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Displaying record number 2124

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MAb ID	PG9
HXB2 Location	gp160	gp160 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, ADCC, antibody binding site, antibody gene transfer, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autoantibody or autoimmunity, binding affinity, broad neutralizer, chimeric antibody, computational epitope prediction, elite controllers, escape, genital and mucosal immunity, germline, glycosylation, immunoprophylaxis, immunotherapy, junction or fusion peptide, memory cells, mother-to-infant transmission, neutralization, polyclonal antibodies, rate of progression, review, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity

Notes

Showing 174 of 174 notes.

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. bNAbs with >25% breadth of neutralization belonged to 20 classes of antibody with a large number of protruding loops and somatic hypermutation (SHM). HIV epitopes recognized 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, whose serum had broad neutralization. The Env sequences of EN3 had much fewer polymorphisms, compared to those of a normal progressor, EN1, 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, neutralization, vaccine antigen design, polyclonal antibodies)
PG9: The Chinese HIV Reference Laboratory produced 124 pseudoviruses from patients with subype 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: The authors mutated two conserved tyrosine (Y) residues within the V2 loop of gp120 Y177 and Y173, individually or in combination, by replacing them with either phenylalanine (F) or alanine (A) in a clade B, tier 1B HIV-1 Env protein (BaL), and in a number of tier 2 HIV-1 Envs from different clades, namely, BG505 (clade A), JR-FL and JR-CSF (clade B), and CM244 (clade E). A consistent hierarchy of neutralization sensitivity was seen among the mutants, with a greater impact of Y177 over Y173 single mutations, of double over single mutations, and of A over F substitutions. The double-alanine mutation in mutant HIV-1 BaL, Y173A Y177A, increased sensitivity to all the weakly neutralizing MAbs tested and even rendered the virus sensitive to non-neutralizing antibodies against the CD4 binding site, such as F105, 654-30D, and b13. When tested against bNAbs instead, there was a trend to decrease neutralization sensitivity compared to WT, with the exception of N6, PGT151, 10E8, and 2G12, for which there was no change, and of 2F5 and 4E10, which were more effective against the mutant compared to the WT. Guzzo2018 (antibody binding site, binding affinity)
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 (antibody interactions, variant cross-reactivity, binding affinity, structure, broad neutralizer)
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 neutralized 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 (DH2070, CH103, CH235 etc.) have lower thermostability than their corresponding inferred UCA antibodies. 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, vaccine antigen design, computational epitope prediction, 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 (ADCC)
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 epitope 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 (ADCC)
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 epitope 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. Ethnically, 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, 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, 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 VH_1-69 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-gp41_ECTO 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 (ADCC, antibody binding site, antibody interactions, 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, 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 (ADCC)
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 epitope 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 Arg94_LC,Ser95_LC and His95_LC (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 envelop polypeptide. Pancera2013 (antibody binding site, 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 (ADCC, 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 (ADCC, 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 (ADCC, antibody interactions)
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 epitope 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:The reason for natural resistance of a patient Env obtained from plasma of a slow progressing Indian patient to PG9/PG16 MAbs in sharp contrast to its contemporaneous autologous Envs was investigated. Based on the experiments conducted for 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 and neutralization by PG9/16 is balanced by the glycans, net positive charge in β sheet C region of the V2 loop against PG9/16 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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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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

Doria-Rose2014 Nicole A. Doria-Rose, Chaim A. Schramm, Jason Gorman, Penny L. Moore, Jinal N. Bhiman, Brandon J. DeKosky, Michael J. Ernandes, Ivelin S. Georgiev, Helen J. Kim, Marie Pancera, Ryan P. Staupe, Han R. Altae-Tran, Robert T. Bailer, Ema T. Crooks, Albert Cupo, Aliaksandr Druz, Nigel J. Garrett, Kam H. Hoi, Rui Kong, Mark K. Louder, Nancy S. Longo, Krisha McKee, Molati Nonyane, Sijy O'Dell, Ryan S. Roark, Rebecca S. Rudicell, Stephen D. Schmidt, Daniel J. Sheward, Cinque Soto, Constantinos Kurt Wibmer, Yongping Yang, Zhenhai Zhang, NISC Comparative Sequencing Program, James C. Mullikin, James M. Binley, Rogier W. Sanders, Ian A. Wilson, John P. Moore, Andrew B. Ward, George Georgiou, Carolyn Williamson, Salim S. Abdool Karim, Lynn Morris, Peter D. Kwong, Lawrence Shapiro, and John R. Mascola. Developmental Pathway for Potent V1V2-Directed HIV-Neutralizing Antibodies. Nature, 509(7498):55-62, 1 May 2014. PubMed ID: 24590074. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

Hua2016 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. Show all entries for this paper.

Huang2012a Jinghe Huang, Gilad Ofek, Leo Laub, Mark K. Louder, Nicole A. Doria-Rose, Nancy S. Longo, Hiromi Imamichi, Robert T. Bailer, Bimal Chakrabarti, Shailendra K. Sharma, S. Munir Alam, Tao Wang, Yongping Yang, Baoshan Zhang, Stephen A. Migueles, Richard Wyatt, Barton F. Haynes, Peter D. Kwong, John R. Mascola, and Mark Connors. Broad and Potent Neutralization of HIV-1 by a gp41-Specific Human Antibody. Nature, 491(7424):406-412, 15 Nov 2012. PubMed ID: 23151583. Show all entries for this paper.

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. Show all entries for this paper.

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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. Show all entries for this paper.

Julien2013 Jean-Philippe Julien, Jeong Hyun Lee, Albert Cupo, Charles D. Murin, Ronald Derking, Simon Hoffenberg, Michael J. Caulfield, C. Richter King, Andre J. Marozsan, Per Johan Klasse, Rogier W. Sanders, John P. Moore, Ian A. Wilson, and Andrew. B Ward. Asymmetric Recognition of the HIV-1 Trimer by Broadly Neutralizing Antibody PG9. Proc. Natl. Acad. Sci. U.S.A., 110(11):4351-4356, 12 Mar 2013. PubMed ID: 23426631. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

Kwong2009 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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

Kwong2018 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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

Lewis2010 George K. Lewis. Challenges of Antibody-Mediated Protection against HIV-1. Expert Rev. Vaccines, 9(7):683-687, Jul 2010. PubMed ID: 20624038. Show all entries for this paper.

Li2017 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. Show all entries for this paper.

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. Show all entries for this paper.

Liao2013b Hua-Xin Liao, Mattia Bonsignori, S. Munir Alam, Jason S. McLellan, Georgia D. Tomaras, M. Anthony Moody, Daniel M. Kozink, Kwan-Ki Hwang, Xi Chen, Chun-Yen Tsao, Pinghuang Liu, Xiaozhi Lu, Robert J. Parks, David C. Montefiori, Guido Ferrari, Justin Pollara, Mangala Rao, Kristina K. Peachman, Sampa Santra, Norman L. Letvin, Nicos Karasavvas, Zhi-Yong Yang, Kaifan Dai, Marie Pancera, Jason Gorman, Kevin Wiehe, Nathan I. Nicely, Supachai Rerks-Ngarm, Sorachai Nitayaphan, Jaranit Kaewkungwal, Punnee Pitisuttithum, James Tartaglia, Faruk Sinangil, Jerome H. Kim, Nelson L. Michael, Thomas B. Kepler, Peter D. Kwong, John R. Mascola, Gary J. Nabel, Abraham Pinter, Susan Zolla-Pazner, and Barton F. Haynes. Vaccine Induction of Antibodies Against a Structurally Heterogeneous Site of Immune Pressure within HIV-1 Envelope Protein Variable Regions 1 and 2. Immunity, 38(1):176-186, 24 Jan 2013. PubMed ID: 23313589. Show all entries for this paper.

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Liu2011 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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

Lynch2011 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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

Mascola2010 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. Show all entries for this paper.

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. Show all entries for this paper.

McGuire2014 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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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Mikell2012 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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

Morales2016 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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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 doi, 2020. PubMed ID: 31859609 Show all entries for this paper.

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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. Show all entries for this paper.

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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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

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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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

Wibmer2013 Constantinos Kurt Wibmer, Jinal N. Bhiman, Elin S Gray, Nancy Tumba, Salim S. Abdool Karim, Carolyn Williamson, Lynn Morris, and Penny L. Moore. Viral Escape from HIV-1 Neutralizing Antibodies Drives Increased Plasma Neutralization Breadth through Sequential Recognition of Multiple Epitopes and Immunotypes. PLoS Pathog, 9(10):e1003738, Oct 2013. PubMed ID: 24204277. Show all entries for this paper.

Wilen2011 Craig B. Wilen, Nicholas F. Parrish, Jennifer M. Pfaff, Julie M. Decker, Elizabeth A. Henning, Hillel Haim, Josiah E. Petersen, Jason A. Wojcechowskyj, Joseph Sodroski, Barton F. Haynes, David C. Montefiori, John C. Tilton, George M. Shaw, Beatrice H. Hahn, and Robert W. Doms. Phenotypic and Immunologic Comparison of Clade B Transmitted/Founder and Chronic HIV-1 Envelope Glycoproteins. J Virol, 85(17):8514-8527, Sep 2011. PubMed ID: 21715507. Show all entries for this paper.

Willis2016 Jordan R. Willis, Jessica A. Finn, Bryan Briney, Gopal Sapparapu, Vidisha Singh, Hannah King, Celia C. LaBranche, David C. Montefiori, Jens Meiler, and James E. Crowe, Jr. Long Antibody HCDR3s from HIV-Naive Donors Presented on a PG9 Neutralizing Antibody Background Mediate HIV Neutralization. Proc. Natl. Acad. Sci. U.S.A., 113(16):4446-4451, 19 Apr 2016. PubMed ID: 27044078. Show all entries for this paper.

Wu2011a Xueling Wu, Anita Changela, Sijy O'Dell, Stephen D. Schmidt, Marie Pancera, Yongping Yang, Baoshan Zhang, Miroslaw K. Gorny, Sanjay Phogat, James E. Robinson, Leonidas Stamatatos, Susan Zolla-Pazner, Peter D. Kwong, and John R. Mascola. Immunotypes of a Quaternary Site of HIV-1 Vulnerability and Their Recognition by Antibodies. J. Virol., 85(9):4578-4585, May 2011. PubMed ID: 21325411. Show all entries for this paper.

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. Show all entries for this paper.

Wu2018 Xilin Wu, Jia Guo, Mengyue Niu, Minghui An, Li Liu, Hui Wang, Xia Jin, Qi Zhang, Ka Shing Lam, Tongjin Wu, Hua Wang, Qian Wang, Yanhua Du, Jingjing Li, Lin Cheng, Hang Ying Tang, Hong Shang, Linqi Zhang, Paul Zhou, and Zhiwei Chen. Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice. J Clin Invest, 128(6):2239-2251, Jun 1 2018. PubMed ID: 29461979. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

Zhou2014 Jing Zhou, Ning Gan, Tianhua Li, Futao Hu, Xing Li, Lihong Wang, and Lei Zheng. A Cost-Effective Sandwich Electrochemiluminescence Immunosensor for Ultrasensitive Detection of HIV-1 Antibody Using Magnetic Molecularly Imprinted Polymers as Capture Probes. Biosens. Bioelectron., 54:199-206, 15 Apr 2014. PubMed ID: 24280050. Show all entries for this paper.

Zhou2017 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. Show all entries for this paper.

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. Show all entries for this paper.

Displaying record number 2824

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MAb ID	3BC315
HXB2 Location	gp160	gp160 Epitope Map
Author Location
Epitope
Ab Type	gp41-gp41 interface
Neutralizing	P View neutralization details
Contacts and Features	View contacts and features
Species (Isotype)	human(IgG)
Patient	Patient 3
Immunogen	HIV-1 infection
Country	Germany
Keywords	antibody binding site, antibody generation, antibody interactions, antibody lineage, assay or method development, binding affinity, broad neutralizer, neutralization, polyclonal antibodies, structure, vaccine antigen design

Notes

Showing 11 of 11 notes.

3BC315: 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 3BC315 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)
3BC315: A weakly neutralizing antibody was isolated, CAP248-2B. The glycan dependence of CAP248-2B was compared to other known gp120-gp41 interface targeting bNAbs (8ANC195, 35O22, PGT151, 3BC315). CAP248-2B blocks the binding of 35O22, 3BC315, and PGT151 (but not 8ANC195 or 4E10) to cell surface envelope trimers. Wibmer2017 (antibody interactions)
3BC315: 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
3BC315: 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. gp41-binding 3BC315 did not compete with any other bNAb tested despite its overlap of epitopes with 35O22. Derking2015 (antibody interactions, neutralization, binding affinity, structure)
3BC315: 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 trimers have reduced affinity for the Ab 3BC315 and their pseudotyped viruses were not neutralized by it either. Julien2015 (assay or method development, structure)
3BC315: 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 bNAb 3BC315 to trimers was unaffected by trimer cross-linking. Schiffner2016 (assay or method development, binding affinity, structure)
3BC315: 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 15/20 BG505 SOSIP.664-D7324 trimer-immunized rabbits as well as 7/8 rabbit sera induced by trimers made in 293S GnT^-/- were capable of inhibiting 3BC315 binding to gp41, but gp140-immunized and gp120-immunized sera could not. Sanders2015 (antibody generation, neutralization, binding affinity, polyclonal antibodies)
3BC315: 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. bNAb 3BC315, 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)
3BC315: 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. gp41 and interface-binding gl-3BC315 precursor bound to 2/3 trimers, BG505 and ZM197M. Sliepen2015 (binding affinity, antibody lineage)
3BC315: Structural analyses mapped the epitopes of 3BC315 and 3BC176 using the Fabs bound to BG505.SOSIP.664. A conserved glycan at N88 was shown to play a role in the binding kinetics of the 2 mAbs. 3BC315 binds between two gp41 subunits and neutralizes the virus by accelerating trimer decay; this modality is unlike other between-subunit mAbs such as 35O22, though all 3 bnAbs do not require MPER to bind. 3BC315 bound with higher occupancy, a maximum stoichiometry of 2 Fabs per trimer. 3BC315's paratope is complementary in shape to the pre-fusion but not the 6-helix-bundle post-fusion conformation of gp41. Lee2015 (antibody binding site, structure)
3BC315: A single-cell Ab cloning method is described to isolate neutralizing Abs using truncated gp160 transfected cells as bait. Among the 15 Abs reported, only two are found to be broadly neutralizing and bind to a novel conformational HIV-1 spike epitope. 3BC315 was effective to neutralize 10 out of 36 viruses and complement the spectrum of viruses neutralized by anti-CD4bs. 3BC315 recognizes a conformational, yet-to-be-defined epitope which differs from the epitopes that are recognized by traditional anti-V3 loop, anti-CD4bs, and anti-CD4i antibodies. Klein2012 (antibody binding site, antibody generation, neutralization, broad neutralizer)

References

Showing 11 of 11 references.

Isolation Paper
Klein2012 Florian Klein, Christian Gaebler, Hugo Mouquet, D. Noah Sather, Clara Lehmann, Johannes F. Scheid, Zane Kraft, Yan Liu, John Pietzsch, Arlene Hurley, Pascal Poignard, Ten Feizi, Lynn Morris, Bruce D. Walker, Gerd Fätkenheuer, Michael S. Seaman, Leonidas Stamatatos, and Michel C. Nussenzweig. Broad Neutralization by a Combination of Antibodies Recognizing the CD4 Binding Site and a New Conformational Epitope on the HIV-1 Envelope Protein. J. Exp. Med., 209(8):1469-1479, 30 Jul 2012. PubMed ID: 22826297. Show all entries for this paper.

Lee2015 Jeong Hyun Lee, Daniel P. Leaman, Arthur S. Kim, Alba Torrents de la Peña, Kwinten Sliepen, Anila Yasmeen, Ronald Derking, Alejandra Ramos, Steven W. de Taeye, Gabriel Ozorowski, Florian Klein, Dennis R. Burton, Michel C. Nussenzweig, Pascal Poignard, John P. Moore, Per Johan Klasse, Rogier W. Sanders, Michael B. Zwick, Ian A. Wilson, and Andrew B. Ward. Antibodies to a Conformational Epitope on gp41 Neutralize HIV-1 by Destabilizing the Env spike. Nat. Commun., 6:8167, 25 Sep 2015. PubMed ID: 26404402. Show all entries for this paper.

Sanders2015 Rogier W. Sanders, Marit J. van Gils, Ronald Derking, Devin Sok, Thomas J. Ketas, Judith A. Burger, Gabriel Ozorowski, Albert Cupo, Cassandra Simonich, Leslie Goo, Heather Arendt, Helen J. Kim, Jeong Hyun Lee, Pavel Pugach, Melissa Williams, Gargi Debnath, Brian Moldt, Mariëlle J. van Breemen, Gözde Isik, Max Medina-Ramírez, Jaap Willem Back, Wayne C. Koff, Jean-Philippe Julien, Eva G. Rakasz, Michael S. Seaman, Miklos Guttman, Kelly K. Lee, Per Johan Klasse, Celia LaBranche, William R. Schief, Ian A. Wilson, Julie Overbaugh, Dennis R. Burton, Andrew B. Ward, David C. Montefiori, Hansi Dean, and John P. Moore. HIV-1 Neutralizing Antibodies Induced by Native-Like Envelope Trimers. Science, 349(6244):aac4223, 10 Jul 2015. PubMed ID: 26089353. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

Wibmer2017 Constantinos Kurt Wibmer, Jason Gorman, Gabriel Ozorowski, Jinal N. Bhiman, Daniel J. Sheward, Debra H. Elliott, Julie Rouelle, Ashley Smira, M. Gordon Joyce, Nonkululeko Ndabambi, Aliaksandr Druz, Mangai Asokan, Dennis R. Burton, Mark Connors, Salim S. Abdool Karim, John R. Mascola, James E. Robinson, Andrew B. Ward, Carolyn Williamson, Peter D. Kwong, Lynn Morris, and Penny L. Moore. Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape. PLoS Pathog., 13(1):e1006074, Jan 2017. PubMed ID: 28076415. Show all entries for this paper.

Displaying record number 2586

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MAb ID	3BNC117 (3BNC117_dRU3)
HXB2 Location	gp160	gp160 Epitope Map
Author Location	Env
Epitope
Ab Type	gp120 CD4BS
Neutralizing	P (tier 2) View neutralization details
Contacts and Features	View contacts and features
Species (Isotype)	human(IgG)
Patient	Patient 3
Immunogen	HIV-1 infection
Country	United States
Keywords	acute/early infection, ADCC, antibody binding site, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autologous responses, binding affinity, broad neutralizer, chimeric antibody, computational epitope prediction, contact residues, elite controllers, escape, genital and mucosal immunity, glycosylation, HAART, ART, HIV reservoir/latency/provirus, immunoprophylaxis, immunotherapy, junction or fusion peptide, mutation acquisition, neutralization, polyclonal antibodies, review, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses

Notes

Showing 73 of 73 notes.

