harrison, Barton F. Haynes, Beatrice H. Hahn, and George M. Shaw. Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth. Science, 371(6525), 8 Jan 2021. PubMed ID: 33214287.
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Rujas2022
Edurne Rujas, Hong Cui, Jonathan Burnie, Clare Burn Aschner, Tiantian Zhao, Sara Insausti, Krithika Muthuraman, Anthony Semesi, Jasper Ophel, Jose L. Nieva, Michael S. Seaman, Christina Guzzo, Bebhinn Treanor, and Jean-Philippe Julien. Engineering Pan-HIV-1 Neutralization Potency through Multispecific Antibody Avidity. Proc. Natl. Acad. Sci. U.S.A., 119(4), 25 Jan 2022. PubMed ID: 35064083.
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Rusert2016
Peter Rusert, Roger D. Kouyos, Claus Kadelka, Hanna Ebner, Merle Schanz, Michael Huber, Dominique L. Braun, Nathanael Hozé, Alexandra Scherrer, Carsten Magnus, Jacqueline Weber, Therese Uhr, Valentina Cippa, Christian W. Thorball, Herbert Kuster, Matthias Cavassini, Enos Bernasconi, Matthias Hoffmann, Alexandra Calmy, Manuel Battegay, Andri Rauch, Sabine Yerly, Vincent Aubert, Thomas Klimkait, Jürg Böni, Jacques Fellay, Roland R. Regoes, Huldrych F. Günthard, Alexandra Trkola, and Swiss HIV Cohort Study. Determinants of HIV-1 Broadly Neutralizing Antibody Induction. Nat. Med., 22(11):1260-1267, Nov 2016. PubMed ID: 27668936.
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Schiffner2016
Torben Schiffner, Natalia de Val, Rebecca A. Russell, Steven W. de Taeye, Alba Torrents de la Peña, Gabriel Ozorowski, Helen J. Kim, Travis Nieusma, Florian Brod, Albert Cupo, Rogier W. Sanders, John P. Moore, Andrew B. Ward, and Quentin J. Sattentau. Chemical Cross-Linking Stabilizes Native-Like HIV-1 Envelope Glycoprotein Trimer Antigens. J. Virol., 90(2):813-828, 28 Oct 2015. PubMed ID: 26512083.
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Schommers2020
Philipp Schommers, Henning Gruell, Morgan E. Abernathy, My-Kim Tran, Adam S. Dingens, Harry B. Gristick, Christopher O. Barnes, Till Schoofs, Maike Schlotz, Kanika Vanshylla, Christoph Kreer, Daniela Weiland, Udo Holtick, Christof Scheid, Markus M. Valter, Marit J. van Gils, Rogier W. Sanders, Jörg J. Vehreschild, Oliver A. Cornely, Clara Lehmann, Gerd Fätkenheuer, Michael S. Seaman, Jesse D. Bloom, Pamela J. Bjorkman, and Florian Klein. Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody. Cell, 180(3):471-489.e22, 6 Feb 2020. PubMed ID: 32004464.
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Schorcht2020
Anna Schorcht, Tom L. G. M. van den Kerkhof, Christopher A. Cottrell, Joel D. Allen, Jonathan L. Torres, Anna-Janina Behrens, Edith E. Schermer, Judith A. Burger, Steven W. de Taeye, Alba Torrents de la Peña, Ilja Bontjer, Stephanie Gumbs, Gabriel Ozorowski, Celia C. LaBranche, Natalia de Val, Anila Yasmeen, Per Johan Klasse, David C. Montefiori, John P. Moore, Hanneke Schuitemaker, Max Crispin, Marit J. van Gils, Andrew B. Ward, and Rogier W. Sanders. Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers. J. Virol., 94(24), 23 Nov 2020. PubMed ID: 32999024.