3BNC117: 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 (immunotherapy, review)
3BNC117: 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 3BNC117 were used for comparison purposes. Zhang2022 (neutralization, immunotherapy, broad neutralizer)
3BNC117: An elite 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 3BNC117 was used as a comparison in an assay of ADCC. Pinto2019 (ADCC)
3BNC117: 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, HIV reservoir/latency/provirus)
3BNC117: 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 (mutation acquisition, neutralization, immunotherapy)
3BNC117: 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. Analysis of generated cyroEM structure of BG505 SOSIP.664-3BNC117 (resolution of ˜4.4A) revealed that residues in 3BNC117 HFR3 interact favorably with binding site elements including H71a with N197 glycan and W71d with Env 308 (32%R & 39%H) on the adjacent gp120 protomer. Comparison with generated cryoEM structure of BG505 SOSIP.664-3BNC117-PGT145 (resolution of ˜4.3A) revealed that 3BNC117-binding induced subtle increase in spacing between N160 glycan triad which would provide greater apical site access for PGT145. Lee2017 (antibody binding site, structure)
3BNC117: Humanized mice were grafted with CD34+ T cells isolated from human umbilical cords, and later challenged by intra-rectal infection with HIV-1 strain NL4-3. Mice treated with a mix of 3 bNAbs (10-1074, 3BNC117, and SF12) resisted mucosal infection. Vanshylla2021 (neutralization, immunotherapy)
3BNC117: 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)
3BNC117: A novel CD4bs bNAb, 1-18, is identified with breadth (97% against a 119-strain multiclade panel) and potency (IC₅₀ = 0.048 µg/mL) exceeding most V_H1-46 and V_H1-2 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. While 1-18 targets the CD4bs like VRC01-like Abs, it recognizes the epitope differently. Neutralizing activity against VRC01 Ab-class escapes is maintained by 1-18. In humanized mice infected by strain 1_YU2, viral suppression is also maintained by 1-18. V_H1-46-derived B cell clone 4.1 from patient IDC561 produced potent, broadly active Abs. 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 BG505_SOSIP.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. Variation in glycosylation is thought to confer higher neutralizing activity on 1-18 over 1-55. Schommers2020 (antibody binding site, antibody generation, antibody interactions, neutralization, escape, binding affinity, antibody sequence, structure, broad neutralizer, contact residues)
3BNC117: 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 increasing their effectiveness as a vaccine. Castillo-Menendez2019 (vaccine antigen design, structure)
3BNC117: 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-enriched 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)
3BNC117: A dose-escalation phase 1b study in HIV-1-infected individuals to evaluate the safety, pharmacokinetics and antiretroviral activity of the combination of the Abs 3BNC117 and 10–1074 has been reported. Participants in groups 1A and 1B were virologically suppressed on ART and were randomized in a 2:1 ratio to receive one intravenous infusion of each of 3BNC117 and 10–1074 or placebo. Viremic individuals off ART were enrolled in group 1C or group 3, and received one intravenous infusion (group 1C) or three intravenous infusions (group 3, every two weeks) of each 3BNC117 and 10–1074. The combination of 3BNC117 and 10–1074 was more effective in suppressing viremia than either antibody alone. However, 3BNC117 and 10–1074 infusions failed to suppress viremia to undetectable levels in the two dual antibody-sensitive individuals with the highest pre-infusion viral load despite persistent reductions for up to 12 weeks. Bar-On2018 (neutralization, immunotherapy, HAART, ART)
3BNC117: 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 3BNC117 and can neutralize the CH505 TF (IC50 0.03 mg/mL). 3BNC117 has reduced breadth and potency against C clade viruses. Bricault2019 (antibody binding site, vaccine antigen design, computational epitope prediction, broad neutralizer)
3BNC117: 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 all 3 regimens were able to outcompete 3BNC117 binding to C97 gp140, suggesting that the sera contains antibodies that bind in the vicinity of CD4bs. Bricault2018 (antibody generation, vaccine-induced immune responses, polyclonal antibodies)
3BNC117: 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. 3BNC117 + CAP256-VRC26.25 was the most potent combination against subtype D. Wagh2018 (immunotherapy)
3BNC117: 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. 3BNC117 was used in analysis of monoclonal bNAb combinations. Hraber2018 (assay or method development, neutralization)
3BNC117: 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)
3BNC117: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. 3BNC117 was isolated from human B cell clones and is functionally similar to VRC01. Both 3BNC117 and 3BNC117-LS are in Phase I clinical trials (Table 2). Antigenic region CD4 binding site (Table:1). Walker2018 (antibody binding site, review, broad neutralizer)
3BNC117: 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)
3BNC117: 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)
3BNC117: 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 3BNC117 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 (binding affinity, structure)
3BNC117: M428L and N434S mutations [referred to as “LS”] were introduced into the genes encoding the crystallizable fragment domains of 3BNC117 and 10-1074 bNAbs to increase their half-lives. The efficacy of modified bNAbs in blocking infections following repeated low dose mucosal challenges of rhesus macaques with the Tier 2 SHIVAD8-EO was evaluated. The most striking result was the long period of protective efficacy conferred by a single injection of crystallizable fragment domain-modified hbNAbs in macaques compared to that previously reported. A single intravenous infusion of the 10-1074-LS bNAb protected a cohort of 6 monkeys for up to 8.5 months (18 to 37 weeks). LS mutation in 10-1074 lengthened the median time until SHIVAD8-EO acquisition from 12.5 to 27 weeks, with 10-1074-LS bNAb measurable in the serum for 26 to 41 weeks and a calculated half-life of 3.8 weeks. The effects of the LS change on 3BNC117 were more modest than 10-1074, with a shorter half-life (2.6 versus 3.8 weeks), smaller increase in half-life (2 vs. 3.8-fold), and lower initial serum concentrations. Gautam2018 (immunoprophylaxis)
3BNC117: 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)
3BNC117: Early administration of bNAbs in a macaque-SHIV model is associated with a persistent very low level of viremia resulting in long-term infection control. Passive combination immunotherapy of 3BNC117 and 10-1074, 3 days after intrarectal infection, and targeting non-overlapping epitopes on the Env spike effected viremic suppression for 56-177 days, with rebound directly correlated to plasma concentration of bNAb. On day 56 macaque MVJ experienced SHIV_AD8-EO rebound when plasma 3BNC117 decayed below 1 µg/ml. Nishimura2017 (acute/early infection, immunotherapy)
3BNC117: 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 epitope prediction)
3BNC117: 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)
3BNC117: 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)
3BNC117: 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)
3BNC117: Infusions of 3BNC117 were given to 13 HIV-infected individuals during analytical treatment interruption. The antibody was well tolerated. Infusions were associated with a delay in viral rebound. In most individuals, rebound viruses showed increased resistance to 3BNC117, but in 30% of patients the virus showed no sign of escape over a period of 9-19 weeks. Scheid2016 (escape, immunotherapy)
3BNC117: 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)
3BNC117: This review classified and mapped the binding regions of 32 bNAbs isolated 2010-2016. Wu2016 (review)
3BNC117: 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, NIH45-46^G54W, and to a lesser extent 3BNC117. Gardner2016 (antibody interactions)
3BNC117: 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 (ADCC)
3BNC117: 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)
3BNC117: bNAbs were found to have potent activating but not inhibitory FcγR-mediated effector function that can confer protection by blocking viral entry or suppressing viremia. bNAb activity is augmented with engineered Fc domains when assessed in in vivo models of HIV-1 entry or in therapeutic models using HIV-1-infected humanized mice. Enhanced FcγR engagement is not restricted by epitope specificity or neutralization potency as chimeras composed of human anti-CD4bs 3BNC117 Fab and mouse Fc had improved or reduced in vivo activity depending on the Fc used. Bournazos2014 (neutralization, chimeric antibody)
3BNC117: 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, 3BNC117 recognizes trimer similarly to CH103, CH106, 1NC9 and VRC01, and is inhibited by sCD4. It enhanced binding of several V1/V2-glycan, V3-glycan or outer domain (OD)-glycan bNAbs; and 3BNC117 binding is enhanced by Ab 8ANC195. OD-glycan bNAbs, PGT135 and PGT136, though ˜ 5x less efficient binders of trimer, were able to unidirectionally inhibit binding of 3BNC117, as also other CD4bs bNAbs, VRC01, 2BNC60, NIH45-46. 3BNC117, alongwith 1NC9 differs slightly from more typical CD4bs bNAbs by its dependence on N-276 glycan. Derking2015 (antibody interactions, neutralization, binding affinity, structure)
3BNC117: 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 2BNC117 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)
3BNC117: 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. 3BNC117 is a CD4bs-specific bnAb that has been administered in both primate and human trials. Stephenson2016 (immunotherapy, review)
3BNC117: 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)
3BNC117: 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)
3BNC117: 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 3BNC117 was able to neutralize only 1/16 tested non-M primary isolates at an IC₅₀< 10µg/ml, RBF208,M/O at 0.63 µg/ml. Morgand2015 (neutralization, subtype comparisons)
3BNC117: 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. 3BNC117, a CD4bs bnAb belonged to a group with slopes >1. Webb2015 (neutralization)
3BNC117: 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. The overall charge on 3BNC117 is +5, average for VRC01-class antibodies. It requires the A61P substitution in mature bNAb for maximal neutralization, even though it thermally destabilizes the helix in that part of 3BNC117. Scharf2016 (structure)
3BNC117: The dynamics and characteristics of anti-antibody responses were described for monkeys that received adenovirus-mediated delivery of either rhesus anti-SIV antibody constructs (4L6 or 5L7) in prevention trials, or a combination of rhesusized human anti-HIV antibodies (1NC9/8ANC195/3BNC117 or 10-1074/10E8/3BNC117) in therapy trials. Anti-antibody responses to the human mAbs were correlated to the distance from the germline Ab sequences. Martinez-Navio2016 (immunotherapy)
3BNC117: Based on the results of 3BNC117 administered to human subjects, mathematical modeling was unable to recapitulate the kinetics of the viral decline. Revision of the model to fit the data suggested that the antibody may clear infected cells, in addition to neutralizing free virions. In in vitro experiments, 3BNC177, PG16, and 10-1074 were able to stain cells infected with HIV-1 YU2. Both 3BNC117 and 10-1074 recognized cells infected with primary virus isolates from human subjects that had been previously infused with 3BNC117. Either 3BNC117 alone, or in combination with 10-1074, was able to accelerate the clearance of YU2-infected cells in humanized mice, decreasing the half life of the infected cell. This result was shown to be mediated by the Fc-gamma receptor. Lu2016 (ADCC, immunotherapy)
3BNC117: A single infusion of 3BNC117 was administered to 27 HIV-1-infected individuals. Analysis of env sequences over time revealed significant increases in sequence diversity. Improved neutralizing responses to tier-2 viruses were seen in nearly all study subjects over a 6-month period, while untreated individuals showed little change. Viremic individuals receiving 3BNC117, however, produced Abs to autologous virus that were sensitive or resistant. It is unknown how passively-administered antibodies accelerate the emergence of bnAbs, but this appears to be the case. Schoofs2016 (immunotherapy)
3BNC117: 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 viruses, neutralizing 70% of a clade-B pseudovirus panel and 6 out of 9 cross-clade Env pseudoviruses as opposed to bNAb 3BNC117's neutralizing 7/9 of the same psuedoviral panel. Freund2015 (neutralization, broad neutralizer)
3BNC117: 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 3BNC117 had strong ADCC. Bruel2016 (ADCC, binding affinity)
3BNC117: 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 3BNC117 was the first to be tested in a human trial and has also shown promising results in studies in humanized mice and macaques. Halper-Stromberg2016 (immunotherapy, review)
3BNC117: 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 3BNC117 heavy and light chains and binding surfaces were reported (Table-S5). Wu2015 (structure, antibody lineage)
3BNC117: Four bNAbs (VRC01, VRC01-LS, 3BNC117, and 10-1074) were administered, singly or in combination, to macaques, followed by weekly challenges with clade B SHIV_AD8. 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)
3BNC117: 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. 3BNC117 was one of the antibodies in the VH gene restricted, 8ANC131-like class. Zhou2015 (neutralization, structure, antibody lineage, broad neutralizer)
3BNC117: 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)
3BNC117: 3BNC117 infusion in humans was well tolerated, demonstrated favorable pharmacokinetics, and reduced the viral load in HIV-1-infected individuals. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days, with significantly reduced viremia. Contact residues and several mutations in gp120 after immunotherapy are mentioned for different subjects, including G459D, Q363H, S461D and S274Y. Caskey2015 (immunotherapy)
3BNC117: This study reports the generation of a human CD4- and human CCR5-expressing transgenic luciferase reporter mouse that facilitates measurement of peritoneal and genitomucosal HIV-1 pseudovirus entry in vivo for the preclinical evaluation of prophylactic or vaccine candidates. The results showed that passive transfer of neutralizing Abs can protect HIV-LucTG mice from cervicovaginal infection with HIV-1 pseudoviruses. Gruell2013 (genital and mucosal immunity, immunotherapy)
3BNC117: 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)
3BNC117_dRU3: 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 this Ab. Zhou2013a (antibody sequence, structure, antibody lineage)
3BNC117: 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.) 3BNC117 was used to compare the heavy & light chain sequences as a template of VRC01 class Ab. Its crystal structure was studied. Zhu2013a (antibody sequence, structure)
3BNC117: Profound therapeutic efficacy of PGT121 and PGT121-containing monoclonal antibody cocktails was demonstrated in chronically SHIV-SF162P3 infected rhesus monkeys. Cocktails included 1, 2, and 3 mAb combinations of PGT121, 3BNC117 and b12. Cocktails including PGT121 were efficient, 3BNC117 alone resulted in only a transient small reduction of plasma viral loads. Barouch2013a (immunotherapy)
3BNC117: 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 3BNC117, against 181 diverse HIV-1 strains with available Ab-Ag complex structures. Chuang2013 (computational epitope prediction)
3BNC117: "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 10E8-like cluster. Georgiev2013 (neutralization)
3BNC117: 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, neutralization, escape, polyclonal antibodies)
3BNC117: 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 epitope prediction)
3BNC117: 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, 3BNC117 family. Kwong2012 (review, structure, broad neutralizer)
3BNC117: 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) and 454 deep sequencing. Bonsignori2012b (vaccine antigen design, vaccine-induced immune responses, review)
3BNC117: 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. 3BNC117, a CD4Bs Ab, was among the 17 bnAbs which were used in studying the mutations in FWR. Crystal structure of 3BNC117/gp120 was compared with 3BNC60 in the context of insertion mutations in FWR and its role in increasing neutralizing activities. Klein2013 (neutralization, structure, antibody lineage)
3BNC117: 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. 3BNC117 was studied as anti-CD4BS bnAbs belongs to VRC01 class. McGuire2013 (neutralization, antibody lineage)
3BNC117: 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. 3BNC117 has been referred as a PVL in discussing the breadth and potency of antiCD4 abs. West2012a (antibody lineage)
3BNC117: A single-cell Ab cloning method is described to isolate neutralizing Abs using truncated gp160 transfected cells as bait. Among the 15 Abs reported, only two are found to be broadly neutralizing and bind to a novel conformational HIV-1 spike epitope. Klein2012 (neutralization)
3BNC117: 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. The epitopes for both groups contain a potential N-linked glycosylation site (PNGS) at Asn332gp120 and the base of the V3 loop of the gp120 subunit of the HIV spike. However, the 10-1074–like Abs required an intact PNGS at Asn332gp120 for their neutralizing activity, whereas PGT121-like antibodies were able to neutralize some viral strains lacking the Asn332gp120 PNGS. 3BNC117 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)
3BNC117: Neutralization activity was compared against MAb 10E8 and other broad and potent neutralizers in a 181-isolate Env-pseudovirus panel. 2F5 neutralized 84% of viruses at IC₅₀ <50 μg/ml and 77% of viruses at IC₅₀ <1 μg/ml, compared with 98% and 72% of MAb 10E8, respectively. Huang2012a (neutralization)
3BNC117: 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. 3BNC117 bound very strongly to the gp120 core and RSC3, strongly bound to gp120 core D368R, weakly bound to RSC3/G367R but did not bind to RSC3 Δ3711, and RSC3 Δ3711/P363N. Lynch2012 (binding affinity)
3BNC117: 576 new HIV antibodies were cloned from 4 unrelated individuals producing expanded clones of potent broadly neutralizing CD4bs antibodies that bind to 2CC core. In order to amplify highly somatically mutated immunoglobulin genes, new primer set with 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. 3BNC117 arises from IgVH1-2 and IgVK1D-33 germline genes and neutralized 100% of 118 isolates representing major HIV-1 clades, and 1/5 VRC01-resistant isolates, with IC₅₀ <50μg/ml. 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. 3BNC117 was polyreactive - reacted with dsDNA and LPS, but not with ssDNA or insulin. Scheid2011 (antibody generation, neutralization, antibody sequence, broad neutralizer)

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Barouch2013a Dan H. Barouch, James B. Whitney, Brian Moldt, Florian Klein, Thiago Y. Oliveira, Jinyan Liu, Kathryn E. Stephenson, Hui-Wen Chang, Karthik Shekhar, Sanjana Gupta, Joseph P. Nkolola, Michael S. Seaman, Kaitlin M. Smith, Erica N. Borducchi, Crystal Cabral, Jeffrey Y. Smith, Stephen Blackmore, Srisowmya Sanisetty, James R. Perry, Matthew Beck, Mark G. Lewis, William Rinaldi, Arup K. Chakraborty, Pascal Poignard, Michel C. Nussenzweig, and Dennis R. Burton. Therapeutic Efficacy of Potent Neutralizing HIV-1-Specific Monoclonal Antibodies in SHIV-Infected Rhesus Monkeys. Nature, 503(7475):224-228, 14 Nov 2013. PubMed ID: 24172905. Show all entries for this paper.

Bournazos2014 Stylianos Bournazos, Florian Klein, John Pietzsch, Michael S. Seaman, Michel C. Nussenzweig, and Jeffrey V. Ravetch. Broadly Neutralizing Anti-HIV-1 Antibodies Require Fc Effector Functions for In Vivo Activity. Cell, 158(6):1243-1253, 11 Sep 2014. PubMed ID: 25215485. Show all entries for this paper.

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. Show all entries for this paper.

Caskey2015 Marina Caskey, Florian Klein, Julio C. C. Lorenzi, Michael S. Seaman, Anthony P. West, Jr., Noreen Buckley, Gisela Kremer, Lilian Nogueira, Malte Braunschweig, Johannes F. Scheid, Joshua A. Horwitz, Irina Shimeliovich, Sivan Ben-Avraham, Maggi Witmer-Pack, Martin Platten, Clara Lehmann, Leah A. Burke, Thomas Hawthorne, Robert J. Gorelick, Bruce D. Walker, Tibor Keler, Roy M. Gulick, Gerd Fätkenheuer, Sarah J. Schlesinger, and Michel C. Nussenzweig. Viraemia Suppressed in HIV-1-Infected Humans by Broadly Neutralizing Antibody 3BNC117. Nature, 522(7557):487-491, 25 Jun 2015. PubMed ID: 25855300. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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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. Show all entries for this paper.

Gautam2018 Rajeev Gautam, Yoshiaki Nishimura, Natalie Gaughan, Anna Gazumyan, Till Schoofs, Alicia Buckler-White, Michael S. Seaman, Bruce J. Swihart, Dean A. Follmann, Michel C. Nussenzweig, and Malcolm A. Martin. A Single Injection of Crystallizable Fragment Domain-Modified Antibodies Elicits Durable Protection from SHIV Infection. Nat. Med., 24(5):610-616, May 2018. PubMed ID: 29662199. Show all entries for this paper.

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LaBranche2018 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. Show all entries for this paper.

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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. Show all entries for this paper.

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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. Show all entries for this paper.

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Nishimura2017 Yoshiaki Nishimura, Rajeev Gautam, Tae-Wook Chun, Reza Sadjadpour, Kathryn E. Foulds, Masashi Shingai, Florian Klein, Anna Gazumyan, Jovana Golijanin, Mitzi Donaldson, Olivia K. Donau, Ronald J. Plishka, Alicia Buckler-White, Michael S. Seaman, Jeffrey D. Lifson, Richard A. Koup, Anthony S. Fauci, Michel C. Nussenzweig, and Malcolm A. Martin. Early Antibody Therapy Can Induce Long-Lasting Immunity to SHIV. Nature, 543(7646):559-563, 23 Mar 2017. PubMed ID: 28289286. Show all entries for this paper.

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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. Show all entries for this paper.

Sather2012 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. Show all entries for this paper.

Scharf2016 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. Show all entries for this paper.

Scheid2016 Johannes F. Scheid, Joshua A. Horwitz, Yotam Bar-On, Edward F. Kreider, Ching-Lan Lu, Julio C. C. Lorenzi, Anna Feldmann, Malte Braunschweig, Lilian Nogueira, Thiago Oliveira, Irina Shimeliovich, Roshni Patel, Leah Burke, Yehuda Z. Cohen, Sonya Hadrigan, Allison Settler, Maggi Witmer-Pack, Anthony P. West, Jr., Boris Juelg, Tibor Keler, Thomas Hawthorne, Barry Zingman, Roy M Gulick, Nico Pfeifer, Gerald H. Learn, Michael S. Seaman, Pamela J. Bjorkman, Florian Klein, Sarah J. Schlesinger, Bruce D. Walker, Beatrice H. Hahn, Michel C. Nussenzweig, and Marina Caskey. HIV-1 Antibody 3BNC117 Suppresses Viral Rebound in Humans during Treatment Interruption. Nature, 535(7613):556-560, 28 Jul 2016. PubMed ID: 27338952. Show all entries for this paper.

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. Show all entries for this paper.

Schoofs2016 Till Schoofs, Florian Klein, Malte Braunschweig, Edward F. Kreider, Anna Feldmann, Lilian Nogueira, Thiago Oliveira, Julio C. C. Lorenzi, Erica H. Parrish, Gerald H. Learn, Anthony P. West, Jr., Pamela J. Bjorkman, Sarah J. Schlesinger, Michael S. Seaman, Julie Czartoski, M. Juliana McElrath, Nico Pfeifer, Beatrice H. Hahn, Marina Caskey, and Michel C. Nussenzweig. HIV-1 Therapy with Monoclonal Antibody 3BNC117 Elicits Host Immune Responses against HIV-1. Science, 352(6288):997-1001, 20 May 2016. PubMed ID: 27199429. Show all entries for this paper.

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. Show all entries for this paper.

Vanshylla2021 Kanika Vanshylla, Kathrin Held, Tabea M Eser, Henning Gruell, Franziska Kleipass, Ricarda Stumpf, Kanika Jain, Daniela Weiland, Jan Münch, Berthold Grüttner, Christof Geldmacher, and Florian Klein. CD34T+ Humanized Mouse Model to Study Mucosal HIV-1 Transmission and Prevention. Vaccines, 9(3), 27 Feb 2021. PubMed ID: 33673566. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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 doi, 2021. PubMed ID: 34603284 Show all entries for this paper.

Pinto2019 Dora Pinto, Craig Fenwick, Christophe Caillat, Chiara Silacci, Serafima Guseva, Francois Dehez, Christophe Chipot, Sonia Barbieri, Andrea Minola, David Jarrossay, Georgia D. Tomaras, Xiaoying Shen, Agostino Riva, Maciej Tarkowski, Olivier Schwartz, Timothee Bruel, Jeremy 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):623-637e8 doi, Nov 2019. PubMed ID: 31653484 Show all entries for this paper.

Zhang2022 Baoshan Zhang, Jason Gorman, Sijy O’Dell, Leland F. Damron, Krisha McKee, Mangaiarkarasi Asokan, 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, , :, 22 Apr 2022. Show all entries for this paper.

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 doi, 2021. PubMed ID: 34322136 Show all entries for this paper.

Displaying record number 2651

Download this epitope record as JSON.

MAb ID	PGT145 (PGT-145)
HXB2 Location	gp160	gp160 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	antibody binding site, antibody gene transfer, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autoantibody or autoimmunity, binding affinity, broad neutralizer, computational epitope prediction, elite controllers, escape, glycosylation, immunoprophylaxis, immunotherapy, neutralization, polyclonal antibodies, rate of progression, review, structure, subtype comparisons, therapeutic vaccine, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity

Notes

Showing 72 of 72 notes.

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 CD4 receptor binding site 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, whose serum had broad neutralization. The Env sequences of EN3 had much fewer polymorphisms, compared to those of a normal progressor, EN1, 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, 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. bNAbs with >25% breadth of neutralization belonged to 20 classes of antibody with a large number of protruding loops and somatic hypermutation (SHM). HIV epitopes recognized 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 increasing 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 (antibody interactions, variant cross-reactivity, binding affinity, structure, broad neutralizer)
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, vaccine antigen design, computational epitope 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: The DS-SOSIP.4mut is a soluble, closed pre-fusion-state HIV-1 Env trimer that has improved stability and immunogenicity. It has 4 specific alterations at M154, M300, M302 and L320. PGT145 recognizes this trimer antigenically. Chuang2017 (antibody interactions)
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 epitope 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 epitope 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. Ethnically, 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, 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, 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-gp41_ECTO 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 (neutralization, 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 epitope 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 V_H 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 V_H replacements. The details of PGT145 V_H 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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Isolation Paper
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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

Verkerke2016 Hans P. Verkerke, James A. Williams, Miklos Guttman, Cassandra A. Simonich, Yu Liang, Modestas Filipavicius, Shiu-Lok Hu, Julie Overbaugh, and Kelly K. Lee. Epitope-Independent Purification of Native-Like Envelope Trimers from Diverse HIV-1 Isolates. J. Virol., 90(20):9471-9482, 15 Oct 2016. PubMed ID: 27512064. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

Stanfield2020 Robyn L. Stanfield, Zachary T. Berndsen, Ruiqi Huang, Devin Sok, Gabrielle Warner, Jonathan L. Torres, Dennis R. Burton, Andrew B. Ward, Ian A. Wilson, and Vaughn V. Smider. Structural basis of broad HIV neutralization by a vaccine-induced cow antibody. Sci Adv, 6(22):eaba0468 doi, May 2020. PubMed ID: 32518821 Show all entries for this paper.

Displaying record number 3147

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MAb ID	35O22 (35022)
HXB2 Location	gp160	gp160 Epitope Map
Author Location
Epitope	(Discontinuous epitope)
Subtype	B
Ab Type	gp41-gp41 interface
Neutralizing	P (tier 2) View neutralization details
Contacts and Features	View contacts and features
Species (Isotype)	human(IgG)
Patient	Donor N152
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 epitope prediction, elite controllers, escape, glycosylation, immunoprophylaxis, neutralization, polyclonal antibodies, review, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses

Notes

Showing 31 of 31 notes.

35022: 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 CD4 receptor binding site with no contact of the other CDRs to the rest of the Env trimer. Stanfield2020 (structure)
35O22: 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. bNAbs with >25% breadth of neutralization belonged to 20 classes of antibody with a large number of protruding loops and somatic hypermutation (SHM). HIV epitopes recognized 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. 35O22-Env formed a distinct group within the Subunit Interface category, Class 35O22. Data for 35O22 complexed to (i) Clade G X1193.ct SOSIP.664 prefusion trimer as a 3.4A resolution crystal structure was found in PDB ID: 5FYJ; (ii) Clade A BG505 SOSIP.664 trimer was found in PDB ID: 5FYL; and (iii) PDB ID: 5CEZ. Chuang2019 (antibody binding site, antibody interactions, neutralization, binding affinity, antibody sequence, structure, antibody lineage, broad neutralizer)
35O22: 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, whose serum had broad neutralization. The Env sequences of EN3 had much fewer polymorphisms, compared to those of a normal progressor, EN1, 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, neutralization, vaccine antigen design, polyclonal antibodies)
35O22: 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 increasing their effectiveness as a vaccine. 35O22 broadly neutralized HIV-1AD8 full-length and cytoplasmic tail-deleted Envs. Castillo-Menendez2019 (vaccine antigen design, structure)
35O22: 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 gp120-gp41 interface recognized by PGT151 and 35O22, 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)
35O22: 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. 35O22 was used as a reference Ab. Crooks2015 (glycosylation, neutralization)
35O22: This review discusses how the identification of super-antibodies, where and how such antibodies may be best applied and future directions for the field. 35O22, a prototype super-Ab, was isolated from human B cell clones. Antigenic region gp120–gp41 interface (Table:1). Walker2018 (antibody binding site, review, broad neutralizer)
35O22: 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)
35O22: 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 35O22 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)
35O22: 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-gp41-gp120 interface NAb 35O22, 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)
35O22: The DS-SOSIP.4mut is a soluble, closed pre-fusion-state HIV-1 Env trimer that has improved stability and immunogenicity. It has 4 specific alterations at M154, M300, M302 and L320. 35O22 recognizes this trimer antigenically. Chuang2017 (antibody interactions)
35O22: 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)
35O22: 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, structure)
35O22: 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)
35O22: 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 epitope prediction)
35O22: A weakly neutralizing antibody was isolated, CAP248-2B. The glycan dependence of CAP248-2B was compared to other known gp120-gp41 interface targeting bNAbs (8ANC195, 35O22, PGT151, 3BC315). CAP248-2B blocks the binding of 35O22, 3BC315, and PGT151 (but not 8ANC195 or 4E10) to cell surface envelope trimers. Wibmer2017 (antibody interactions)
35O22: This review classified and mapped the binding regions of 32 bNAbs isolated 2010-2016. Wu2016 (review)
35O22: 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)
35O22: 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)
35O22: 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. gp120-gp41 Ab, 35O22 did not bind cell surface whether gp160 was missing C-terminal or not, but did weakly neutralize 92UG037.8 HIV-1 isolate. Chen2015 (neutralization, binding affinity)
35O22: 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). gp120-gp41_ECTO interface glycan bNAb, 35O22, was not able to neutralize or bind B41 pseudovirus and trimer. Pugach2015
35O22: 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
35O22: 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 gp120-gp41_ECTO binding bNAbs, 35O22 reciprocally competes 8ANC195, but not PGT151. Surprisingly, 35O22 was competed out in a non-reciprocal manner by anti-V1/V2 glycan NAb, PGT145. Derking2015 (antibody interactions, neutralization, binding affinity, structure)
35O22: 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 trimers have no affinity for the gp120-gp41 interface-binding NAb 35O22 and their pseudo typed viruses were not neutralized by 35O22. Julien2015 (assay or method development, structure)
35O22: 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 bNAb 35O22 to trimers was unaffected by trimer cross-linking. Schiffner2016 (assay or method development, binding affinity, structure)
35O22: 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 11/20 BG505 SOSIP.664-D7324 trimer-immunized rabbits were capable of inhibiting 35O22 binding to gp120-gp41 interface epitopes, but most gp140-immunized and all gp120-immunized sera could not. Sanders2015 (antibody generation, neutralization, binding affinity, polyclonal antibodies)
35O22: Structural analyses mapped the epitopes of 3BC315 and 3BC176 using their Fabs bound to BG505.SOSIP.664. A conserved glycan at N88 was shown to play a role in the binding kinetics of the 2 mAbs. 3BC315 binds between two gp41 subunits and neutralizes the virus by accelerating trimer decay; this modality is unlike other between-subunit mAbs such as 35O22, though all 3 bnAbs do not require MPER to bind. Lee2015 (antibody binding site, structure)
35O22: 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. bNAb 35O22 was able to neutralize 1/16 tested non-M primary isolates at an IC₅₀< 10µg/ml, YBF16,O at 1.44 µg/ml. Morgand2015 (neutralization, subtype comparisons)
35O22: 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. gp41 and interface-binding gl-35O22 did not bind any trimers. Sliepen2015 (binding affinity, antibody lineage)
35O22: 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)
35O22: This is a broad and extremely potent MAb (62% of 181 viruses neutralized with median IC₅₀ 0.033 μg/ml), isolated from the same donor, N152, as for MAb 10E8. 35O22 did not bind monomeric Env, but bound the trimeric BG505 SOSIP.664 at the new site of HIV vulnerability, which includes 4 potential N-linked glycosylation sites N88, N230, N241, N625 as determined by alanine substitution. These sites are in close proximity to the 35O22 heavy chain in the structure reconstructed from images of the 35O22 - BG505 SOSIP.664 complex. N230Q, N624D, and especially N625Q mutations were present in the patient's autologous plasma virus and diminished neutralization when introduced into HIV pseudoviruses, suggesting escape. This MAb derives from IGHV-1-18*02 and IGLV-2-14*02 germline genes, is highly somatically mutated, has CDR H3 composed of 14 amino acids, and an insertion of 8 amino acids in FR3. Huang2014 (antibody binding site, antibody generation, glycosylation, neutralization, escape, structure)

References

Showing 32 of 32 references.

Isolation Paper
Huang2014 Jinghe Huang, Byong H. Kang, Marie Pancera, Jeong Hyun Lee, Tommy Tong, Yu Feng, Ivelin S. Georgiev, Gwo-Yu Chuang, Aliaksandr Druz, Nicole A. Doria-Rose, Leo Laub, Kwinten Sliepen, Marit J. van Gils, Alba Torrents de la Peña, Ronald Derking, Per-Johan Klasse, Stephen A. Migueles, Robert T. Bailer, Munir Alam, Pavel Pugach, Barton F. Haynes, Richard T. Wyatt, Rogier W. Sanders, James M. Binley, Andrew B. Ward, John R. Mascola, Peter D. Kwong, and Mark Connors. Broad and Potent HIV-1 Neutralization by a Human Antibody That Binds the gp41-gp120 Interface. Nature, 3 Sep 2014. PubMed ID: 25186731. Show all entries for this paper.

Barnes2018 Christopher O. Barnes, Harry B. Gristick, Natalia T. Freund, Amelia Escolano, Artem Y. Lyubimov, Harald Hartweger, Anthony P. West, Jr., Aina E. Cohen, Michel C. Nussenzweig, and Pamela J. Bjorkman. Structural Characterization of a Highly-Potent V3-Glycan Broadly Neutralizing Antibody Bound to Natively-Glycosylated HIV-1 Envelope. Nat. Commun., 9(1):1251, 28 Mar 2018. PubMed ID: 29593217. Show all entries for this paper.

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. Show all entries for this paper.

Displaying record number 2580

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MAb ID	NIH45-46 (45-46, 45)
HXB2 Location	Env	Env Epitope Map
Author Location
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	ADCC, antibody binding site, antibody gene transfer, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autoantibody or autoimmunity, binding affinity, broad neutralizer, chimeric antibody, computational epitope prediction, germline, glycosylation, immunoprophylaxis, immunotherapy, memory cells, neutralization, review, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity

Notes

Showing 44 of 44 notes.

NIH45-46: 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 CD4 receptor binding site with no contact of the other CDRs to the rest of the Env trimer. Contact residues were shown for structures of NC-Cow1, CD4, NIH45-46, and VRC13. Stanfield2020 (antibody binding site)
NIH45-46: 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. NIH45-46 was used for analyzing clade sensitivity and the CD4bs signature summaries. Bricault2019 (antibody binding site, vaccine antigen design, computational epitope prediction, broad neutralizer)
NIH45-46: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. NIH45-46 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)
NIH45-46: 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)
NIH45-46: 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 NIH45-46 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)
NIH45-46: Assays of poly- and autoreactivity demonstrated that broadly neutralizing NAbs are significantly more poly- and autoreactive than non-neutralizing NAbs. NIH45-46 is polyreactive, but not autoreactive. Liu2015a (autoantibody or autoimmunity, antibody polyreactivity)
NIH45-46: 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)
NIH45-46: 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, NIH45-46^G54W, and to a lesser extent 3BNC117. Gardner2016 (antibody interactions)
NIH45-46: 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, NIH45-46 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)
NIH45-46: 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. As with CD4bs binding bNAbs, NIH45-46 is inhibited by sCD4. It enhanced binding of several V1/V2-glycan, V3-glycan or outer domain (OD)-glycan bNAbs; and also modestly enhanced binding of non-NAb, 17b. OD-glycan bNAbs, PGT135 and PGT136, though ˜ 5x less efficient binders of trimer, were able to unidirectionally inhibit binding of NIH45-46, as also other CD4bs bNAbs, VRC01, 2BNC60, 3BNC117. Derking2015 (antibody interactions, neutralization, binding affinity, structure)
NIH45-46: 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 trimers have high affinity for bNAb NIH45-46, and the structure of a complex of ZM197M SOSIP.664 with NIH45-46 single-chain Fv at 4.4 A by X-ray crystallography had a 0.95 correlation with the structure of the Clade A trimer. Julien2015 (assay or method development, structure)
NIH45-46: 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 NIH45-46 to trimers was minimally affected by trimer cross-linking. Schiffner2016 (assay or method development, binding affinity, structure)
NIH45-46: 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 NIH45-46 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)
NIH45-46: VRC01-class bNAb like NIH45-46 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)
NIH45-46: 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. NIH45-46 was the most active antibody preventing the cell to cell transmission of virus. Malbec2013
NIH45-46: 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)
NIH45-46: 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 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)
NIH45-46: 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 NIH45-46 had strong ADCC. Bruel2016 (ADCC, binding affinity)
NIH45-46: 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%). NIH45-46 appeared to be somatic variants from a single VRC01 lineage. Wu2015 (antibody lineage)
NIH45-46: 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. CNAE08,CNAE14, CNAE17, and CNAE31 were all shown to be highly resistant to NIH45-46. Chen2016 (neutralization, subtype comparisons)
NIH45-46: 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)
NIH45-46: 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 CD4BS antibodies b12, 2G12 and NIH45-46. Upadhyay2014 (glycosylation, neutralization)
NIH45-46: A set of potent VRC01-like (PVL) MAbs were generated from VRC01-derivatve NIH45-46^G54W and they were more potent than even NIH45-46 or NIH45-46^G54W, 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 (antibody generation, variant cross-reactivity, structure)
NIH45-46: Envs from clades A, B and C were screened for binding to the germline predecessors of anti-CD4bs bNAbs b12, NIH45-46 and 3BNC60. Mature Abs reacted with diverse Envs, but not the germ-line Abs. Engineered chimeric Abs with mature and germ-line heavy and light chain combinations showed the importance of both mature chains for the cross-reactivity. Hoot2013 (antibody lineage, chimeric antibody)
NIH45-46: The structures of germline Ab VH1-2*02 alone and a chimeric germline heavy chain/mature light chain NIH45-46 MAb complexed with gp120 are reported. VH1-2*02 residues make extensive contacts, but not the critical CDRH3 contacts with gp120 inner domain, which confer improved potency to NIH45-46. Scharf2013 (structure)
NIH45-46: 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.) NIH45-46 was used to compare the heavy & light chain sequences as a template of VRC01 class Ab. Zhu2013a (antibody sequence)
NIH45-46: This is a review of a satellite symposium at the AIDS Vaccine 2012 conference, focusing on antibody gene transfer. Pamela Bjorkman presented studies that have used structure-based design to improve the potency of antibodies to the CD4-binding site on gp120, as well as to overcome the common escape mutations the virus acquires to evade such antibodies. MAb 45-46m2, neutralized 96% of HIV strains in a cross-clade panel and neutralized a set of viral isolates resistant to all other known broadly neutralizing antibodies. A second variant, 45-46m7, designed to thwart resistance to the engineered antibody NIH45-46G54W, restores the neutralization of consensus escape mutants and thus effectively targets a common route of viral escape from this class of antibodies. 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)
NIH45-46: 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, NIH45-46, against 181 diverse HIV-1 strains with available Ab-Ag complex structures. Chuang2013 (computational epitope prediction)
NIH45-46: "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)
NIH45-46: 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. NIH45-46 was mentioned in the context of CD4 binding sites. Korkut2012 (structure)
NIH45-46: 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 epitope prediction)
NIH45-46: 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)
NIH45-46: 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) and 454 deep sequencing. Bonsignori2012b (vaccine antigen design, vaccine-induced immune responses, review)
NIH45-46: 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. NIH45-46, a CD4Bs Ab, was among the 17 bnAbs which were used in studying the mutations in FWR. NIH 45-46 was used in comparing the Ab framework amino acid replacement vs. interactive surface area on Ab. Klein2013 (neutralization, structure, antibody lineage)
NIH45-46: 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 of Clade C Env 426c increases NIH45-46 binding. McGuire2013 (neutralization, antibody lineage)
NIH45-46: 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 NIH45-46 mature and germline antibodies. Jardine2013 (glycosylation, vaccine antigen design, structure, antibody lineage)
NIH45-46: 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)
NIH45-46: 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. NIH45-46 has been referred as a PVL in discussing the breadth and potency of antiCD4 abs. Sequences of VRC01, NIH45-46 and VRC-PG04 revealed a striking correlation for the length of CDRL3 (5 residues). West2012a (antibody lineage)
NIH45-46: The use of computationally derived B cell clonal lineages as templates for HIV-1 immunogen design is discussed. NIH45046 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)
45-46: 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. 45-46 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)
NIH45-46: Neutralization activity was compared against MAb 10E8 and other broad and potent neutralizers in a 181-isolate Env-pseudovirus panel. 2F5 neutralized 85% of viruses at IC50<50 μg/ml and 76% of viruses at IC50<1 μg/ml, compared with 98% and 72% of MAb 10E8, respectively. Huang2012a (neutralization)
NIH45-46: 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. NIH45-46 bound very strongly to the gp120 core and RSC3, weakly bound to RSC3/G367R but did not bind to gp120 core D368R, RSC3 Δ3711, and RSC3 Δ3711/P363N. Lynch2012 (binding affinity)
NIH45-46: The crystal structure of the NIH45-46–gp120 complex verified that NIH45-46 targets the CD4bs. The primary binding surface is the outer domain, including the CD4 binding loop, loop D, and loop V5, but CDRH3_NIH45-46 reaches toward the gp120 inner domain. The most notable difference between NIH45-46 and VRC01 is the four-residue insertion in CDRH3 (residues 99a-99d), which contributes to increased interaction between NIH45-46 and the gp120 inner domain, correlated with enhanced neutralization. Structure-based design was used to create several NIH45-46 mutants with a single substitution at position 54 in CDRH2 to increase contact with the gp120 bridging sheet. NIH45-46_G54W was significantly more potent than NIH45-46_G54. On a panel of 82 viruses from all clades, including NIH45-46-sensitive, resistant and weakly neutralized strains, NIH45-46_G54W gained de novo neutralization activity against 6 NIH45-46–resistant strains, including 3 that were sensitive to VRC01 but resistant to NIH45-46, and for some strains that NIH45-46 neutralizes poorly, NIH45-46_G54W was significantly more potent. Diskin2011 (antibody binding site, neutralization, structure)
NIH45-46: 576 new HIV antibodies were cloned from 4 unrelated individuals producing expanded clones of potent broadly neutralizing CD4bs antibodies that bind to 2CC core. In order to amplify highly somatically mutated immunoglobulin genes, new primer set with 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. NIH45-46, a new more potent clonal variant of VRC01, arises from IgVH1-2 and IgVK3-11 germline genes and neutralized 100% of 118 isolates representing major HIV-1 clades, with IC50<50μg/ml. NIH45-46 was more potent than VRC01 on 62 of the viruses tested but still less potent than 3BNC117. NIH45-46 was polyreactive - reacted with dsDNA, LPS, ssDNA and insulin. Scheid2011 (antibody generation, neutralization, antibody sequence, antibody polyreactivity, broad neutralizer)

References

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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. Show all entries for this paper.

Korkut2012 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. Show all entries for this paper.

Liao2013 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. Show all entries for this paper.

Malbec2013 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. Show all entries for this paper.

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. Show all entries for this paper.

Scharf2013 Louise Scharf, Anthony P. West, Jr., Han Gao, Terri Lee, Johannes F. Scheid, Michel C. Nussenzweig, Pamela J. Bjorkman, and Ron Diskin. Structural Basis for HIV-1 gp120 Recognition by a Germ-Line Version of a Broadly Neutralizing Antibody. Proc. Natl. Acad. Sci. U.S.A., 110(15):6049-6054, 9 Apr 2013. PubMed ID: 23524883. Show all entries for this paper.

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. Show all entries for this paper.

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. Show all entries for this paper.

Displaying record number 2582

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MAb ID	3BNC60
HXB2 Location	Env	Env Epitope Map
Author Location
Epitope
Ab Type	gp120 CD4BS
Neutralizing	P View neutralization details
Contacts and Features	View contacts and features
Species (Isotype)	human(IgG)
Patient	Patient 3
Immunogen	HIV-1 infection
Keywords	antibody binding site, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, binding affinity, broad neutralizer, chimeric antibody, germline, glycosylation, HIV-2, neutralization, review, structure, vaccine antigen design

Notes

Showing 26 of 26 notes.

3BNC60: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. 3BNC60 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)
3BNC60: 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)
3BNC60: 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)
3BNC60: Relationship between precursor frequency and antigen binding affinity and how it affects germinal center (GC) B cell recruitment and clonal expansion was examined through adoptive transfer experiments using 3BNC60ˆ{SI} knock-in B cells that carry a synthetic intermediate in the pathway to anti–HIV-1 bNAb development. The data indicated that immunization with soluble HIV-1 antigens can recruit bNAb precursor B cells to the germinal center (GC) when there are as few as 10 such cells per mouse. However, at low precursor frequencies, the extent of clonal expansion was directly proportional to the affinity of the antigen for the B cell receptor, and recruitment to GCs was variable and dependent on recirculation. Dosenovic2018 (antibody lineage)
3BNC60: 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)
3BNC60: This review discusses host controls of bNAb responses and why highly antigenic vaccine Envs do not induce bNAbs when used as vaccine immunogens. VRC01 is not polyreactive against human proteins but has a high avidity for the phylogenetically conserved ubiquitin protein ligase E3A (UBE3A). In Kl mice expressing VRC01 germline with affinity matured HCDR3, bone marrow B cells were not deleted, but immunization of these mice with Envs designed for VRC01 unmutated common ancestor (UCA) induced limited somatic mutations or affinity maturation. In knock-in mice expressing VRC01 non-rearranged VJ germline, there was no B cell deletion in the bone marrow and no anergy in the periphery; vaccination with sequential Envs resulted in affinity maturation to neutralize glycan deleted HIV mutant viruses; maturation was blocked prior to UBE3A crosreactivity. Kelsoe2017 (review, antibody polyreactivity)
3BNC60: 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)
3BNC60: bNAbs were found to have potent activating but not inhibitory FcγR-mediated effector function that can confer protection by blocking viral entry or suppressing viremia. bNAb activity is augmented with engineered Fc domains when assessed in in vivo models of HIV-1 entry or in therapeutic models using HIV-1-infected humanized mice. Enhanced FcγR engagement is not restricted by epitope specificity or neutralization potency as chimeras composed of human anti-CD4bs 3BNC60 Fab and mouse Fc had improved or reduced in vivo activity depending on the Fc used. Bournazos2014 (neutralization, chimeric antibody)
3BNC60: To track the steps in evolution of bNAbs, VRC01-like anti-CD4bs bNAb 3BNC60 production was studied in human Ig-knock-in mice. Reactive B cell clones were antigen-induced to neutralizing heavy chain production in mature (MuV_H but not germ-line (GLV_H) knock-ins. That initial immunization when followed by immunization with one or a series of related BG505 SOSIP trimers was able to nudge response towards broad neutralization. Dosenovic2015 (neutralization, vaccine antigen design, broad neutralizer)
3BNC60: 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. As with other CD4bs binding bNAbs, 3BNC60 is inhibited by sCD4. It modestly enhanced binding of non-nNAb, 17b. outer domain (OD)-glycan bNAbs, PGT135 and PGT136, though ˜ 5x less efficient binders of trimer, were able to unidirectionally inhibit binding of 3BNC60, as also other CD4bs bNAbs, VRC01, 3BNC117, NIH45-46. Derking2015 (antibody interactions, neutralization, binding affinity, structure)
3BNC60: 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 3BNC60 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)
3BNC60: VRC01-class bNAb like 3BNC60 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)
3BNC60: 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-3BNC60 precursor did not bind to any trimers. Sliepen2015 (binding affinity, antibody lineage)
3BNC60: 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. Two versions of germline-binding gp120s were expressed as gp120 cores with N/C termini and V1-V2 and V3 loop truncations, of which 426c.TM4ΔV1-3 binds to germline versions of 3BNC60. It is reported that 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)
3BNC60: 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)
3BNC60: 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. 3BNC60 was the most active antibody preventing the cell to cell transmission and was active against cell to cell transmission of T/F viruses. Malbec2013
3BNC60: Envs from clades A, B and C were screened for binding to the germline predecessors of anti-CD4bs bNAbs b12, NIH45-46 and 3BNC60. Mature Abs reacted with diverse Envs, but not the germ-line Abs. Engineered chimeric Abs with mature and germ-line heavy and light chain combinations showed the importance of both mature chains for the cross-reactivity. Hoot2013 (antibody lineage, chimeric antibody)
3BNC60: 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.) 3BNC60 was used to compare the heavy chain sequence as a template of VRC01 class Ab. Zhu2013a (antibody sequence)
3BNC60: 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, 3BNC117 family. Kwong2012 (review, structure, broad neutralizer)
3BNC60: 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. 3BNC60, a CD4Bs Ab, was among the 17 bnAbs which were used in studying the mutations in FWR. 3BNC60 was used in comparing the Ab framework amino acid replacement vs. interactive surface area on Ab. Crystal structure revealed the importance of a FWR insertion in 3BNC60 increasing its neutralizing potency (described in Fig 5C). Klein2013 (neutralization, structure, antibody lineage)
3BNC60: 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. 3BNC60 was studied as anti-CD4BS bnAbs belongs to VRC01 class. When germline reverted light chains of 3BNC60 was replced by that of NIH45-46/VRC01, the chimeric Abs recognized the 426c NLGS mutant Envs. McGuire2013 (neutralization, antibody lineage)
3BNC60: 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. 3BNC60 has been discussed as NAb against CD4BS. Kovacs2012 (antibody binding site, neutralization, binding affinity)
3BNC60: 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 3BNC60 mature and germline antibodies. Jardine2013 (glycosylation, vaccine antigen design, structure, antibody lineage)
3BNC60: 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. The epitopes for both groups contain a potential N-linked glycosylation site (PNGS) at Asn332gp120 and the base of the V3 loop of the gp120 subunit of the HIV spike. However, the 10-1074–like Abs required an intact PNGS at Asn332gp120 for their neutralizing activity, whereas PGT121-like antibodies were able to neutralize some viral strains lacking the Asn332gp120 PNGS. 3BNC60 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)
3BNC60: 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. 3BNC60 bound very strongly to the gp120 core and RSC3, strongly bound to gp120 core D368R, weakly bound to RSC3/G367R but did not bind to RSC3 Δ3711, and RSC3 Δ3711/P363N. Lynch2012 (binding affinity)
3BNC60: 576 new HIV antibodies were cloned from 4 unrelated individuals producing expanded clones of potent broadly neutralizing CD4bs antibodies that bind to 2CC core. In order to amplify highly somatically mutated immunoglobulin genes, new primer set with 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. 3BNC60 arises from IgVH1-2 and IgVK1D-33 germline genes and neutralized 15/15 isolates with IC50<15μg/ml, and 1/5 VRC01-resistant isolates. 3BNC60 was not polyreactive - reacted with LPS, but not dsDNA, ssDNA and insulin. Solving the crystal structure of the 3BNC60 Fab and comparison with VRC01's revealed conservation of the contacts to the HIV spike. Scheid2011 (antibody generation, neutralization, antibody sequence, structure, antibody polyreactivity, broad neutralizer)

References

Showing 26 of 26 references.