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Sliepen2019
Kwinten Sliepen, Byung Woo Han, Ilja Bontjer, Petra Mooij, Fernando Garces, Anna-Janina Behrens, Kimmo Rantalainen, Sonu Kumar, Anita Sarkar, Philip J. M. Brouwer, Yuanzi Hua, Monica Tolazzi, Edith Schermer, Jonathan L. Torres, Gabriel Ozorowski, Patricia van der Woude, Alba Torrents de la Pena, Marielle J. van Breemen, Juan Miguel Camacho-Sanchez, Judith A. Burger, Max Medina-Ramirez, Nuria Gonzalez, Jose Alcami, Celia LaBranche, Gabriella Scarlatti, Marit J. van Gils, Max Crispin, David C. Montefiori, Andrew B. Ward, Gerrit Koopman, John P. Moore, Robin J. Shattock, Willy M. Bogers, Ian A. Wilson, and Rogier W. Sanders. Structure and immunogenicity of a stabilized HIV-1 envelope trimer based on a group-M consensus sequence. Nat Commun, 10(1):2355 doi, May 2019. PubMed ID: 31142746
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Spencer2021
David A. Spencer, Delphine C. Malherbe, Nestor Vazquez Bernat, Monika Adori, Benjamin Goldberg, Nicholas Dambrauskas, Heidi Henderson, Shilpi Pandey, Tracy Cheever, Philip Barnette, William F. Sutton, Margaret E. Ackerman, James J. Kobie, D. Noah Sather, Gunilla B. Karlsson Hedestam, Nancy L. Haigwood, and Ann J. Hessell. Polyfunctional Tier 2-Neutralizing Antibodies Cloned following HIV-1 Env Macaque Immunization Mirror Native Antibodies in a Human Donor. J Immunol, 206(5):999-1012 doi, Mar 2021. PubMed ID: 33472907
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Stephenson2016
Kathryn E. Stephenson and Dan H. Barouch. Broadly Neutralizing Antibodies for HIV Eradication. Curr. HIV/AIDS Rep., 13(1):31-37, Feb 2016. PubMed ID: 26841901.
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Stephenson2021
Kathryn E. Stephenson, Boris Julg, C. Sabrina Tan, Rebecca Zash, Stephen R. Walsh, Charlotte-Paige Rolle, Ana N. Monczor, Sofia Lupo, Huub C. Gelderblom, Jessica L. Ansel, Diane G. Kanjilal, Lori F. Maxfield, Joseph Nkolola, Erica N. Borducchi, Peter Abbink, Jinyan Liu, Lauren Peter, Abishek Chandrashekar, Ramya Nityanandam, Zijin Lin, Alessandra Setaro, Joseph Sapiente, Zhilin Chen, Lisa Sunner, Tyler Cassidy, Chelsey Bennett, Alicia Sato, Bryan Mayer, Alan S. Perelson, Allan deCamp, Frances H. Priddy, Kshitij Wagh, Elena E. Giorgi, Nicole L. Yates, Roberto C. Arduino, Edwin DeJesus, Georgia D. Tomaras, Michael S. Seaman, Bette Korber, and Dan H. Barouch. Safety, Pharmacokinetics and Antiviral Activity of PGT121, a Broadly Neutralizing Monoclonal Antibody Against HIV-1: A Randomized, Placebo-Controlled, Phase 1 Clinical Trial. Nat. Med., 27(10):1718-1724, Oct 2021. PubMed ID: 34621054.
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Stewart-Jones2016
Guillaume B. E. Stewart-Jones, Cinque Soto, Thomas Lemmin, Gwo-Yu Chuang, Aliaksandr Druz, Rui Kong, Paul V. Thomas, Kshitij Wagh, Tongqing Zhou, Anna-Janina Behrens, Tatsiana Bylund, Chang W. Choi, Jack R. Davison, Ivelin S. Georgiev, M. Gordon Joyce, Young Do Kwon, Marie Pancera, Justin Taft, Yongping Yang, Baoshan Zhang, Sachin S. Shivatare, Vidya S. Shivatare, Chang-Chun D. Lee, Chung-Yi Wu, Carole A. Bewley, Dennis R. Burton, Wayne C. Koff, Mark Connors, Max Crispin, Ulrich Baxa, Bette T. Korber, Chi-Huey Wong, John R. Mascola, and Peter D. Kwong. Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G. Cell, 165(4):813-826, 5 May 2016. PubMed ID: 27114034.
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Wagh2016
Kshitij Wagh, Tanmoy Bhattacharya, Carolyn Williamson, Alex Robles, Madeleine Bayne, Jetta Garrity, Michael Rist, Cecilia Rademeyer, Hyejin Yoon, Alan Lapedes, Hongmei Gao, Kelli Greene, Mark K. Louder, Rui Kong, Salim Abdool Karim, Dennis R. Burton, Dan H. Barouch, Michel C. Nussenzweig, John R. Mascola, Lynn Morris, David C. Montefiori, Bette Korber, and Michael S. Seaman. Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection. PLoS Pathog., 12(3):e1005520, Mar 2016. PubMed ID: 27028935.