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. Show all entries for this paper.

Dosenovic2015 Pia Dosenovic, Lotta von Boehmer, Amelia Escolano, Joseph Jardine, Natalia T. Freund, Alexander D. Gitlin, Andrew T. McGuire, Daniel W. Kulp, Thiago Oliveira, Louise Scharf, John Pietzsch, Matthew D. Gray, Albert Cupo, Marit J. van Gils, Kai-Hui Yao, Cassie Liu, Anna Gazumyan, Michael S. Seaman, Pamela J. Bjorkman, Rogier W. Sanders, John P. Moore, Leonidas Stamatatos, William R. Schief, and Michel C. Nussenzweig. Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice. Cell, 161(7):1505-1515, 18 Jun 2015. PubMed ID: 26091035. Show all entries for this paper.

Kelsoe2017 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. Show all entries for this paper.

Dosenovic2018 Pia Dosenovic, Ervin E. Kara, Anna-Klara Pettersson, Andrew T. McGuire, Matthew Gray, Harald Hartweger, Eddy S. Thientosapol, Leonidas Stamatatos, and Michel C. Nussenzweig. Anti-HIV-1 B Cell Responses Are Dependent on B Cell Precursor Frequency and Antigen-Binding Affinity. Proc. Natl. Acad. Sci. U.S.A., 115(18):4743-4748, 1 May 2018. PubMed ID: 29666227. Show all entries for this paper.

Andrabi2018 Raiees Andrabi, Jinal N. Bhiman, and Dennis R. Burton. Strategies for a Multi-Stage Neutralizing Antibody-Based HIV Vaccine. Curr. Opin. Immunol., 53:143-151, 15 May 2018. PubMed ID: 29775847. Show all entries for this paper.

Displaying record number 2635

Download this epitope record as JSON.

MAb ID	PGT121 (PGT-121)
HXB2 Location	Env	Env Epitope Map
Author Location
Epitope	(Discontinuous epitope)
Subtype	A
Ab Type	gp120 V3 // V3 glycan (V3g)
Neutralizing	P View neutralization details
Contacts and Features	View contacts and features
Species (Isotype)	human(IgG)
Patient	Donor 17
Immunogen	HIV-1 infection
Keywords	acute/early infection, ADCC, 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, chimeric antibody, computational epitope prediction, contact residues, dynamics, elite controllers, escape, glycosylation, HIV reservoir/latency/provirus, immunoprophylaxis, immunotherapy, junction or fusion peptide, kinetics, mother-to-infant transmission, mutation acquisition, neutralization, polyclonal antibodies, rate of progression, review, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity, viral fitness and reversion

Notes

Showing 107 of 107 notes.

PGT121: 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, neutralization)
PGT121: 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, whose serum had broad neutralization. The Env sequences of EN3 had much fewer polymorphisms, compared to those of a normal progressor, EN1, 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, neutralization, vaccine antigen design, polyclonal antibodies)
PGT121: 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 (immunotherapy, review)
PGT121: 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 PGT121 were used for comparison purposes. Zhang2022 (neutralization, immunotherapy, broad neutralizer)
PGT121: This study describes the design of the CAPRISA 012B human trial to assess the safety and pharmacokinetics of CAP256V2LS. Escalating dosages of CAP256V2LS, alone and in combination with 2 other mAbs (VRC07-523LS, PGT121) will be given to 52 HIV-negative and 14 HIV-positive women. Results will be reported in a future study. Mahomed2020 (immunotherapy)
PGT121: 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 reversion, dynamics, kinetics)
PGT121: The Chinese HIV Reference Laboratory produced 124 pseudoviruses from patients with subype 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)
PGT121: 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, HIV reservoir/latency/provirus)
PGT121: 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 (mutation acquisition, neutralization, immunotherapy)
PGT121: 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 regimen, compared to the C97 regimen, was markedly superior at outcompeting PGT121 binding to gp140 antigens, suggesting that the 4C regimen induced the most robust V3-specific antibodies. Bricault2018 (antibody generation, vaccine-induced immune responses, polyclonal antibodies)
PGT121: 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)
PGT121: 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 V_H1-46 and V_H1-2 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. While 1-18 targets the CD4bs like VRC01-like Abs, it recognizes the epitope differently. Neutralizing activity against VRC01 Ab-class escapes is maintained by 1-18. In humanized mice infected by strain 1_YU2, viral suppression is also maintained by 1-18. V_H1-46-derived B cell clone 4.1 from patient IDC561 produced potent, broadly active Abs. 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 BG505_SOSIP.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 (antibody binding site, antibody generation, antibody interactions, neutralization, escape, binding affinity, antibody sequence, structure, broad neutralizer, contact residues)
PGT121: 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 increasing their effectiveness as a vaccine. PGT121 broadly neutralized HIV-1AD8 full-length and cytoplasmic tail-deleted Envs. Castillo-Menendez2019 (vaccine antigen design, structure)
PGT121: The latent viral reservoir is the critical barrier for the development of an HIV-1 cure. This study showed that the V3 glycan-dependent bNAb PGT121 together with the TLR7 agonist vesatolimod (GS-9620) administered during ART suppression delayed viral rebound following ART discontinuation in SHIV-SF162P3-infected rhesus monkeys that initiated ART during early acute infection. Moreover, the subset of PGT121+GS-9620 treated monkeys that did not show viral rebound following ART discontinuation also did not reveal virus by highly sensitive adoptive transfer and CD8 depletion studies. These data demonstrate the potential of bNAb administration together with innate immune stimulation as a possible strategy to target the viral reservoir. Borducchi2018 (antibody interactions, immunotherapy, HIV reservoir/latency/provirus)
PGT121: 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. PGT121 was unable to bind to the A244 glycopeptides bearing a high-mannose N-glycan but could bind to the glycopeptide with a sialylated complex- type N-glycan placed at the N301 site (Fig: S1). Cai2018 (glycosylation, vaccine antigen design, structure)
PGT121: 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)
PGT121: 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 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)
PGT121: 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. deTaeye2019 (antibody interactions, variant cross-reactivity, binding affinity, structure, broad neutralizer)
PGT121: 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. PGT121 was used for machine learning regression prediction and to analyze statistical details (Table S4). Bricault2019 (antibody binding site, vaccine antigen design, computational epitope prediction, broad neutralizer)
PGT121: 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 8 different versions of tri-specific 10E8Fab-PGT121fv-PGDM1400fv, 3 different versions of tri-specific 10E8Fab-PGT121fv-PGDM1400fv.V8, and a tri-specific PRO-140Fab-PGDM1400fv-PGT121fv. A trispecific containing 10E8-PGT121-PGDM1400 Env-specific binding sites was equally potent (median IC₅₀ of 0.0135 µg/ml), while a trispecific molecule targeting Env and CCR5 simultaneously, (10E8Fab-PGDM1400fv-PRO 140fv) demonstrated even greater potency, with a median IC₅₀ of 0.007 µg/ml. Other trispecifics, using RoAb13Fab in combination with a bi-specific PGT121fv-PRO 140fv, neutralized most of the viruses in the smaller global panel but were not exceptionally potent. Khan2018 (neutralization, bispecific/trispecific)
PGT121: 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 (immunotherapy)
PGT121: Adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 1 (AAV1) vectors were used to deliver bNAb PGT121 in WT and immunocompromised C57BL/6 mice and in HIV-1-infected bone marrow-liver-thymus (BLT) humanized mice. Ad5.PGT121 and AAV1.PGT121 produced functional Ab in vivo. Ad5.PGT121 produced PGT121 rapidly within 6 h, whereas AAV1.PGT121 produced detectable PGT121 in serum by 72 h. Serum PGT121 levels were rapidly reduced by the generation of anti-PGT121 antibodies in immunocompetent mice but were durably maintained in immunocompromised mice. In HIV-1-infected BLT humanized mice, Ad5.PGT121 resulted in a greater reduction of viral loads than did AAV1.PGT121. Ad5.PGT121 also led to more-sustained virologic control than purified PGT121 IgG. Ad5.PGT121 afforded more rapid, robust, and durable antiviral efficacy than AAV1.PGT121 and purified PGT121 IgG in HIV-1-infected humanized mice. Badamchi-Zadeh2018 (immunotherapy)
PGT121: 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)
PGT121: 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 and is in Phase I clinical development. Antigenic region V3 glycan (Table:1). Walker2018 (antibody binding site, review, broad neutralizer)
PGT121: 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)
PGT121: 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 uccessfully bound to target bNAbs with enhanced and selective antigenicity. Yu2018 (glycosylation, vaccine antigen design)
PGT121: 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)
PGT121: 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)
PGT121: 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)
PGT121: 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 F_c 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)
PGT121: 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 PGT121 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)
PGT121: Assays of poly- and autoreactivity demonstrated that broadly neutralizing NAbs are significantly more poly- and autoreactive than non-neutralizing NAbs. PGT121 is neither autoreactive nor polyreactive. Liu2015a (autoantibody or autoimmunity, antibody polyreactivity)
PGT121: 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)
PGT121: 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)
PGT121: 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-V3 variable NAb PGT121, binds at a fraction of the binding of 2G12 to Env-ND, and this binding is sensitive to glutaraldehyde treatment . Witt2017 (vaccine antigen design, binding affinity)
PGT121: 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)
PGT121: The DS-SOSIP.4mut is a soluble, closed pre-fusion-state HIV-1 Env trimer that has improved stability and immunogenicity. It has 4 specific alterations at M154, M300, M302 and L320. PGT121 recognizes this trimer antigenically. Chuang2017 (antibody interactions)
PGT121: 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)
PGT121: 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 epitope prediction)
PGT121: 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)
PGT121: Crystal structures of the HIV-1 Env trimer with fully processed and native glycosylation are presented, complexed with the V3-loop bNAb 10-1074 and IOMA, a new CD4bs bNAb. There were fine specificity differences between bNAb 10-1074 and PGT121-family members. PGT122 was two-fold more potent against strains including the N156 PNGS, whereas 10-1074 was four-fold more potent against strains lacking the N156 PNGS. Gristick2016 (glycosylation)
PGT121: 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)
PGT121: 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)
PGT121: 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 PGT121 is given as: IGHV 4-59*01, IGHJ 6*03, IGLV L3-21*02, IGLJ L3*02. Longo2016 (antibody binding site, antibody sequence)
PGT121: 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. PGT121 was 1 of 2 reference PGT128-like bNAbs - PGT121 and PGT128. Crooks2015 (glycosylation, neutralization)
PGT121: 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)
PGT121: 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)
PGT121: This review classified and mapped the binding regions of 32 bNAbs isolated 2010-2016. Wu2016 (review)
PGT121: 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)
PGT121: 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 (ADCC)
PGT121: 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)
PGT121: bNAbs were found to have potent activating but not inhibitory FcγR-mediated effector function that can confer protection by blocking viral entry or suppressing viremia. bNAb activity is augmented with engineered Fc domains when assessed in in vivo models of HIV-1 entry or in therapeutic models using HIV-1-infected humanized mice. Enhanced FcγR engagement is not restricted by epitope specificity or neutralization potency as chimeras composed of human anti-V3 PGT121 Fab and mouse Fc had improved or reduced in vivo activity depending on the Fc used. Bournazos2014 (neutralization, chimeric antibody)
PGT121: 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 epitope prediction)
PGT121: Factors that independently affect bNAb induction and evolution were identified as viral load, length of untreated infection and viral diversity. Ethnically, 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, broad neutralizer)
PGT121: 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). V3 glycan bNAb, PGT121, neutralized the B41 pseudovirus and bound B41 trimer well. Pugach2015
PGT121: 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
PGT121: 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. PGT121, PGT122, PGT123, PGT125, PGT126 and PGT128, all N332-V3 glycan oligomannose patch-binding bNAbs, were strongly, reciprocally competitive with one another. They inhibited binding of PGT145 strongly, but in a non-reciprocal manner. Non-reciprocal enhancement of PGT121 binding to trimer was seen in the presence of NIH45-46. Derking2015 (antibody interactions, neutralization, binding affinity, structure)
PGT121: 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. Both the Clade C trimers as well as their pseudotyped viruses reacted strongly with and were neutralized by V3-glycan-binding PGT121. Julien2015 (assay or method development, structure)
PGT121: 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-glycan supersite bNAb PGT121 to trimers was minimally affected by trimer cross-linking. Schiffner2016 (assay or method development, binding affinity, structure)
PGT121: 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 2/20 BG505 SOSIP.664-D7324 trimer-immunized rabbits were capable of inhibiting PGT121 binding to V3-glycan. 1/4 similarly trimer-immunized macaque sera also inhibited PGT121 binding by >50%. Sanders2015 (antibody generation, neutralization, binding affinity, polyclonal antibodies)
PGT121: 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 PGT121, 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)
PGT121: 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. PGT121 is distinct from other V3-specific mAbs because it forms a binding site with two functional surfaces. It has been administered in therapeutic trials in primates. Stephenson2016 (immunotherapy, review)
PGT121: This review discusses an array of methods to engineer more effective bNAbs for immunotherapy. Antibody PGT121 is an example of engineering through rational mutations; it has been combined with 10-1074 as part of a strategy to combine the CDRs of bnAbs targeting similar epitopes. Hua2016 (immunotherapy, review)
PGT121: 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, PGT121, to multiple epitopes were determined. Deleting the N137 glycan made BG505.T332N more vulnerable to PGT121, but the corresponding change has no meaningful effect on oligomannose content in the SOSIP.664 trimer context. Behrens2016 (antibody binding site, glycosylation)
PGT121: 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 PGT121 was assayed against BG505 (resistant strain) and BG505-T332N (sensitive strain). Magnus2016 (neutralization, escape)
PGT121: 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. V3 glycan-binding, second-generation mAb, PGT121 when compared had a geometric mean of IC₅₀=0.02 µg/ml for 2/12 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 (neutralization, structure)
PGT121: 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 PGT121 was unable to neutralize any of the 16 tested non-M primary isolates at an IC₅₀< 10µg/ml. Morgand2015 (neutralization, subtype comparisons)
PGT121: 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. PGT121, a V3-glycan bnAb belonged to a group with slopes >1. Webb2015 (neutralization)
PGT121: 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-PGT121 precursor did not bind to any trimers. Sliepen2015 (binding affinity, antibody lineage)
PGT121: Bispecific IgGs were produced, composed of independent antigen-binding fragments with a common Fc region. Parental antibodies of several classes were assessed (VRC07, 10E8, PGT121, PG9-16). A bispecific antibody composed of VRC07 x PG9-16 displayed the most favorable profile, neutralizing 97% of viruses with a median IC₅₀ of 0.055 ug/ml. This bispecific IgG also demonstrated pharmacokinetic parameters comparable to those of the parental bNAbs when administered to rhesus macaques. These results suggest that IgG-based bispecific antibodies are promising candidates for HIV prevention and treatment. Against a panel of 206 resistant and sensitive viruses, PGT121 neutralizes with median IC₈₀ of 0.094 µg/ml. Bispecific with VRC07 median neutralization is 0.355; while in physical combination with the same bNAb, median neutralization of the antibodies is 0.199 µg/ml respectively. Asokan2015 (neutralization, immunotherapy, bispecific/trispecific)
PGT121: 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 PGT121 had strong ADCC. Bruel2016 (ADCC, binding affinity)
PGT121: 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 PGT121 has been associated with viral suppression in a study of rhesus macaques. Halper-Stromberg2016 (immunotherapy, review)
PGT121: 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. A cocktail of PGT121 and VRC07-523, at total doses of 10 mg/kg (5 mg/kg each Ab) and 40 mg/kg (20 mg/kg each Ab) was administered. It was found that PGT121 concentrations in the plasma were consistently higher at both doses than those of VRC07-523. The NmAb cocktail IC₅₀ against SHIVSF162P3 in the TZM-bl assay was 0.0128 μg/ml. There was no evidence of virus rebound in the plasma immunity and all NmAb-treated macaques were free of virus in blood and tissues 6 months after exposure. Experimental data sets have been provided in supplement. Hessell2016 (neutralization, acute/early infection, immunotherapy, mother-to-infant transmission)
PGT121: X-ray and EM structures of inferred precursors of the PGT121 family were generated (inferred intermediate heavy chains 3H, 9H, and 32H were paired with the intermediate light chain 3L). The N137 glycan was determined to be a major factor in affinity maturation of the PGT121 family (affinity maturation was primarily focused on avoiding, accommodating, or binding the N137 glycan). The antibody approach angle differed in the two main branches of the PGT121 lineage. A 3.0 Å crystal structure of a recombinant BG505 SOSIP.664 HIV-1 trimer with a PGT121 family member (3H+109L Ab) was determined. Garces2015 (vaccine antigen design, structure, antibody lineage)
PGT121: 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)
PGT121: PGT121 was produced in a plant system and tested as immunotherapy in non-human primates. In African green monkeys, subcutaneously administered PGT121 exhibited a longer serum half-life than intravenous administration and was more consistent than intramuscular delivery. Subcutaneous administration resulted in sterilizing protection from SHIV challenge in 6 of 6 rhesus macaques, while 3 of 4 control animals became infected. Administration of PGT121 after intravaginal challenge did not provide statistically-significant protection. Rosenberg2016 (vaccine antigen design, immunotherapy)
PGT121: 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)
PGT121: 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)
PGT121: 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 PGT121 the published IMGT predicted allele was IGHV4-59*01 and alternate allele predicted from IGHV alleles in 28 South African individuals was IGHV4-59*1m2, with T94C nucleotide and Y32H amino acid change. Scheepers2015 (antibody lineage)
PGT121: 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. PGT121 was able to neutralize all the N334 glycan site variants in the panel except for the isolates JR-CSF and 92TH021. The PGT121 family of antibodies neutralized N332 glycan site viruses more effectively overall than the PGT128 family or PGT135. Sok2014a (antibody interactions, glycosylation)
PGT121: 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. PGT121 was not effective in blocking cell to cell transmission of virus. Malbec2013
PGT121: 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)
PGT121: 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)
PGT121: 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)
PGT121: 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)
PGT121: Structural studies were performed for bNAbs PGT121, PGT122, and PGT123. The 3 bNAbs have very similar structures, but are divergent in their variable domain sequences. Julien2013b (antibody sequence, structure)
PGT121: 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 PGT121, CS predicted 4 and MI predicted 3 positions, overlapping in position 332. Ferguson2013 (computational epitope prediction, broad neutralizer)
PGT121: 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. PGT121 showed very high neutralization titer against BG505 pseudovirus in a competitive binding assay as shown in Table 1. Hoffenberg2013 (antibody interactions, glycosylation, neutralization)
PGT121: 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. PGT121 is a V3-glycan Ab, with breadth 53%, IC₅₀ 0.08 μg per ml, and its unique feature is that it recognizes V1/V2 and V3 glycan. Similar MAbs include PGT122 and PGT123. Kwong2013 (review)
PGT121: 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. PGT121 was used in CD4 coexpression and competitive binding assay. Veillette2014 (ADCC)
PGT121: To identify bNAbs that have lower mutation frequencies of known bNAbs, but maintain high potency and moderate breadth, linage evolution of bNAbs PGT121-134 was studied with a novel phylogenetic method ImmuniTree. Selected heavy and light chain clones of PGT121 were paired and tested for neutralization breadth and potency on a cross-clade 74-virus panel. A positive correlation between the somatic hypermutation and the development of neutralization breadth and potency was reported. 3H+3L and 32H+3L were compared against PGT121 and b12 to evaluate neutralization activity of the intermediate divergence. 3H+3L showed 15fold less potency and 32H+3L showed 3 fold less potency than PGT121. Sok2013 (antibody lineage)
PGT121: 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. PGT121 wwas used as an anti-gp41 mAb to compare its binding with other PGT151 family Abs. Blattner2014
PGT121: 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. PGT121 was used for comparison. Falkowska2014
PGT121: Profound therapeutic efficacy of PGT121 and PGT121-containing monoclonal antibody cocktails was demonstrated in chronically SHIV-SF162P3 infected rhesus monkeys. Cocktails included 1, 2, and 3 mAb combinations of PGT121, 3BNC117 and b12. A single monoclonal antibody infusion containing PGT121 alone or in a cocktail led to up to 3.1 log decline of plasma viral RNA in 7 days and reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. A subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. Barouch2013a (immunotherapy)
PGT121: This is a review of a satellite symposium at the AIDS Vaccine 2012 conference, focusing on antibody gene transfer. David Baltimore presented results in which humanized mice given vectored immunoprophylaxis (VIP) to express antibody b12 or VRC01 were challenged with the REJO.c transmitted founder strain. Substantial protection was noted in mice expressing VRC01 but not in those expressing b12, consistent with results obtained in vitro for these antibody-strain combinations. Also, all mice expressing VRC07G54W were protected against 20 consecutive weekly challenges with the REJO.c transmitted molecular founder strain. Balazs2013 (immunoprophylaxis)
PGT121: 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)
PGT121: "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 PGT128-like cluster. Georgiev2013 (neutralization)
PGT121: This study uncovered a potentially significant contribution of V_H 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 V_H replacements. The details of PGT121 V_H 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)
PGT121: Protective potency of PGT121 was evaluated in vivo in rhesus macaques. PGT121 efficiently protected against high-dose challenge of SHIV SF162P3 in macaques. Sterilizing immunity was observed in 5/5 animals administered 5 mg/kg antibody dose and in 3/5 animals administered 0.2 mg/kg, suggesting that a protective serum concentration for PG121 is in the single-digit mg/mL. PGT121was effective at serum concentration 600-fold lower than for 2G12 and 100-fold lower than for b12. Moldt2012a (immunoprophylaxis)
PGT121: 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). PGT121 neutralized only 24% 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)
PGT121: 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 epitope prediction)
PGT121: 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 not yet determined, PGT121 class, PGT121 family. Kwong2012 (review, structure, broad neutralizer)
PGT121: 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)
PGT121: 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. PGT121 targets Asn332 to neutralize. Moore2012 (neutralization, escape)
PGT121: 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. The epitopes for both groups contain a potential N-linked glycosylation site (PNGS) at Asn332gp120 and the base of the V3 loop of the gp120 subunit of the HIV spike. However, the 10-1074–like Abs required an intact PNGS at Asn332gp120 for their neutralizing activity, whereas PGT121-like antibodies were able to neutralize some viral strains lacking the Asn332gp120 PNGS. PGT121 clonal members recognize V3 loop and the Asn332 gp120 associated glycan. Crystal structures of unliganded PGT121 and 10-1074 were compared and revealed differential carbohydrate recognition maps to a cleft between (CDR)H2 and CDRH3, occupied by a complex-type N-glycan. Detail information on the binding and neutralization assays are described in the figures S2-S11. Mouquet2012a (glycosylation, neutralization, binding affinity, broad neutralizer)
PGT121: 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 PGT121 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)
PGT121: 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. PGT121 neutralized 70% 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 and alanine substitution analysis suggested that that PGT121 binds to a protein epitope along the gp120 polypeptide backbone that is conformationally dependent on the N332 glycan or that the glycan contributes more strongly to binding in the context of the intact protein. Walker2011 (antibody binding site, antibody generation, variant cross-reactivity, broad neutralizer)

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Displaying record number 2636

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MAb ID	PGT122 (PGT-122)
HXB2 Location	Env	Env Epitope Map
Author Location
Epitope
Subtype	A
Ab Type	gp120 V3 // V3 glycan (V3g)
Neutralizing	P View neutralization details
Contacts and Features	View contacts and features
Species (Isotype)	human(IgG)
Patient	Donor 17
Immunogen	HIV-1 infection
Keywords	antibody binding site, antibody gene transfer, antibody generation, antibody interactions, antibody lineage, antibody sequence, assay or method development, binding affinity, broad neutralizer, chimeric antibody, computational epitope prediction, escape, glycosylation, immunoprophylaxis, neutralization, review, structure, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity

Notes

Showing 21 of 21 notes.

PGT122: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. PGT122 was isolated from human B cell clones and is functionally similar to super-Abs PGT121, PGT128 and PGT135. Antigenic region V3 glycan (Table:1). Walker2018 (antibody binding site, review, broad neutralizer)
PGT122: 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 uccessfully bound to target bNAbs with enhanced and selective antigenicity. Yu2018 (glycosylation, vaccine antigen design)
PGT122: 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)
PGT122: Crystal structures of the HIV-1 Env trimer with fully processed and native glycosylation are presented, complexed with the V3-loop bNAb 10-1074 and IOMA, a new CD4bs bNAb. There were fine specificity differences between bNAb 10-1074 and PGT121-family members. PGT122 was two-fold more potent against strains including the N156 PNGS, whereas 10-1074 was four-fold more potent against strains lacking the N156 PNGS. Gristick2016 (glycosylation)
PGT122: 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 epitope prediction)
PGT122: 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. PGT122, PGT121, PGT123, PGT125, PGT126 and PGT128, all N332-V3 glycan oligomannose patch-binding bNAbs, were strongly, reciprocally competitive with one another. PGT122 inhibited binding of V1/V2 glycan cluster-Abs like PG9 strongly, but in a non-reciprocal manner and markedly but incompletely inhibited CD4-IgG2. Derking2015 (antibody interactions, neutralization, binding affinity, structure)
PGT122: 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 PGT122, 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)
PGT122: X-ray and EM structures of inferred precursors of the PGT121 family were generated (inferred intermediate heavy chains 3H, 9H, and 32H were paired with the intermediate light chain 3L). The N137 glycan was determined to be a major factor in affinity maturation of the PGT121 family (affinity maturation was primarily focused on avoiding, accommodating, or binding the N137 glycan). The antibody approach angle differed in the two main branches of the PGT121 lineage. A 3.0 Å crystal structure of a recombinant BG505 SOSIP.664 HIV-1 trimer with a PGT121 family member (3H+109L Ab) was determined. Garces2015 (vaccine antigen design, structure, antibody lineage)
PGT122: 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 PGT122 the published IMGT predicted allele was IGHV4-59*01 and alternate allele predicted from IGHV alleles in 28 South African individuals was IGHV4-59*1m2, with T94C nucleotide and Y32H amino acid change. Scheepers2015 (antibody lineage)
PGT122: 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. PGT122 neutralized N334 viruses to an intermediate degree. Sok2014a (antibody interactions, glycosylation)
PGT122: 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)
PGT122: 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)
PGT122: Structural studies were performed for bNAbs PGT121, PGT122, and PGT123. The 3 bNAbs have very similar structures, but are divergent in their variable domain sequences. Binding by PGT122 depends on the N332 glycan PGT122 interacts with the gp120 outer domain at a more vertical angle than the previously-characterized PGT128. Julien2013b (antibody sequence, structure)
PGT122: 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. PGT122 showed very high neutralization titer against BG505 pseudovirus in a competitive binding assay as shown in Table 1. Reduced PGT122 binding to mutated BG505 T332 was rescued by a glycosylated N residue, revealing a glycan binding epitope. Hoffenberg2013 (antibody interactions, glycosylation, neutralization)
PGT122: To identify bNAbs that have lower mutation frequencies of known bNAbs, but maintain high potency and moderate breadth, linage evolution of bNAbs PGT121-134 was studied with a novel phylogenetic method ImmuniTree. This Ab showed partial loss of neutralization potency when used without FRL3 insertion against a cross-lade 6 virus panel. Sok2013 (antibody lineage)
PGT122: 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)
PGT122: This study uncovered a potentially significant contribution of V_H 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 V_H replacements. The details of PGT122 V_H 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)
PGT122: 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 not yet determined, PGT121 class, PGT121 family. Kwong2012 (review, structure, broad neutralizer)
PGT122: 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)
PGT122: 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. PGT122 targets Asn332 to neutralize. Moore2012 (neutralization, escape)
PGT122: 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. PGT122 neutralized 65% 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 and alanine substitution analysis suggested that that PGT122 binds to a protein epitope along the gp120 polypeptide backbone that is conformationally dependent on the N332 glycan or that the glycan contributes more strongly to binding in the context of the intact protein. Walker2011 (antibody binding site, antibody generation, variant cross-reactivity, broad neutralizer)

References

Showing 21 of 21 references.

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. Show all entries for this paper.

Displaying record number 658

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MAb ID	17b (1.7b, sCD4-17b, 1.7B)
HXB2 Location	Env	Env Epitope Map
Author Location	gp120
Research Contact	James Robinson, Tulane University, New Orleans, LA, USA
Epitope	(Discontinuous epitope)
Ab Type	gp120 CD4i CoRBS (Cluster C)
Neutralizing	L P (weak) View neutralization details
Contacts and Features	View contacts and features
Species (Isotype)	human
Patient	N70
Immunogen	HIV-1 infection
Keywords	acute/early infection, ADCC, adjuvant comparison, antibody binding site, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autoantibody or autoimmunity, autologous responses, binding affinity, brain/CSF, broad neutralizer, co-receptor, computational epitope prediction, dendritic cells, drug resistance, dynamics, enhancing activity, escape, glycosylation, HAART, ART, immunoprophylaxis, immunotherapy, kinetics, mimics, mimotopes, neutralization, polyclonal antibodies, review, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity, viral fitness and reversion

Notes

Showing 270 of 270 notes.