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Wagh2018
Kshitij Wagh, Michael S. Seaman, Marshall Zingg, Tomas Fitzsimons, Dan H. Barouch, Dennis R. Burton, Mark Connors, David D. Ho, John R. Mascola, Michel C. Nussenzweig, Jeffrey Ravetch, Rajeev Gautam, Malcolm A. Martin, David C. Montefiori, and Bette Korber. Potential of Conventional \& Bispecific Broadly Neutralizing Antibodies for Prevention of HIV-1 Subtype A, C \& D Infections. PLoS Pathog., 14(3):e1006860, Mar 2018. PubMed ID: 29505593.
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Walker2018
Laura M. Walker and Dennis R. Burton. Passive Immunotherapy of Viral Infections: `Super-Antibodies' Enter the Fray. Nat. Rev. Immunol., 18(5):297-308, May 2018. PubMed ID: 29379211.
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Wieczorek2023
Lindsay Wieczorek, Eric Sanders-Buell, Michelle Zemil, Eric Lewitus, Erin Kavusak, Jonah Heller, Sebastian Molnar, Mekhala Rao, Gabriel Smith, Meera Bose, Amy Nguyen, Adwitiya Dhungana, Katherine Okada, Kelly Parisi, Daniel Silas, Bonnie Slike, Anuradha Ganesan, Jason Okulicz, Tahaniyat Lalani, Brian K. Agan, Trevor A. Crowell, Janice Darden, Morgane Rolland, Sandhya Vasan, Julie Ake, Shelly J. Krebs, Sheila Peel, Sodsai Tovanabutra, and Victoria R. Polonis. Evolution of HIV-1 envelope towards reduced neutralization sensitivity, as demonstrated by contemporary HIV-1 subtype B from the United States. PLoS Pathog, 19(12):e1011780 doi, Dec 2023. PubMed ID: 38055771
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Wiehe2018
Kevin Wiehe, Todd Bradley, R. Ryan Meyerhoff, Connor Hart, Wilton B. Williams, David Easterhoff, William J. Faison, Thomas B. Kepler, Kevin O. Saunders, S. Munir Alam, Mattia Bonsignori, and Barton F. Haynes. Functional Relevance of Improbable Antibody Mutations for HIV Broadly Neutralizing Antibody Development. Cell Host Microbe, 23(6):759-765.e6, 13 Jun 2018. PubMed ID: 29861171.
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Willis2022
Jordan R. Willis, Zachary T. Berndsen, Krystal M. Ma, Jon M. Steichen, Torben Schiffner, Elise Landais, Alessia Liguori, Oleksandr Kalyuzhniy, Joel D. Allen, Sabyasachi Baboo, Oluwarotimi Omorodion, Jolene K. Diedrich, Xiaozhen Hu, Erik Georgeson, Nicole Phelps, Saman Eskandarzadeh, Bettina Groschel, Michael Kubitz, Yumiko Adachi, Tina-Marie Mullin, Nushin B. Alavi, Samantha Falcone, Sunny Himansu, Andrea Carfi, Ian A. Wilson, John R. Yates III, James C. Paulson, Max Crispin, Andrew B. Ward, and William R. Schief. Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors. Immunity, 55(11):2149-2167e9 doi, Nov 2022. PubMed ID: 36179689
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Wilson2021
Andrew Wilson, Leyn Shakhtour, Adam Ward, Yanqin Ren, Melina Recarey, Eva Stevenson, Maria Korom, Colin Kovacs, Erika Benko, R. Brad Jones, and Rebecca M. Lynch. Characterizing the Relationship between Neutralization Sensitivity and env Gene Diversity During ART Suppression. Front. Immunol., 12:710327, 15 Sep 2021. PubMed ID: 34603284.
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Zhang2022
Baoshan Zhang, Deepika Gollapudi, Jason Gorman, Sijy O'Dell, Leland F. Damron, Krisha McKee, Mangaiarkarasi Asokan, Eun Sung Yang, Amarendra Pegu, Bob C. Lin, Cara W. Chao, Xuejun Chen, Lucio Gama, Vera B. Ivleva, William H. Law, Cuiping Liu, Mark K. Louder, Stephen D. Schmidt, Chen-Hsiang Shen, Wei Shi, Judith A. Stein, Michael S. Seaman, Adrian B. McDermott, Kevin Carlton, John R. Mascola, Peter D. Kwong, Q. Paula Lei, and Nicole A. Doria-Rose. Engineering of HIV-1 Neutralizing Antibody CAP256V2LS for Manufacturability and Improved Half Life. Sci. Rep., 12(1):17876, 25 Oct 2022. PubMed ID: 36284200.
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