17b: Single chain variable fragments (scFvs) were constructed for mAbs 916B2, 4E9C, and 25C4b. Coverage of neutralization by the scFvs against a panel of 66 multiclade pseudoviruses was 89% for 4E9C, 95% for 25C4b, and 100% for 916B2. 25C4b bound the region spanning multiple domains of hairpin 1 (H1) and H2 of the bridging sheet and V3 base, similar to mAb 17b. For 4E9C, V3-base dependent binding was apparent based on lack of binding to mutants containing a V3 truncation. In contrast, binding of 916B2 was dependent on the H1 region. The study also assayed the binding of additional mAbs (17b, 12G10, 917B11, 5D6S, A32) to gp120 mutants in the CD4i region. Tanaka2017 (antibody binding site)
17b: 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 (ADCC, neutralization, subtype comparisons)
17b: 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 reversion, dynamics, kinetics)
17b: 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 increasing their effectiveness as a vaccine. The CD4i Ab 17b exhibited poor neutralization against HIV-1AD8 full-length and cytoplasmic tail-deleted Envs. Castillo-Menendez2019 (vaccine antigen design, structure)
17b: 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)
17b: 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 17b recognized L193A variants of CH58 and CH77 IMCs with a significant increase compared to the WT. Prevost2018 (ADCC)
17b: 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 17b 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)
17b: 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 17b in ELISA EC50 and Surface Plasmon Resonance (SPR) assays. 6240.B gp120 exhibited binding to 17b. Wen2018 (glycosylation, vaccine antigen design)
17b: Assays of poly- and autoreactivity demonstrated that broadly neutralizing NAbs are significantly more poly- and autoreactive than non-neutralizing NAbs. 17b is neither autoreactive nor polyreactive. Liu2015a (autoantibody or autoimmunity, antibody polyreactivity)
17B: The study identified a HIV-1–neutralizing protein in breast milk, Tenascin-C (TNC). TNC is an extracellular matrix protein important in fetal development and wound healing. TNC bound the HIV-1 Envelope protein at a site that is induced upon engagement of its primary receptor, CD4, and is blocked by monoclonal antibodies that bind to the V3 loop (19B and F39F) and chemokine coreceptor binding site (17B). Fouda2013 (antibody binding site)
17b: 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 co-receptor binding site for 17b. Hogan2018 (vaccine antigen design)
17b: 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. deTaeye2018 (broad neutralizer)
17b: 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-gp120 non-NAb 17b, binds at a fraction of the binding of 2G12 to Env-ND, and this binding is slightly sensitive to glutaraldehyde treatment . Witt2017 (vaccine antigen design, binding affinity)
17b: 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)
17b: 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 (including 17b), 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)
17b: 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. Chen2016b (antibody binding site, vaccine antigen design, vaccine-induced immune responses, structure)
17b: The amino acid at gp120 position 375 is embedded in the Phe43 cavity, which affects susceptibility to ADCC. Most M-group strains of HIV-1 have serine at position 375, but CRF01 typically has histidine, which is a bulky residue. MAbs 2G12 and 10E8 were not affected by changes in residue 375, while recognition by CD4i mAbs 17b and A32 was increased by mutations of residue 375 to histidine or tryptophan. Participants in the AIDSVAX vaccine trial were infected by CRF01, and a significant part of the efficacy of this vaccine rested on ADCC responses. The ADCC response of MAbs derived from AIDSVAX participants (CH29, CH38, CH40, CH51, CH52, CH54, CH77, CH80, CH81, CH89, CH91, CH94) was dependent on the presence of 375H and greatly decreased by the presence of 375S. Prevost2017 (ADCC, vaccine-induced immune responses)
17b: 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. Mabs 17b and LF17 were used as anti-CoRBS Abs. Ding2015 (ADCC)
17b: 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)
17b: 15e: 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 17b showing a loss of tier 2 phenotype. The results are in Table S5. Crooks2015 (glycosylation, neutralization)
17b: 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
17b: 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 (ADCC)
17b: 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 CD4i Ab, 17b did not bind cell surface or neutralize 92UG037.8 HIV-1 isolate, but it did bind well in the presence of sCD4. Chen2015 (neutralization, binding affinity)
17b: 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 gp41_ECTO (F240); and to V3 (447-52D, 39F, CO11, 19b and 14e), none neutralized B41 (IC₅₀ >50µg/ml). Pugach2015
17b: 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. CD4i non-NAb, 17b binding was modestly increased by the initial binding of CD4bs bNAbs, VRC01, 3BNC60, NIH45-46. Derking2015 (antibody interactions, neutralization, binding affinity, structure)
17b: 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 almost no affinity for the CD4induced non-NAb, 17b, and 17b was unable to neutralize the equivalent pseudotyped viruses for either trimer. Julien2015 (assay or method development, structure)
17b: 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 CD4i-epitope-recognizing non-NAb, 19b, to trimers was almost completely eliminated by trimer cross-linking. Schiffner2016 (assay or method development, binding affinity, structure)
17b: 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-CDi non-NAb 17b 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)
17b: 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. 17b was compared to the newly-derived mAbs; it didn't cross-react with gut bacteria, and tested negative in 2 tests of autoreactivity. Jeffries2016 (antibody polyreactivity)
17b: A solution-phase ECL assay for ultrasensitive and quantitative analysis of binding affinities of HIV receptor and MAb interactions has been demonstrated. This study of binding of gp120 with anti CD4 mAb Q4120-CD4-tag and 17b-gp120 with CD4-tag shows that Q4120 can completely block the binding of gp120 with CD4-tag, while 17b can only partially block their binding. The results indicate that Q4120 can serve as a more effective neutralizing antibody than 17b to potentially block the HIV infection of T cells. Xu2013 (antibody interactions, assay or method development)
17B: 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. MAb 17B itself did not block Env-Galcer binding, suggesting that the C1 Ab-induced gp120 conformational changes resulted in alteration in a Galcer binding site distant from the CD4i 17B MAb binding site. Dennison2014 (ADCC, antibody binding site, antibody interactions, glycosylation)
17b: 17b 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 CCR5BS binding Nab bound well at <10 nM to 3/5 chronic Envs, 3/6 Consensus Envs and 6/7 T/F Envs. Liao2013c (antibody interactions, binding affinity)
17b: The neutralization profile of 1F7, a human CD4bs mAb, is reported and compared to other bnNAbs. 1F7 competed with 17b for binding with gp120. Gach2013 (neutralization)
17b: This study reported the Ab binding titers and neutralization of 51 patients with chronic HIV-1 infection on supressive ART for 3 yrs. A high titer of Ab against gp120, gp41, and MPER was found. Patient sera were evaluated for binding against recombinant gp120_JR-FL mutants lacking either the V1/V2 loop or the V3 loop. Significantly higher end point binding titers and HIV1_JR-FL neutralization were noticed in patients with >10 compared to <10 yrs of detectable HIV RNA. 17b was used as a CD4b Ab control. Gach2014 (neutralization, HAART, ART)
17b: 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. 17b was used in co-expression and cryoelectron tomography assays to understand the conformational changes in Env upon CD4 binding. Veillette2014 (ADCC, structure)
17b: 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. 17b was used as a control and A32 showed 4-6 fold higher ADCC activity than 17b. Ferrari2011a (ADCC)
17b: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 with the CD4i binding site of 17b. Acharya2013 (neutralization)
17b: 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 17b, against 181 diverse HIV-1 strains with available Ab-Ag complex structures. Chuang2013 (computational epitope prediction)
17b: The complexity of the epitopes recognized by ADCC responses in HIV-1 infected individuals and candidate vaccine recipients is discussed in this review. 17b is discussed as the CD4i CoRBS (Cluster C) region-targeting, neutralizing anti-gp120 mAb exhibiting ADCC activity and having a discontinuous epitope. Co-localization of the gp120_HXBc2core CD4/17b complex (PDB:1GC1) was studied by tomogram of the chimera. Pollara2013 (ADCC, review, structure)
1.7B: This study mapped the amino acid changes in epitopes that led to escape from the initial autologous neutralizing Ab response in two HIV-1 B infected individuals. Escape occurred by different pathways but the responses appeared to be directed against the same region of gp120. In conclusion, a region just below the base of the V3 loop, near the coreceptor binding domain of gp120, can be a target for autologous neutralization. MAb 1.7B was used as a noncompeting human Ab in cross competition analysis. Tang2011 (autologous responses, glycosylation, neutralization, escape, HAART, ART, structure)
17b: 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.17b was used as the classical CoRBS Ab control in different assays, especially competition ELISA assays to determine epitope specificity. Guan2013 (ADCC, antibody interactions)
17b: This study uncovered a potentially significant contribution of V_H 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. The V_H replacement "footprints" within CD4i Abs preferentially encode negatively charged amino acids within IgH CDR3. The details of 17b V_H replacement products in IgH gene and mutations and amino acid sequence analysis are described in Table 1,Table 2 and Fig 3. Liao2013a (antibody sequence)
17b: 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 foot print of m36 binding on gp120 is near the base of the V3 loop which resembles a "fully open" conformation similar to the coreceptor targeted CD4i mAb, 17b. Meyerson2013 (antibody binding site, structure)
Lists 7 mAbs derived from patient N70: 15E, 1.9B, 2.3A, 2.3B, 2.1H, F91, 1.7B. Robinson1992
17b: 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 17b Ab-bound states. Korkut2012 (structure)
17b: Design, synthesis, characterization and structures of gp120 in complex with dual hot-spot HIV-1 entry inhibitor small-molecules is reported. 17b was used as a surrogate for the co-receptor and structure of HIV-1 CD4:gp120:17b complex is described. LaLonde2012 (structure)
17b: 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. 17b 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 (ADCC, assay or method development)
17b: 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. 17b was used as a CoRB-specific MAb to compare binding specificity of VRC06. Li2012
17b: 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)
17b: 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)
17b: 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 epitope prediction)
17b: 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 MF59 adjuvant, but there was 3-fold decrease of antigenicity with FIA, C971, C974, C971+MF59 C971+MF59 as compared to the unadjuvanted sample. Lai2012 (adjuvant comparison)
17b: 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. 17b had limited neutralizing activity recognizing the CD4 induced site and carried fewer somatic mutations than bnAbs. Fig S4C described the comparison of Ab framework amino acid replacement vs. interactive surface area on 17b. Klein2013 (neutralization, structure, antibody lineage)
17b: 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. Immobilized 17b Fab could capture gp120 even in the absence of CD4 and CD4 binding greatly increased the strength of interaction. In contrast, gp140 trimer bound to 17b Fab only in the presence of CD4, suggesting that gp120 portions of unligated epitope trimer are tightly confined in a conformation distinct from the CD4-bound state. Kovacs2012 (antibody binding site, neutralization, binding affinity)
17b: 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. CD4 independence of the glycoprotein variants exhibits strong correlation with 17b binding. The viral sensitivity increases with the S375W mutation to 17b. Haim2011 (antibody interactions)
17b: 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. 17b was used as BnAb to screen Env clones. N197H mutation caused increase in neutralization by 17b, but failed in highest concentration. ORourke2012 (neutralization)
17b: 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. 17b was used as a positive control Abs in competitive binding assay with non human primates mAbs. Sundling2012 (vaccine-induced immune responses)
17b: The goal of this study was to improve the humoral response to HIV-1 by targeting trimeric Env gp140 to B cells. The gp140 was fused to a proliferation-inducing ligand (APRIL), B cell activation factor (BAFF) and CD40 ligand (CD40L). These fusion proteins increased the expression of activation-induced-cytidine deaminase (AID) responsible for somatic hypermutation, Ab affinity maturation, and Ab class switching. The Env-APRIL induced high anti-Env responses against tier1 viruses. 17b was used in immunoprecipitation assay. Melchers2012 (neutralization)
17b: 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. 17b was used to determine and compare the immunogenicity of homo and heterotrimers gp140s and to investigate the relative exposure of the CCR5 co-receptor binding site. The relative binding of 17b to the Q461/SF162 nonlinker heterotrimer was greater than expected. Sellhorn2012 (vaccine antigen design)
17b: 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. 17b was used as a control to prove whether the purified and crystallized gp120 is in the CD4 bound conformational state or not. Kwon2012 (structure)
17b: Role of envelope deglycosylation in enhancing antigenicity of HIV-1 gp41 epitopes is reported. The mechanism of induction of broad neutralizing Abs is discussed. The hypothesis of presence of "holes" in the naive B cell repertoires for unmutated B cell receptor against HIV-1 Env was tested. 17b was used in binding assays to compare glycosylated or deglycosylated JFRL and didn't exhibit strong binding to deglycosylated JRFL. The authors inferred that glycan interferences control the binding of unmutated ancestor Abs of broad neutralizing mAb to Env gp41. Ma2011 (glycosylation, neutralization)
17b: 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. 17b was used as a control to compare the neutralizing activity of patients' sera. Mutated glycan 241 (N241S) had an increase neutralization sensitivity to 17b. Lavine2012 (neutralization)
17b: 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. In the absence of CD4, the CD4i epitope MAb 17b, 48d, and 412d bound poorly to Env-wild-type and Env-hGM-CSF but efficiently to Env-ΔV1V2. Adding soluble CD4 substantially increased the binding of these MAb to Env-ΔV1V2 and especially to Env-wild-type, but binding to Env-hGM-CSF was improved only modestly, suggesting that the presence of GM-CSF in the V1V2 region either limits the accessibility of the CD4i epitopes or blocks the conformational changes that expose them. vanMontfort2011 (vaccine antigen design)
17b: 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). MAbs 17b and E51, with restricted neutralizing activity, had pIs from 7 to 7.85. Plasma-derived, anti-gp120 IgG fractions in this range also had narrow neutralization breadth. Sajadi2012 (polyclonal antibodies)
17b: Small sized CD4 mimetics (miniCD4s) were engineered. These miniCD4s by themselves are poorly immunogenic and do not induce anti-CD4 antibodies. Stable covalent complexes between miniCD4s and gp120 and gp140 were generated through a site-directed coupling reaction. These complexes were recognized by CD4i antibodies as well as by the HIV co-receptor CCR5 and elicited CD4i antibody responses in rabbits. A panel of MAbs of defined epitope specificities, including MAb 17b, was used to analyze the antigenic integrity of the covalent complexes using capture ELISA. Martin2011 (mimics, binding affinity)
17b: The long-term effect of broadly bNAbs on cell-free HIV particles and their capacity to irreversibly inactivate virus was studied. MPER-specific MAbs potently induced gp120 shedding upon prolonged contact with the virus, rendering neutralization irreversible. The kinetic and thermodynamic requirements of the shedding process were virtually identical to those of neutralization, identifying gp120 shedding as a key process associated with HIV neutralization by MPER bNAbs. Neutralizing and shedding capacity of 7 MPER-, CD4bs- and V3 loop-directed MAbs were assessed against 14 divergent strains. 17b was largely ineffective in both inducing neutralization and shedding. Ruprecht2011 (neutralization, kinetics)
17b: Deglycosylations were introduced into the 24 N-linked glycosylation sites of a R5 env MWS2 cloned from semen. Mutants N156-T158A, N197-S199A, N262-S264A and N410-T412A conferred decreased infectivity and enhanced sensitivity to a series of antibodies and entry inhibitors. Mutant N156-T158A showed enhanced neutralization sensitivity to MAb 17b in the absence of soluble CD4, suggesting that deglycosylation in these sites on gp120 may be beneficial for the exposure of a CD4 induced epitope which only exists in the CD4-liganded form of gp120. Huang2012 (glycosylation, neutralization)
17b: 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)
17b: A way to produce conformationally intact, deglycosylated soluble, cleaved recombinant Env trimers by inhibition of the synthesis of complex N-glycans during Env production, followed by treatment with glycosidases under conditions that preserve Env trimer integrity is described to facilitate crystallography and immunogenicity studies. Deglycosylation had no effect on basal or sCD4-induced interactions between the trimers and the coreceptor binding site-directed MAb 17b. Depetris2012 (glycosylation, binding affinity)
17b: 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. 17b did not bind to gp120 core, gp120 core D368R, RSC3, RSC3/G367R, RSC3 Δ3711, and RSC3 Δ3711/P363N. Lynch2012 (binding affinity)
17b: The study followed the dynamics of alternating viral neutralization phenotype over time in 7 patients monitored for 1-5 years starting from seroconversion. While the development of neutralization resistance, including escape from the autologous antibody response was observed, there was also temporal emergence of viruses exquisitely sensitive to both autologous and heterologous Nabs. All Envs with heightened serum sensitivity were also potently neutralized by sCD4 and/or IgG1b12.Neutralization by 17b in the absence of sCD4 was also observed. In contrast, out of nineteen serum resistant env-chimeras only three were neutralized by 17b in absence of sCD4. Aasa-Chapman2011 (autologous responses, escape)
17b: To test whether HIV-1 particle maturation alters the conformation of the Env proteins, a sensitive and quantitative imaging-based Ab-binding assay was used to probe the conformations of full-length and cytoplasmic tail (CT) truncated Env proteins on mature and immature HIV-1 particles. In the absence of sCD4, binding of MAb 17b to immature particles was approximately 40% less than binding to mature particles. 17b, A1g8, and E51 binding to immature virions was stimulated by sCD4 to a greater or equal extent vs. mature particles, with MAb 17b exhibiting the greatest increase. Truncation of the CT abolished the enhanced sCD4-induced binding of 17b to immature particles. This suggested that CD4 binding triggers exposure of some epitopes to an equal extent on immature and mature virions and other epitopes to a greater extent on immature virions. Joyner2011 (binding affinity)
17b: 17b MAb was used to study mechanism of neutralization by bnMAbs. 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)
17b: 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. 17b was studied among other antibodies that derive from a common IGHV1-69 allele to assess how atypical the VRC01-like antibody convergence was. T The angular difference in heavy-chain orientation between 17b, 412d, and X5 was over 90°, or roughly 10 times as much as among the VRC01-like antibodies. 17b had 41-62% sequence identity of its heavy and light chains to respective chains of VRC-PG04 and VRC-CH31. Wu2011 (structure)
17b: Molecular architectures of the soluble CD4 (sCD4)-bound states of SIV Env trimers for three different strains (SIVmneE11S, SIVmac239, and SIV CP-MAC) have been determined using cryo-electron tomography that showed only minor conformational changes following sCD4 binding in marked contrast to HIV-1 BaL, SIVmneE11S and SIVmac239. Binding of trimeric HIV-1gp120 to either sCD4 alone or to sCD4 in combination with the coreceptor mimic 17b results in an opening of the trimeric Env structure. Due to a dramatic difference between the angle of approach of MAbs 17b and that of SIV MAb 7D3, these Abs target epitopes on gp120 that are on opposites sides of the coreceptor binding site and in the vicinity of the V3 loop. White2011 (antibody binding site, structure)
17b: To address the controversy of significant differences in chosen atomic coordinates of monomeric SIV gp120 in unliganded, and monomeric HIV-1 gp120 in various liganded and antibodybound states, the molecular architectures of trimeric Env from SIVmneE11S, SIVmac239 and HIV-1 R3A strains are shown to be closely comparable to that previously determined for HIV-1 BaL. The gp120 density profiles obtained from the coordinates of the trimeric Env complex with sCD4/17b (1GC1) and b12 (2NY7) are similar even though there are important differences in their atomic resolution structures. White2010 (structure)
17b: 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. This MAb is noted in the review to be CD4i antibody and to have weak neutralizing activity against most HIV-1 isolates, with increased activity when soluble CD4 is added. Gonzalez2010 (neutralization, variant cross-reactivity, escape, review)
17b: 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, structure)
17b: 37 Indian clade C HIV-1 Env clones obtained at different time points from five patients with recent infection, were studied in neutralization assays for sensitivities to their autologous plasma antibodies and mAbs. One Env clone each from patients IVC2 and IVC3 was neutralized by 17b suggesting spontaneous exposure of CD4i epitopes. Ringe2010 (neutralization)
17b: This paper shows that a highly neutralization-resistant virus is converted to a neutralization sensitive virus with a rare single mutation D179N in the C-terminal portion of the V2 domain. A panel of mutants were tested to determine whether they can improve the neutralization sensitivity of an extremely neutralization-resistant clinical isolate. 17b neutralized wildtype sensitive clone and 6 out of 9 mutants tested (D179N, D179E, D179Q, D179H, D179S and D179A). ORourke2010 (neutralization, variant cross-reactivity)
17b: MAb m9 showed superior neutralization potency compared to scFv 17b in a TZM-bl assay, where it neutralized all 15 isolates compared to 17b that neutralized only 2 isolates. Unlike m9, 17b did not compete with R5Nt for binding to gp120, indicating that the epitope for m9 differs from that of 17b. Zhang2010 (neutralization)
17b: A side-by-side comparison was performed on the quality of Ab responses in humans elicited by three vaccine studies focusing on Env-specific Abs. High frequency and titers of 17b-like Abs were detected in all three vaccine trials. 58% of sera from the HVTN 203 trial, 75% of sera from the HVTN 041 trial, and 81% of sera from the DP6-001 trial were able to outcompete binding to 17b MAb. Vaine2010 (antibody interactions)
17b: 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)
17b: A mathematical framework is designed to determine the number of Abs required to neutralize a single trimer called the stoichiometry of trimer neutralization. 15 different virus antibody combinations divided into five groups based on antibody binding sites were used in the designed model. 17b was classified into CD4i group as it binds CD4. The number of 17b Abs needed to neutralize a single trimer was determined to equal 1 with 99.8% probability. Magnus2010
17b: Four human anti-phospholipid mAbs were reported to inhibit HIV-1 infection of human PBMC's by binding to monocytes and releasing soluble chemokines. The ability of different anti-phospholid mAbs to inhibit pseudovirus infection was studied. MAb 17b was able to capture HIV-1 pseudovirions only in the presence of soluble CD4 and not in its absence. 17b did not induce the production of chemokines. Moody2010 (binding affinity)
17b: The antigenic structure of Gag-Env pseudovirions was characterized and it was shown that these particles can recapitulate native HIV virion epitope structures. 17b exhibited low level binding to the Gag-Env pseudovirions that was markedly improved in the presence of sCD4, indicating presence of native trimers. The Gag-Env pseudovirions were further used to identify a subset of antigen-specific B cells in chronically infected HIV subjects. Hicar2010 (binding affinity, structure)
17b: 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 17b to gp120 was inhibited by B40t77, which is suggested to be due to the overlapping binding sites of the two molecules. Joubert2010 (binding affinity, structure)
17b: Biological effects of mutating I309L in HIV-1 subtype C Envs was examined. 4/11 mutated Envs showed moderate increase in their neutralization sensitivity to 17b after incubation with sCD4, indicating that I309L affects the efficiency with which the coreceptor binding site is formed. Lynch2010 (antibody binding site, neutralization)
17b: Unlike the MPER MAbs tested, 17b did not show any Env-independent virus capture in the conventional or in the modified version of the virus capture assay. Leaman2010
17b: 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. coreceptor binding site (CoRbs) directed MAb 17b bound similarly to WT and 368D/R trimers but its binding affinity was completely abrogated for 423/425/431 trimers. Douagi2010 (binding affinity)
17b: Peptide ligands for CD4i epitopes on native dualtropic Env were selected by phage display. The correct exposure of CD4i epitopes was detected with 17b, and incubation with sCD4 greatly enhanced its binding. An optimized synthetic peptide derivative (XD3) bound to all Env proteins analyzed with different coreceptor usage and inhibited binding of MAb 17b to immobilized gp120 in the presence and absence of sCD4 by 30 percent and 50 percent, respectively. Dervillez2010 (binding affinity)
17b: 21c binding, autoreactivity, polyreactivity and protective benefits are discussed and compared to other autoreactive MAbs, such as 2F5 and 4E10. Regulation of CD4i MAbs, such as 21c and 17b, by tolerance mechanisms is discussed. Haynes2010 (autoantibody or autoimmunity, antibody polyreactivity)
17b: Expression of gp120 was shown to lead to the accumulation of both monomeric gp120 and aberrant dimeric gp120 forms. Dimeric forms of gp120 were not recognized by CD4i MAbs, such as 17b, nor by MAbs against the gp120 inner domain, but were recognized by CD4BS MAbs. 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)
17b: 17b was linked with sCD4 and the construct was tested for its neutralization breadth and potency. sCD4-17b showed significantly greater neutralization breadth and potency compared to other MAbs (b12, 2G12, 2F5 and 4E10), neutralizing 100% of HIV-1 primary isolates of subtypes A, B, C, D, F, CRF01_AE and CRF02_AG. Unlike the other MAbs, sCD4-17b was equivalently active against virus particles generated from different producer cell types. Lagenaur2010 (neutralization, variant cross-reactivity, subtype comparisons)
17b: 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. In the absence of sCD4, 17b bound and neutralized ΔV1V2 variants more potently than the full-length trimer. Addition of sCD4 did not enhance 17b binding, as it was close to optimal without sCD4. 17b did not bind to the ΔV1V2 variant with V120K substitution. For the uncleaved variants, 17b bound to the ΔV1V2 but did not bind well to the full-length virus, unaffected by presence of sCD4. Bontjer2010 (neutralization, binding affinity)
17b:The effect of amino acid polymorphisms on the structural stability and cooperative interactions of gp120, from A and B subtype HIV-1, were compared using microcalorimetric techniques. The impact of these polymorphisms on the binding mechanisms of gp120-A and gp120-B to the host cell surface receptors and coreceptors was also studied for development of entry inhibitors. The binding affinity of 17b is increased by CD4 for gp120-B but only minimally increased for gp120-A. Binding of 17b to gp120-A induced smaller enthalpy and entropy changes compared to 17b binding to gp120-B, indicating that binding of this Ab to gp120-A induces smaller conformational changes. The epitope for this Ab is highly conserved between gp120-A and gp120-B proteins, although 17b has 3-fold weaker affinity for gp120-A. Brower2010 (kinetics, binding affinity, subtype comparisons)
17b: Neutralizing activities of 17b were similar against parent and GnTI (complex glycans of the neutralizing face are replaced by fully trimmed oligomannose stumps) viruses, and the N301Q mutant virus (glycan at position 301 is removed), with all viruses being resistant to neutralization by this Ab. Binley2010 (glycosylation, neutralization)
17b: Binding of 17b to Env HIV-1 JR-FL increased gradually as the amount of CD4-mimicking small compound NBD-556 increased. Pretreatment by NBD-556 remarkably increased binding of 17b to JR-FL Env, indicating enhancement of 17b epitope accessibility by NBD-556. Yoshimura2010 (mimics, binding affinity)
17b: A panel of 109 HIV-1 pseudoviruses was assessed for neutralization sensitivities to 17b MAb and patient plasma pools from genetically diverse HIV-1 positive samples. Clustering analyses revealed that the 109 viruses could be divided to 4 sub-groups, based on their neutralization sensitivity to the plasma pools: very high (Tier 1A), above-average (Tier 1B), moderate (Tier 2), and low (Tier 3) sensitivity. 3 Tier 1A, 6 Tier 1B, 1 Tier 2 but no Tier 3 viruses were found to be sensitive to neutralization by 17b. Seaman2010 (neutralization)
1.7B: gp41 L669S mutant virus was moderately sensitive to neutralization by 1.7B while the L669 wild type virus was resistant. This indicates that conformational changes in the MPER could alter the exposure of neutralization epitopes in other regions of HIV-1 Env. Shen2010 (neutralization)
17b: Fusion of CD4 with 17b scFv resulted in CD4-scFv17b reagent with neutralization potency comparable to other CD4-CD4i complexes. The neutralization potency was improved by inclusion of an IgG Fc region and by linkage of CD4 to the heavy chain of 17b. The resulting CD4hc-IgG17b neutralized a range of clade A, B and C viruses with potency comparable to other broadly neutralizing Abs. The complex, however, had low expression levels. West2010 (neutralization, variant cross-reactivity, subtype comparisons)
17b: 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. 17b 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 17b than the wild type, indicating that the HA tag had resulted in localized alternation of gp120. Pantophlet2009 (neutralization)
17b: NAb specificities of a panel of HIV sera were systematically analyzed by selective adsorption with native gp120 and specific mutant variants. The integrity of gp120 beads in adsorption assay were validated by binding analysis to 17b. gp120 point mutation D368R was used to screen the sera for CD4bs- Abs, and it was shown that this mutant could adsorb binding activity of 17b. To test for presence of coreceptor binding region MAbs in sera, gp120 I420 mutant was used. This mutant was not recognized by 17b, and it could not adsorb binding activity of 17b in adsorption assay. In some of the broadly neutralizing sera, the gp120-directed neutralization was mapped to CD4bs. Some sera were positive for NAbs against coreceptor binding region. A subset of sera also contained NAbs directed against MPER. Li2009c (assay or method development)
17b: The review discusses the implications of HIV-1 diversity on vaccine design and induction of neutralizing Abs, and possible novel approaches for rational vaccine design that can enhance coverage of HIV diversity. Patterns of within-clade and between-clade diversity in core epitopes of known potent neutralizing Abs is displayed. Korber2009 (review)
17b: 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. Most V1/V2 deleted viruses were sensitive to neutralization by 17b, while the wild type and the evolved variants were resistant. This indicated that deletion of V1/V2 increases exposure of 17b epitope, and that the compensation mutations in the evolved viruses damage 17b epitope. Bontjer2009 (antibody binding site, neutralization)
17b: 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. 17b bound with high affinity to CD4-bound but not to non-CD4-bound gp120 conformation. The number of mutations from the germline and the number of mutated contact residues for 17b were smaller than those for VRC01. Zhou2010 (neutralization, binding affinity, structure)
17b: 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 17b. Memory B cells were selected that bound to RSC3 and full IgG mAbs were expressed. Binding of 17b to gp120 was enhanced by the addition of two newly detected mAbs VRC01 and VRC02. Wu2010 (antibody interactions, binding affinity)
17b: Flexibility and rigidity of gp120 structures in isolation and in complex with CD4, CD4-mimics, and NAbs was analyzed using Floppy Inclusion and Rigid Substructure Topography program. The mean global flexibility of CD4/17b-bound gp12 was lower than that of b12-bound gp120. A common rigid core including residues 335-352 of gp120 was found, regardless of the strain or binding patterns. Tan2009 (antibody binding site)
17b: Combinations of loop alternations, filling hydrophobic pockets (F-mutations) and introduction of inter-domain cysteine pairs (D-mutations) were used to construct four immunogens with stabilized gp120 core. Modified truncations of the V1V2 and the V3 loop significantly increased 17b binding, even in the absence of CD4, and introduction of stabilizing F and D mutations significantly increased the on-rates of 17b interaction. Immunization assays revealed that the truncated core protein induced much higher titer of CD4bs-directed Abs than CD4i Abs, while conformationally stabilized mutant did the opposite. Dey2009 (kinetics, binding affinity)
17b: A review about the in vivo efficacy of MAbs against HIV-1, and about inhibition of HIV-1 infection by MAb fragments (Fab, scFv), including single molecules or fusion proteins of 17b. Also, the efficacy of engineered human Ab variable domains or "domain antibodies" (dAbs) as therapeutic agents is reviewed. Chen2009b (neutralization, immunotherapy, review)
17b: Affinity and changes in enthalpy and entropy of 17b binding to gp120/sCD4 complex were evaluated. S22 peptide, which is a 22 aa tyrosine-sulfated peptide corresponding to the CCR5 N-terminal region, competitively inhibited 17b. Brower2009 (kinetics, binding affinity)
17b: 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 17b. Wu2009a (binding affinity)
17b: 17b competed slightly with the broadly neutralizing Ab PG9 for binding to gp120. Walker2009a
17b: Δ9-12a, a mutant virus derived from an in-vitro passaged virus with four residues removed from the V3 stem, was shown to be completely resistant to CCR5 inhibitors and to neutralization by 17b. TA1, a mutant with a 15 amino acid deletion of the distal half of V3, was extremely sensitive to neutralization by 17b. Nolan2009 (neutralization)
17b: Binding of 17b to gp120 was not inhibited by YZ23, an Ab derived from mice immunized with eletcrophilic analogs of gp120 (E-gp120), indicating no overlap of these MAb epitopes. Nishiyama2009
17b: EpiSearch is an algorithm that predicts the location of conformational epitopes on the surface of an antigen by using peptide sequences from phage display experiments as input and ranking surface exposed patches according to the frequency distribution of similar residues in the peptides and in the patch. When tested for 17b, the conformational epitope was predicted correctly with terminal cysteine residues, but when these were omitted the accuracy of the method was lowered. Negi2009 (computational epitope prediction)
17b: Subtype A gp140 SOSIP trimers were recognized by 17b. Kang2009
17b: The Ig usage for variable heavy chain of this Ab was as follows: IGHV:1-69, IGHD:nd, D-RF:nd, IGHJ:1. 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. Anti-CD4i mAbs exclusively used the VH1 gene family. Gorny2009 (antibody sequence)
17b: Ten new non-neutralizing, cross-reactive mAbs were found in immunized mice. 17b was able to bind free virions, which was increased by addition of sCD4, while the newly detected mAbs could not bind free virions. Gao2009
17b: Two chimeras were constructed from a new HIV-2KR.X7 proviral scaffold where the V3 region was substituted with the V3 from HIV-1 YU2 and Ccon, generating subtype B and C HIV-2 V3 chimera. Both chimera, and the wildtype HIV-2KR and its derivatives HIV-2KR.X4 and HIV-2KR.X7 were resistant to neutralization by 17b. Davis2009 (neutralization)
17b: Two different but genetically related viruses, CC101.19 and D1/85.16, which are resistant to small molecule CCR5 inhibitors, and two clones from their inhibitor sensitive parental strain CC1/85, were used to analyze interactions of HIV-1 with CCR5. CC101.19 had 4 substitutions in the V3 region and D1/85.16 had 3 changes in gp41. CC101.19 was the most neutralization sensitive to 17b, while this Ab had limited neutralization activity to the two parental clones and to D1/85.16. However, gp120 from CC1/85 and D1/85.16 were the most reactive with 17b, and gp120 from all four viruses was equally reactive with 17b when sCD4 was added. This indicates that at least one major element of the CCR5 binding site has become accessible in the inhibitor-resistant CC101.19 virus. Berro2009 (neutralization)
17b: 17b neutralized Tier 1 but not Tier 2 viruses. Crystal structure of F105 in complex with gp120 revealed that 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 bound by 17b, suggesting that 17b does not rely on access to the hydrophobic surface for binding. Binding affinity and kinetics of 17b binding to several gp120 variants as assessed. Chen2009 (neutralization, kinetics, binding affinity)
17b: 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. 17b 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)
17b: An R5X4 HIV-1 strain, R3A, could tolerate partial loss of its V3 loop, but was poorly functional. After passage in tissue culture, the virus (now called TA1) still had a truncated V3 loop, but had acquired five mutations in its env gene and had also regained its function. TA1 was sensitive to neutralization by 17b MAb while the parental R3A was resistant to neutralization by this Ab. Viruses with Envs containing two or three of the five adaptive mutations were less sensitive to neutralization by 17b than TA1. Thus, the V3 truncation played a central role in sensitivity to 17b, but the adaptive mutations substantially increased sensitivity of the virus to 17b. Agrawal-Gamse2009 (neutralization)
17b: 17b neutralized infection of PBLs with R5 HIV-1 strains with higher potency than X4 HIV-1 strains. However, 17b did not inhibit transcytosis of cell-free or cell-associated virus across a monolayer of epithelial cells. A mixture of 13 MAbs directed to well-defined epitopes of the HIV-1 envelope, including 17b, 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 (neutralization)
17b: 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 17b-gp120 interaction, but the CNV alone had a limited effect, indicating that the chimera has the high affinity binding property of the CNV molecule and the inhibitory property of the 12p1 peptide. McFadden2007
17b: This review summarizes data on possible vaccine targets for elicitation of neutralizing Abs and discusses whether it is more practical to design a clade-specific than a clade-generic HIV-1 vaccine. Development of a neutralizing Ab response in HIV-1 infected individuals is reviewed, including data that show no apparent division of different HIV-1 subtypes into clade-related neutralization groups. The neutralizing activity of CD4i Abs, such as 17b, is discussed. McKnight2007 (review)
17b: This review provides information on the HIV-1 glycoprotein properties that make it challenging to target with neutralizing Abs. 17b 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)
17b: 17b structure, binding, neutralization, and strategies that can be used for vaccine antigen design to elicit 17b-like Abs, are reviewed in detail. Lin2007 (review, structure)
17b: This review summarizes 17b Ab epitope, properties and neutralization activity. The effect of differential CCR5 cell surface expression on 17b neutralization activity is discussed. Kramer2007 (co-receptor, neutralization, review)
17b: gp120 proteins with double mutation T257S+S375W, which alters the cavity at the epicenter of the CD4 binding region, showed a weak interaction with 17b in the absence of CD4 and efficient interaction with maximal 17b binding in the presence of 17b. Similar results were observed with unmodified gp120, indicating that although properly folded, the mutant proteins were not completely stabilized in the CD4-bound conformation by the two mutations. The gp120 proteins with double mutation T257S+S375W were used to immunize rabbits. The ability of rabbit sera to affect binding of CD4 to unmodified gp120 proteins was tested. CD4 binding to gp120 was enhanced by 17b. Dey2007a (binding affinity)
17b: The various effects that neutralizing and non-neutralizing anti-envelope Abs have on HIV infection are reviewed, such as Ab-mediated complement activation and Fc-receptor mediated activities, that both can, through various mechanisms, increase and decrease the infectivity of the virus. The importance of these mechanisms in vaccine design is discussed. The unusual features of the 17b MAb are described. Willey2008 (review)
17b: A mathematical model was developed and used to derive transmitted or founder Env sequences from individuals with acute HIV-1 subtype B infection. All of the transmitted or early founder Envs were resistant to neutralization by 17b, while Envs from three chronically infected patients were unusually sensitive to neutralization by 17b. This indicated that the coreceptor binding surfaces on transmitted/founder Envs are conformationally masked. Keele2008 (neutralization, acute/early infection)
1.7b: Transmission of HIV-1 by immature and mature DCs to CD4+ T lymphocytes was significantly higher for CXCR4- than for CCR5-tropic strains. Preneutralization of R5 virus with 1.7b prior to capture efficiently blocked transmission to 44%, while preineutralization of X4 virus with 1.7b had no effect, indicating that 1.7b treatment results in more efficient transfer of X4 than of R5 HIV-1. vanMontfort2008 (co-receptor, neutralization, dendritic cells)
17b: An R5 HIV variant, in contrast to its parental virus, was shown to infect T-cell lines expressing low levels of cell surface CCR5 and to infect cells in the absence of CD4. The variant was seven-fold more sensitive to neutralization by 17b than the parental virus, indicating that the CCR5 binding site of gp120 is partially exposed on the mutant virus without prior binding to CD4. These properties of the mutant virus were determined by alternations in gp41. Taylor2008 (co-receptor, neutralization)
17b: Trimeric envelope glycoproteins with a partial deletion of the V2 loop derived from subtype B SF162 and subtype C TV1 were compared. The magnitude of 17b binding to subtype C trimer was lower than to subtype B trimer, either in the presence or absence of CD4. However, the fold increase in binding of 17b in presence of CD4 was similar for both subtypes, indicating similar structural rearrangements. Subtype C trimer had many biophysical, biochemical, and immunological characteristics similar to subtype B trimer, except for a difference in the three binding sites for CD4, which showed cooperativity of CD4 binding in subtype C but not in subtype B. Srivastava2008 (binding affinity, subtype comparisons)
17b: In order to assess whether small molecule CCR5 inhibitor resistant viruses were more sensitive to neutralization by NAbs, two escape mutant viruses, CC101.19 and D1/85.16, were tested for their sensitivity to neutralization by 17b, compared to the sensitivity of CC1/85 parental isolate and the CCcon.19 control isolate. The CC101.19 escape mutant has 4 sequence changes in V3 while the D1/85.16 has no sequence changes in V3 and relies on other sequence changes for its resistance. None of the control or resistant viruses were sensitive to neutralization by 17b. Pugach2008 (co-receptor, neutralization)
17b: The sensitivity of R5 envelopes derived from several patients and several tissue sites, including brain tissue, lymph nodes, blood, and semen, was tested to a range of inhibitors and Abs targeting CD4, CCR5, and various sites on the HIV envelope. All but one envelopes from brain tissue were macrophage-tropic while none of the envelopes from the lymph nodes were macrophage-tropic. Macrophage-tropic envelopes were also less frequent in blood and semen. None of the patient envelopes were inhibited by 17b, indicating that 17b epitope is not more exposed on macrophage-tropic envelopes than on non-macrophage tropic ones. Peters2008a (neutralization)
17b: Crystal structures of CD4M47 (a derivative of a synthetic miniprotein with HIV-1 gp120 binding surface of the CD4 receptor incorporated) and a phenylalanine variant ((Phe23)M47) were determined in ternary complexes with HIV-1 gp120 and 17b Ab. The structures revealed correlation between mimetic affinity of the miniprotein for gp120 and overall mimetic-gp120 interactive surface. Stricher2008 (structure)
17b: 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 17b Ab. Inhibition was found to be concentration-dependent. 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. No inhibition of gp120 binding to 17b was observed for position 7 homoalanine-derived conjugates. Gopi2008
17b: Requirements for elicitation of CD4i Abs were examined by immunizing non-primate monkeys, rabbits, and human-CD4 transgenic (huCD4) rabbits with trimeric gp140. The trimers were well recognized by 17b in the absence of CD4 but the relative binding affinity increased 2-5-fold in the presence of sCD4. The avidity of the trimers for 17b in the absence of CD4 was determined to be in the low nanomolar range. Sera from immunized monkeys were able to inhibit 17b binding at a 10-fold higher dilution than sera from immunized rabbits. 17b could bind to the gp140 trimers bound to cell-surface CD4 as well, confirming that the co-receptor site is accessible after trimer binding to membrane-bound CD4. Forsell2008 (antibody binding site, binding affinity)
17b: Neutralization of JRFL, ADA, and YU2 isolates by 17b increased only modestly with increased dose of sCD4, and was never above 50%, indicating that the dose of sCD4, although enough to expose the V3 region, was insufficient to induce full conformational exposure of the co-receptor binding site. Wu2008 (neutralization)
17b: 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 17b 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 intact 17b epitope. gp140DF162ΔV2 was purified by the miniCD4 method to assess its ability to capture gp140 trimers. Binding of 17b 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)
17b: Variable domains of three heavy chain Abs, the VHH, were characterized. The Abs were isolated from llamas, who produce immunoglobulins devoid of light chains, immunized with HIV-1 CRF07_BC, to gp120. It was hypothesized that the small size of the VHH, in combination with their protruding CDR3 loops, and their preference for cleft recognition and binding into active sites, may allow for recognition of conserved motifs on gp120 that are occluded from conventional Abs.17b provided some inhibition of binding of the three neutralizing VHH Abs to gp120, suggesting that 17b imposes steric hinderance to binding of the VHH Abs to gp120. Forsman2008 (antibody interactions)
17b: Three-dimensional structures of trimeric Env displayed on native HIV-1 in complex with CD4 and the Fab fragment of 17b were compared to the unligated state, using cryo-electron tomography combined with three-dimensional image classification and averaging. Binding of 17b and CD4 resulted in dramatic conformational changes, including lever-like opening of the trimer. Binding of CD4 made way for exposure of gp41 stalk, and the V3 region was released from the lateral edge of the spike to point towards the target cell. V1/V2 and CD4 binding site moved away from the centre of the spike. Liu2008 (antibody binding site, structure)
17b: V3 loop deletions were introduced into three different primary HIV-1 strains: R3A, DH12, and TYBE. The deletions included: ΔV3(12,12) containing the first and the last 12 residues of the V3 loop, ΔV3(9,9) containing first and last 9 residues, and ΔV3(6,6) containing first and last 6 residues. Only HIV-1 R3A ΔV3(9,9) was able to support cell fusion. Passaging of this virus resulted in a virus strain (TA1) that replicated with wildtype kinetics, and that acquired several adaptive changes in gp120 and gp41 while retaining the V3 loop truncation. 17b neutralized a ΔV1/V2 virus but failed to neutralize R3A or LAI. TA1 was 100-fold more sensitive to neutralization by 17b than the ΔV1/V2 virus. Laakso2007 (neutralization)
17b: HIV-1 env clones resistant to cyanovirin (CV-N), a carbohydrate binding agent, showed amino acid changes that resulted in deglycosylation of high-mannose type residues in the C2-C4 region of gp120. Compared to their parental virus HIV-1 IIIB, these resistant viruses maintained similar sensitivity to 17b, as the glycan at position 301 in the V3 loop was intact. Hu2007 (neutralization, escape)
17b: 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. 17b captured both pseuduvirion preparations weakly in the absence of sCD4, but its binding was increased when sCD4 was also present. 17b failed to inhibit infection by either pseudovirus. Dey2008 (binding affinity)
17b: 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 17b was used to analyze antigenic properties of construct 92UG-gp140-Fd, derived from isolate 92UG037.8 and stabilized by a C-terminal foldon tag. Uncleaved 92UG-gp140-Fd binds 17b, but only in the presence of CD4. Frey2008 (binding affinity)
17b: 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 17b compared to wildtype. Also, there was no association between increased sensitivity to 17b neutralization and enhanced macrophage tropism. Dunfee2007 (neutralization)
17b: This review summarizes data on the development of HIV-1 centralized genes (consensus and ancestral) for induction of neutralizing antibody responses. Functionality and conformation of native epitopes in proteins based on the centralized genes was tested and confirmed by binding to 17b and other MAbs. Binding of 17b following CD4 also indicated presence of functionally relevant conformational changes of the proteins. Gao2007 (review)
17b: Macaques were immunized with either CD4, gp120, cross-linked gp120-human CD4 complex (gp120-CD4 XL), and with single chain complex containing gp120 rhesus macaque CD4 domains 1 and 2 (rhFLSC). Sera from the rhFLSC immunized animals showed highest competition titers, being able to block gp120-CD4 complex interactions with 17b more efficiently than sera from animals immunized with the three other proteins. DeVico2007 (neutralization)
17b: Interactions of this Ab with gp120 monomer and two cleavage-defective gp140 trimers were studied. It was shown that 17b interactions with the soluble monomers and trimers were dramatically decreased by GA cross-linking of the proteins, indicating that the 17b epitope was affected by cross-linking. This Ab was associated with a large entropy change upon gp120 binding. 17b was shown to have a kinetic disadvantage as it bound to gp120 much slower than the highly neutralizing Abs 2G12 and IgG1b12. Yuan2006 (antibody binding site, antibody interactions, kinetics, binding affinity)
17b: The neutralizing activity of coreceptor-binding site Abs, such as 17b, is reviewed. Pantophlet2006 (antibody binding site, neutralization)
17b: The G314E escape variant highly resistant to KD-247 was shown to be more sensitive to 17b Ab than the wildtype virus. 17b was shown to be able to bind and neutralize the escape virus even in the absence of rsCD4 while rsCD4 was necessary for binding of 17b to the wildtype virus, indicating that the G314E mutation induces the expression of epitopes for Abs against CD4i epitope and V3 loop. Yoshimura2006 (neutralization, escape, binding affinity)
17b: Binding of 17b in the presence or absence of CD4 to wt gp120 and two constructs with 5 and 9 residues deleted in the middle of the beta3-beta5 loop in the C2 region of gp120 was examined. In concordance with previous studies, 17b did not bind wt gp120 in absence of CD4 but did bind it in the presence of CD4. In contrast, the two deletion constructs did not bind 17b regardless of presence or absence of CD4 indicating that the loop-deleted gp120 is unable to close up the bridging sheet and display the coreceptor site and the 17b epitope. Rits-Volloch2006 (antibody binding site, binding affinity)
17b: gp120 (monomer), gp120deltaV2 (trimer), gp140 (monomer) and gp140deltaV2 (trimer) from subtype B SF162 were expressed in cells and their affinity for 17b was assessed. All four Envs bound to 17b in the absence of CD4 but the monomers showed 3-fold higher affinity for this Ab than trimers. In the presence of CD4, the 17b epitope was up-regulated in all Envs. Sharma2006 (antibody binding site, binding affinity)
17b: This Ab was used in a microcantilever deflection assay to detect gp120 from solution. Deflection twice that of the baseline that was detected upon specific binding of gp120 to cantilevers decorated on one side with A32 was further increased by subsequent incubation with 17b. Lam2006 (assay or method development)
17b: Viruses with V2 mutations R166K, D167N and P175L were resistant to 17b and a reduction of binding 17b to these viral variants was observed. Shibata2007 (escape, binding affinity)
1.7b: 1.7b-neutralized HIV-1 captured on Raji-DC-SIGN cells or immature monocyte-derived DCs (iMDDCs) was successfully transferred to CD4+ T lymphocytes, indicating that the 1.7b-HIV-1 complex was disassembled upon capture by DC-SIGN-cells. vanMontfort2007 (neutralization, dendritic cells)
17b: Chimeric VLPs, containing chimeric Con-S ΔCFI Env proteins with heterologous signal peptide (SP), transmembrane (TM), and cytoplasmic tail (CT) sequences, were all induced to bind to 17b after binding to CD4, indicating that chimeric Envs in VLPs undergo conformational changes induced by CD4. Wang2007a (antibody binding site, vaccine antigen design, binding affinity)
17b: The structure of the 17b MAb, particularly its CDRH3 region tyrosine sulfation, is reviewed. Also, the mechanism of its binding to the coreceptor binding site of gp120, and comparisons of the neutralizing potencies of 17b Ab fragments vs the whole IgG molecule are discussed. Engineering of Abs based on revealed structures of broadly neutralizing MAbs is discussed. Burton2005 (antibody binding site, neutralization, review, structure)
17b: Monomeric gp120 and trimeric gp140CF proteins synthesized from an artificial group M consensus Env gene (CON6) did not bind to 17b directly, but bound to it following binding to sCD4 and A32, indicating correct conformational change and subsequent exposure of the 17b epitope. Gao2005a (antibody binding site, binding affinity)
17b: The structure of the V3 region in the context of gp120 core complexed to the CD4 receptor and to the 17b Ab was attempted to be determined by X-ray resolution, but only the structure for V3 complexed with CD4 and X5 Ab was solved. Accessibility of the co-receptor binding site to this MAb is shown in a 3D figure. Huang2005 (antibody binding site, structure)
17b: 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. 17b exhibited similar levels of binding to both the LLP-2 mutant and wildtype viruses, indicating that sCD4 binding to the LLP-2 mutant successfully triggered conformational change of gp120 and exposure of the co-receptor binding site. Kalia2005 (antibody binding site, binding affinity)
17b: 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 17b, three of the modified proteins expressed in insect cells, including dV1V2 mutant (V1V2 deletions) followed by 3G-dV2-1G mutant (3G being mutations in three glycosylation sites and 1G being a mutation near the TM domain) and 3G-dV2 mutant, showed higher binding to the Ab than the wildtype did. This indicated that the dV1V2 mutant may expose 17b epitope better than the other Env proteins. When expressed in animal cells, only mutants 3G and dV2 showed enhanced binding to 17b but only at high concentrations of the MAb. Kang2005 (antibody binding site, binding affinity)
17b: 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 trimers for CD4 and for 17b. Both the CNG-gp120 trimers and the D457V mutants showed a restricted stochiometry to 17b of one Ab molecule binding per trimer. Removal of the V1-V2 loops resulted in binding of three 17b molecules per trimer. Pancera2005a (binding affinity, structure)
17b: R-FL and YU2 HIV-1 strains were not neutralized by 17b.17b 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.17b, 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)
17b: Escape mutations in HR1 of gp41 that confer resistance to Enfuvirtide reduced infection and fusion efficiency and also delayed fusion kinetics of HIV-1. The mutations also conferred increased neutralization sensitivity of virus to 17b. Enhanced neutralization correlated with reduced fusion kinetics, indicating that the mutations result in Env proteins remaining in the CD4-triggered state for a longer period of time. Reeves2005 (antibody binding site, drug resistance, neutralization, escape, HAART, ART)
17b: 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, variant cross-reactivity, review, structure)
17b: This Ab bound with an intermediate affinity to gp120IIIb, it did not prevent uptake of gp120 by APCs, and had no inhibitory effect on gp120 antigen presentation by MHC class II. 17b disassociated from gp120 at acidic pH. Lysosomal enzyme digestion of gp120 treated with 17b yielded fragmentation similar to that of gp120 alone, and digestion rate was intermediate, between the rapid digestion of gp120 alone and the slow digestion of gp120 in complex with high-affinity Ab5145A. It is thus concluded that CD4i Ab 17b does not have an inhibitory effect on gp120 processing and presentation. Tuen2005 (antibody interactions, binding affinity)
17b: 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)
17b: A substantial fraction of soluble envelope glycoprotein trimers contained inter-subunit disulfide bonds. Reduction of these disulfide bonds decreased binding of 17b to the glycoprotein, indicating that the inter-S-S bonds contribute to the exposure of the CD4-induced region. Yuan2005 (antibody binding site)
17b: Conformation of two gp120 constructs, gp120 bound to CD4D12 (the first two domains of human CD4), and gp120 bound to M9 (a 27-residue CD4 analog), was characterized by binding assays with Ab b17 in the presence or absence of soluble CD4D12. JRFL gp120 alone did not bind to b17 in the absence of CD4D12 but did bind in the presence of CD4D12. The gp120-CD4D12 construct bound to b17 in the absence of soluble CD4D12, and no enhancement in binding was observed when soluble CD4D12 was present, suggesting that all of the single chain was properly folded in the CD4i conformation. gp120-M9 construct also bound to 17b but with much lower affinity, and the binding was enhanced with presence of soluble CD4D12. This suggested that gp120-M9 single chain may contain both molecules where gp120 is bound to M9 in the CD4i conformation, and molecules resembling free gp120. Varadarajan2005 (antibody binding site, kinetics, binding affinity)
17b: A reverse capture assay was developed to assess what kind of human MAbs were produced in EBV B-cell transformation assays performed on PBMC sampled at different time-points from three HIV-1 infected patients on HAART. The reverse capture assay was validated by the solid phase MAbs that could not capture biotin-MAbs of the same or overlapping specificity when reacted with patient virus envelope glycoproteins preincubated with or without sCD4. Reverse capture assay showed that the produced Abs from the patients were able to block binding of biotin-labeled 17b, indicating presence of CD4i Abs. These were the most frequently produced Abs from all three patients, suggesting that CD4i epitopes are much more immunogenic than previously appreciated. Robinson2005 (assay or method development, HAART, ART)
17b: This review summarizes data on 447-52D and 2219 crystallographic structures when bound to V3 peptides and their corresponding neutralization capabilities. 17b, like 447-52D and like other HIV-1 neutralizing Abs, was shown to have long CDR H3 loop, which is suggested to help Abs access recessed binding sites on the virus. Stanfield2005 (antibody binding site, review, structure)
17b: A T-cell line adapted strain (TCLA) of CRF01_AE primary isolate DA5 (PI) was more neutralization sensitive to 17b 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 17b then the PI strain. Deglycosylated subtype B mutants at positions 197 and 234 were slightly more neutralizable by 17b. Teeraputon2005 (antibody binding site, neutralization, subtype comparisons)
17b: 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). 17b bound to SF162gp140 and ΔV3gp140 more efficiently than to ΔV2gp140 and ΔV2ΔV3gp140. The neutralization of SF162 by 17b was enhanced in a concentration-dependent manner by pre-incubation with sCD4. Derby2006 (antibody binding site, neutralization)
17b: This Ab bound to the Fc-gp120 construct, but only weakly to the chimeras lacking the V3 loop. sCD4 restored high affinity binding to all constructs. Binley2006 (binding affinity)
17b: A fusion protein (FLSC R/T-IgG1) that targets CCR5 was expressed from a synthetic gene linking a single chain gp120-CD4 complex containing an R5 gp120 sequence with the hinge-Ch2-Ch3 portion of human IgG1. Binding of this protein to the CCR5 co-receptor was inhibited by MAb 17b in a dose-dependent manner. The fusion protein did not activate the co-receptor by binding, and it potently neutralized primary R5 HIV-1. Vu2006 (co-receptor)
17b: Cloned Envs (clades A, B, C, D, F1, CRF01_AE, CRF02_AG, CRF06_cpx and CRF11_cpx) derived from donors either with or without broadly cross-reactive neutralizing antibodies were shown to be of comparable susceptibility to neutralization by 17b. Cham2006 (neutralization, variant cross-reactivity, subtype comparisons)
17b: Neutralization of HIV-1 primary isolates from clade B by different formats of 17b was determined in cells expressing high or low surface concentrations of CD4 and CCR5 receptors. CD4 cell surface concentration had no effect on the inhibitory activity of this Ab while the CCR5 surface concentration had a significant effect decreasing the 50% inhibitory concentration of 17b in cell lines with low CCR5. Choudhry2006 (co-receptor, neutralization, variant cross-reactivity)
1.7b: This Ab did not inhibit HIV-1 BaL replication in macrophages or in PHA-stimulated PBMCs. Holl2006 (neutralization, dendritic cells)
17b: 17b was used as a negative control to test CDR3 tyrosine sulfation of MAbs 47e, 412d, CM51, E51, C12 and Sb1, since its CDR3 tyrosines are buried. As expected, 17b did not incorporate sulfates while the other MAbs did. Thus, the expression of 17b, or its binding to gp120 bound to CD4-Ig, was not affected by sulfation-inhibition. In addition, 17b was used as a positive control to test whether MAbs 47e, 412d, E51, Sc1 and C12 are CD4i Abs. Binding efficiency of all MAbs to ADA gp120 was doubled in the presence of CD4, showing that they are CD4-induced. scFv 17b was shown to efficiently bind to gp120 of three R5 isolates and to the HXBc2 X4 isolate. Neutralization assays showed that 17b was less efficient at neutralizing primary R5 and R5X4 isolates than MAbs 412d and E51, however, it was more efficient at neutralizing X4 isolates than these MAbs. Choe2003 (antibody binding site, neutralization)
17b: The CDR3 regions of CD4i Abs (E51, 412d, 17b, C12 and 47e) were cloned onto human IgG1 and tested for their ability to inhibit CCR5 binding. Only E51 successfully immunoprecipitated gp120. Dorfman2006 (co-receptor)
17b: The gp140δCFI protein of CON-S M group consensus protein and gp140CFI and gp140CF proteins of CON6 and WT viruses from HIV-1 subtypes A, B and C were expressed in recombinant vaccinia viruses and tested as immunogens in guinea pigs. Both CD4 induced and A32 induced 17b was shown to bind specifically to all recombinant proteins except for the gp140δFI derived from subtype C virus. This Ab also bound specifically to one of the two tested subtype B gp120 proteins. The specific binding of his Ab to CON-S indicated that its conformational epitope was intact. Liao2006 (antibody binding site, vaccine antigen design, subtype comparisons)
17b: The small molecule HIV-1 entry inhibitor IC9564 significantly enhanced binding of 17b Ab to gp120 on cell surface and on viral particles. The binding was independent of the presence of soluble CD4 suggesting that IC9564 induces conformational change in gp120 that exposes the concealed 17b epitope. Significant increase in neutralizing activity of 17b in the presence of IC9564 was observed for NLDH120 and NL4-3 virus strains. In contrast to CD4, IC9564 does not induce a conformational change in gp41, and inhibits CD4-induced gp41 conformational changes. Huang2007 (antibody binding site)
17b: 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 sCD4 in the WT and stabilized forms. Non-neutralizing MAbs PA-1 and b6 bound less efficiently to the stabilized trimer. Dey2007 (vaccine antigen design)
17b: This Ab was found to be able to bind to a highly stable trimeric rgp140 derived from a HIV-1 subtype D isolate containing intermonomer V3-derived disulfide bonds and lacking gp120/gp41 cleavage. Protein disulfide isomerase treatment of rgp120 and rgp140 was found to severely inhibit binding of 17b, suggesting a structural need for V3-derived disulfide bonds in coreceptor binding. gp140 binding to 17b was 2-fold enhanced with by sCD4, indicating the proteolytically immature protein was able to undergo CD4i conformational changes. Billington2007 (antibody binding site, co-receptor, vaccine antigen design)
17b: Four consensus B Env constructs: full length gp160, uncleaved gp160, truncated gp145, and N-linked glycosylation-site deleted (gp160-201N/S) were compared. All were packaged into virions, and all but the fusion defective uncleaved version mediated infection using the CCR5 co-receptor. CD4 inducible MAbs 17b and E51 were tested for the ability to neutralize the various forms of Con B; as anticipated gp160 and gp145 were not neutralized by these two MAbs, but the gp160-201N/S mutant was neutralized with IC50 values of 10 ug/ml, suggesting increased formation and/or exposure of the co-receptor binding site. The poorly infectious clone WITO4160.27 was also somewhat susceptible to neutralization by these clones. Kothe2007 (vaccine antigen design, variant cross-reactivity)
17b: 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. CD4i MAbs (48d, 17b) did not bind to either GDMR or mCHO even with sCD4. Selvarajah2005 (vaccine antigen design, vaccine-induced immune responses)
17b: 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 F105, IgG1b12, 17b and 48d, 2G12 and 447-52D. 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
17b: The epitope for the MAb D19 is conserved and embedded in V3. D19 is unique in that for R5 viruses, it was cryptic and did not bind without exposure to sCD4, and for X4 and R5X4 isolates it was constitutively exposed. D19b is unique among CD4i antibodies in that it binds to the V3 loop. CD4i MAbs 17b and 48d were used as controls for CD4i characterization; in contrast to D19, other CD4i MAbs bind to the conserved bridging sheet and do not differentiate between R5 and X4 using strains. 17b, like D19, was able to neutralize the BaL isolate only in combination with sCD4. Lusso2005
17b: IgG antibody phage display libraries were created from HIV-1+ individuals after pre-selection of PBMC with gp120, as an alternative to using bone marrow for generating libraries. 17b was among a set of Abs used for competition studies to define the binding sites of the newly isolated MAbs, representing a MAb with a CD4i epitope. Koefoed2005
17b: Called 1.7B. Of 35 Env-specific MAbs tested, only 2F5, 4E10, IgG1b12, and two CD4BS adjacent MAbs (A32 and 1.4G) and gp41 MAbs (2.2B and KU32) had binding patterns suggesting polyspecific autoreactivity, and similar reactivities may be difficult to induce with vaccines because of elimination of such autoreactivity. 1.7B has no indication of polyspecific autoreactivity. Haynes2005 (antibody binding site)
17b: 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 17b. Pantophlet2004 (vaccine antigen design)
17b: 17b is known to be comprised of elements from four discontinuous beta strands. Using 17b MAb to select peptides from a combinatorial library, and analyzing the peptides using a novel discontinuous epitope reconstruction program, enabled epitope prediction. Segments of gp120 were reconstructed as an antigenic protein mimetic recognized by 17b. Comparisons then were made with a similar prediction of contact residues for CG10, a CD4i MAb that competes with 17b, but has a distinct binding site. Database note: First author "Enshell-Seijffers" is also found as "EnshellSeijffers" on annotated papers in this database. Enshell-Seijffers2003 (antibody binding site, mimotopes, computational epitope prediction)
17b: V1V2 was determined to be the region that conferred the neutralization phenotype differences between two R5-tropic primary HIV-1 isolates, JRFL and SF162. JRFL is resistant to neutralization by many sera and MAbs, while SF162 is sensitive. All MAbs tested, anti-V3, -V2, -CD4BS, and -CD4i, (except the broadly neutralizing MAbs IgG1b12, 2F5, and 2G12 which neutralized both strains), neutralized the SF162 pseudotype but not JRFL, and chimeras that exchanged the V1V2 loops transferred the neutralization phenotype. Three CD4i MAbs were tested; all preferentially neutralized SF162, and JRFL became neutralization sensitive to CD4i Abs if the SF162 V1V2 loop was exchanged. Pinter2004 (variant cross-reactivity)
17b: A set of HIV-1 chimeras that altered V3 net charge and glycosylation patterns in V1V2 and V3, involving inserting V1V2 loops from a late stage primary isolate taken after the R5 to X4 switch, were studied with regard to phenotype, co-receptor usage, and MAb neutralization. The loops were cloned into a HXB2 envelope with a LAI viral backbone. It was observed that the addition of the late-stage isolate V1V2 region and the loss of V3-linked glycosylation site in the context of high positive charge gave an X4 phenotype. R5X4, R5, and X4 viruses were generated, and sCD4, 2G12 and b12 neutralization resistance patterns were modified by addition of the late stage V1V2, glycosylation changes, and charge in concert, while neutralization by 2F5 was unaffected. 15e, 17b, and 48d could not neutralize any of the variants tested. Nabatov2004 (antibody binding site, co-receptor)
17b: Sera from two HIV+ people and a panel of MAbs were used to explore susceptibility to neutralization in the presence or absence of glycans within or adjacent to the V3 loop and within the C2, C4 and V5 regions of HIV-1 SF162 env gp120. The loss of the glycan within the V3 loop (GM299 V3) and two sites adjacent to V3, C2 (GM292 C2) and (GM329 C3), increased neutralization susceptibility to CD4i FAb X5, but each of the glycan mutants and SF162 were refractive to neutralization with 48d and 17b. The loss of sites in C4 (GM438 C4), or V5 (GM454 V5) did not increase neutralization susceptibility to FAb X5. V3 glycans tended to shield V3 loop, CD4 and co-receptor MAb binding sites, while C4 and V5 glycans shielded V3 loop, CD4, gp41 but not co-receptor MAb binding sites. Selective removal of glycans from a vaccine candidate may enable greater access to neutralization susceptible epitopes. McCaffrey2004 (antibody binding site, vaccine antigen design)
17b: 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 17b 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)
17b: 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)
17b: A32-rgp120 complexes opened up the CCR5 co-receptor binding site, but did not induce neutralizing antibodies with greater breadth among B subtype isolates than did uncomplexed rgp120 in vaccinated guinea pigs. 17b was used as a control to show A32-bound rgp120 had enhanced binding to this CD4-inducible MAb. Liao2004 (vaccine antigen design)
17b: 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 it a promising lead for therapeutic design. Biorn2004
17b: Vaccination of a gp120-CD4 fusion complex in six transgenic XMG2 XenoMouse mice that produce human IgG2 with K light chain did not produce any neutralizing antibodies. 36/39 MAbs derived from one of these mice were in one of two competition groups that were conformational and specific for the complex, suggesting this chimeric vaccine may be of little value, as immunodominant responses recognized epitopes not present in native Env. MAbs from the two CD4-gp120 complex-specific competition groups did not compete with MAbs with known targets on HIV-1 gp120, but their binding was enhanced by binding of 17b. He2003
17b: Using a cell-fusion system, it was found CD4i antibodies 17b, 48d, and CG10 reacted faintly with Env expressing HeLA cells even in the absence of sCD4 or CD4 expressing target cells. Reactivity increased after sCD4 addition, but not after CD4 expressing target cell addition, and binding was not increased at the cell-to-cell CD4-Env interface. This suggests the CD4i co-receptor binding domain is largely blocked at the cell-fusion interface, and so CD4i antibodies would not be able access this site and neutralize cell-mediated viral entry. Finnegan2001
17b: This review summarizes MAbs directed to HIV-1 Env. There are six CD4 inducible MAbs and Fabs in the database. The MAb forms neutralize TCLA strains only, but the smaller Fabs and scFv fragments can neutralize primary isolates. Gorny2003 (antibody binding site, review)
17b: 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)
17b: scFv 4KG5 reacts with a conformational epitope. Of a panel of MAbs tested, only NAb b12 enhanced 4KG5 binding to gp120. MAbs to the V2 loop, V3 loop, V3-C4 region, and CD4BS diminished binding, while 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. This is a CD4i MAb that had no impact on 4KG5 binding. Zwick2003a (antibody interactions)
17b: The HIV-1 primary isolate DH012 has preserved the epitopes for the MAbs IgG1b12, 2G12, 17b, however natural DH012 infection in chimpanzees and DH012 gp120 vaccination in guinea pigs does not give rise to Abs against these epitopes. Zhu2003 (vaccine-induced immune responses)
17b: 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. 17b recognized most variants, some from each of the four individuals, by gp120 immunoprecipitation. Ohagen2003 (brain/CSF, variant cross-reactivity)
17b: 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)
17b: This paper describes the generation of CD4i MAb E51, that like CD4i MAb 17b, blocks CCR5 binding to sCD4-bound gp120. E51 has more cross-neutralizing potency than other prototype CD4i MAbs (17b) for B and C clade isolates. E51 and 17b both neutralized HIV-1 clade B strains HXBc2 and ADA, while JR-FL and 89.6 were only neutralized by E51, not 17b. Clade C strains MCGP1.3 and SA32 were both inhibited by 17b and E51, but E51 was more potent against SA32. 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, variant cross-reactivity, subtype comparisons)
17b: This study shows the fragments of CD4i MAbs are better able to neutralize virus than whole IgG. Neutralization of HIV-1 R5 isolates JRFL, JR-CSF and ADA by CD4i MAbs X5, 17b, and 48d decreased with increased molecule size, the neutralizing potency of single-chain Fv (scFv) > than Fab fragments > whole Ab molecules. (With the exception of IgG 48d neutralization of HIV-1 ADA.) HIV-1 X4 isolates 89.6 and HxB2 are both relatively sensitive even to the larger IgG version. R5X4 isolate neutralization was dependent on the isolate and co-receptor usage. The CD4i MAb fragments neutralize HIV-1 subsequent to CD4 binding. The CD4i MAbs bind near the co-receptor binding sites on gp120. Co-receptors bind to the conserved beta19 strand and part of the V3 loop, regions that are masked by the V1V2 loops in the CD4-unbound state. When CD4 is bound, the co-receptor site is exposed near the membrane surface where it would be optimally accessible to co-receptors, and the smaller versions of the molecules are better able to overcome the steric hindrance. Labrijn2003 (antibody binding site, co-receptor, variant cross-reactivity)
17b: Anti-gp41 MAbs were tested in a cell-cell fusion system to investigate the antigenic changes in gp41 during binding and fusion. Cluster I and Cluster II MAbs required CD4 expression on HIV HXB2 Env expressing HeLa target cells, but not the CXCR4 co-receptor, binding to a fusion intermediate. 17b was used to demonstrate that the Cluster I and II MAbs bound to gp120/gp41 complexes, not to gp41 after shedding of gp120. Finnegan2002
17b: A sCD4-17b single chain chimera was made that can bind to the CD4 binding site, then bind and block co-receptor interaction. This chimeric protein is a very potent neutralizing agent, more potent than IgG1b12, 2G12 or 2F5 against Ba-L infection of CCR5-MAGI cells. It has potential for prophylaxis or therapy. It neutralized 5/6 R5 and X4 strains from the B clade, but was only moderately protective against a D clade isolate, and did not neutralize clade A, C, E, and F isolates. Dey2003 (co-receptor, immunoprophylaxis, variant cross-reactivity, immunotherapy, subtype comparisons)
17b: Called 1.7b. The MAb B4e8 binds to the base of the V3 loop, neutralizes multiple primary isolates and was studied for interaction with other MAbs. B4e8 enhanced binding of CD4i MAbs 4.8d, 1.7b, and A1g8 to R5X4 virus 92HT593, but only of 48d to the R5 virus 92US660, and there was only a modest impact of the combination of B4e8 and CD4i MAbs on neutralization. Cavacini2003 (antibody interactions, co-receptor)
17b: This study examined antibody 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-V3 MAb B4a1 increased binding of CD4i MAbs 48d, 17b and A1g8, but only A1g8 binding was increased by B4a1 to the R5 isolate. Additive effects on neutralization of the R5X4 isolate with B4a1 and CD4i MAbs was observed, presumably due to increased exposure of the CD4i binding site, but not for the R5 isolate. Anti-gp41 MAb F240 had a synergistic effect on neutralization with CD4i MAbs 48d and 17b, but not with A1g8 for the R5X4 virus. Cavacini2002 (antibody interactions, co-receptor, variant cross-reactivity)
17b: The SOS mutant envelope protein introduces a covalent disulfide bond between gp120 surface and gp41 transmembrane proteins into the R5 isolate JR-FL by adding cysteines at residues 501 and 605. Pseudovirions bearing this protein bind to CD4 and co-receptor bearing cells, but do not fuse until treatment with a reducing agent, and are arrested prior to fusion after CD4 and co-receptor engagement. CD4i Abs 17b and X5 were weakly neutralizing in all formats, WT, SOS, and when added postbinding. Binley2003 (vaccine antigen design)
17b: NIH AIDS Research and Reference Reagent Program: 4091.
17b: The two N-terminal domains of CD4, termed D1 and D2, when expressed in the absence of the remaining domains of CD4 retain the capacity to bind to gp120---coding sequences of D1D2 and Igαtp were fused to create a large, multivalent rec protein D1D2Igαtp, which, unlike CD4, does not enhance infection at sub-optimal concentrations---the MAb 17b can also enhance viral replication at sub-optimal concentrations, but D1D2-Igα inhibited the 17b enhancement of two primary isolates. Arthos2002 (variant cross-reactivity)
17b: 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
17b: 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 for 17b was dramatically increased and no longer inducible in the presence of sCD4---V3 mutants R298A and R327A were not recognized by 17b except in the presence of sCD4---mutations in the β19 strand dramatically reduced 17b affinity in the presence or absence of sCD4, consistent with known 17b contact residues in this region. Basmaciogullar2002
17b: 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---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---non-neutralizing MAbs C11 and A32 bound with lower affinity than NAb IgG1b12---the MAb 17b was sCD4 inducible on gp160ΔCT PL. Grundner2002 (vaccine antigen design)
17b: Truncation of the gp41 cytoplasmic domain of X4, R5, and X4R5 viruses forces a conformation that more closely resembles the CD4 bound state of the external Envelope, enhancing binding of CD4i MAbs 17b and 48d and of CD4BS MAbs F105, b12, and in most cases of glycosylation site dependent MAb 2G12 and the anti-gp41 MAb 246D -- in contrast, binding of the anti-V2 MAb 697D and the anti-V3 MAb 694/98D were not affected -- viruses bearing the truncation were more sensitive to neutralization by MAbs 48d, b12, and 2G12 -- the anti-C5 MAb 1331A was used to track levels of cell surface expression of the mutated proteins. EdwardsBH2002 (vaccine-induced immune responses)
17b: Five CD4i MAbs were studied, 17b, 48d and three new MAbs derived by Epstein-Barr virus transformation of PBMC from an HIV+ long term non-progressor -- 23e and 21c were converted to hybridomas to increase Ab production -- all compete with the well-characterized 17b CD4i MAb in an ELISA antigen capture assay -- critical binding residues are mapped and the CD4i MAb epitopes were distinct but share a common element near isoleucine 420, also important for CCR5 binding, and all five can block CCR5 binding to a sCD4-gp120 complex -- the MAb 48d has the epitope most similar to the CCR5 binding site. Xiang2002b (antibody binding site)
17b: 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 (variant cross-reactivity)
17b: CD4 residue Phe43 significantly contributes to the affinity of CD4-gp120 interactions -- despite decreased affinities for gp120, CD4 proteins and CD4-mimetic peptides lacking a Phe side-chain enhance binding of gp120 to 17b in a manner similar to Phe-bearing ligands indicating the Phe42 interaction is not critical for CD4-induced conformational changes in gp120. Dowd2002
17b: 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
17b: Ab binding characteristics of SOS gp140 were tested using SPR and RIPA -- SOS gp140 is gp120-gp41 bound by a disulfide bond -- NAbs 2G12, 2F5, IgG1b12, CD4 inducible 17b, and 19b bound to SOS gp140 better than uncleaved gp140 (gp140unc) and gp120 -- non-neutralizing MAbs 2.2B (binds to gp41 in gp140unc) and 23A (binds gp120) did not bind SOS gp140. Schulke2002 (vaccine antigen design)
17b: The fusion process was slowed by using a suboptimal temperature (31.5 C) to re-evaluate the potential of Abs targeting fusion intermediates to block HIV entry -- preincubation of E/T cells at 31.5 C enabled polyclonal anti-N-HR Ab and anti-six-helix bundle Abs to inhibit fusion, indicating six-helix bundles form prior to fusion -- the preincubation 31.5 C step did not alter the inhibitory activity of neutralizing Abs anti-gp41 2F5, or anti-gp120 2G12, IG1b12, 48d, and 17b. GoldingH2002
17b: Oligomeric gp140 (o-gp140) derived from R5 primary isolate US4 was characterized for use as a vaccine reagent -- antigen capture ELISA was used to compare the antigenicity of gp120 and o-gp140 using a panel of well characterized MAbs -- 17b recognized both gp120 monomer and o-gp140. Srivastava2002
17b: Structural aspects of the interaction of neutralizing Abs with HIV-1 Env are reviewed -- Env essentially has three faces, one is largely inaccessible on the native trimer, and two that exposed but have low immunogenicity on primary viruses -- neutralization is suggested to occur by inhibition of the interaction between gp120 and the target cell membrane receptors as a result of steric hindrance and it is noted that the attachment of approximately 70 IgG molecules per virion is required for neutralization, which is equivalent to about one IgG molecule per spike -- the 2G12, 17b and b12 epitopes are discussed in detail -- the 17b epitope is masked prior to CD4 binding by the V1-V2 loop and in contrast to sCD4, the binding of cell surface CD4 to virus does not appear to make the epitope accessible to binding by 17b to allow neutralization. Poignard2001 (antibody binding site, review)
17b: 17b binds to a CD4 inducible epitope which partially overlaps the CCR5 binding site -- JRFL, YU2, 89.6, and HXB2 and their C1-, V1/V2-, C5 -deletion mutants were used to study how 17b binding affects gp120-CD4 interactions -- 17b reduced CD4-gp120 interactions by decreasing the on-rate and increasing the off-rate of sCD4, while enhanced binding of sCD4 binding was observed for the 17b-bound, V1/V2 deleted gp120s -- 17b was considered to be a surrogate for CCR5, and the authors suggest that 17b binding may shift V1/V2 into a position that interferes with CD4 binding, forcing a release. Zhang2001a (antibody binding site, kinetics)
17b: 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 -- 17b bound at somewhat greater levels to 168C than to 168P, but this is not a general feature of 17b binding to primary versus TCLA strains. York2001 (variant cross-reactivity)
17b: 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 17b---only the CD4i antibodies 17b and 48d showed an increased affinity of the CD4 independent viruses relative to wild-type. Kolchinsky2001 (antibody binding site, variant cross-reactivity)
SHIV-HXBc2 is a neutralization sensitive non-pathogenic virus, and several in vivo passages through monkey's 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 (variant cross-reactivity)
17b: Mutagenesis defines Ile-420, Lys-421, Gln-422, Pro-438, and Gly-441 to be important residues for CCR5 binding -- these positions are located on two strands that connect the gp120 bridging sheet and outer domain, suggesting a mechanism for conformational shifts induced by CD4 binding to facilitate CCR5 binding. Rizzuto2000 (antibody binding site)
17b: 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)
17b: Soluble gp140 derived from SF162, a neutralization-resistant primary isolate, and SF162AV2 a neutralization-susceptible isolate with 30 amino acids deleted from the V2 loop, were generated with or without the gp120-gp41 cleavage site intact -- all forms are recognized by oligomer-specific MAb T4 and show enhanced binding of CD4i MAb 17b when sCD4 is bound -- the fused forms are less efficiently recognized than the cleaved forms by polyclonal neutralizing sera from HIV-infected patients -- the V3 loop is more exposed on the fused form. Stamatatos2000 (vaccine antigen design)
17b: sCD4 can activate fusion between effector cells expressing Env and target cells expressing coreceptor (CCR5 or CXCR4) alone without CD4 -- CD4i MAbs 17b and 48d have little effect on a standard cell fusion assay but potently block sCD4 activated fusion -- 17b was broadly cross-reactive inhibiting sCD4 activated fusion with Env from clades A, B, C, D, E, F, and F/B. Salzwedel2000 (subtype comparisons)
17b: 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 -- the mutation L544P reduced binding of all MAbs against gp120 by causing conformational changes. Park2000 (antibody binding site)
17b: SF162 is a neutralization-resistant HIV-1 isolate -- N-linked glycosylation modifications in the V2 loop of the SF162 gp120 revealed that these sites prevent neutralization by CD4BS MAbs (IgG1b12 and IgGCD4), and protect against neutralization by V3 MAbs (447-D and 391-95D) -- V2-region glycosylation site mutations did not alter neutralization resistance to V2 MAbs (G3.4 and G3.136) or CD4i MAbs (17b and 48d) -- V2 glycosylation site modification allows infection of macrophages, probably due to glycosylated forms requiring fewer CCR5 molecules for viral entry. Ly2000 (variant cross-reactivity)
17b: To determine the antigenicity of virus killed by thermal and chemical inactivation, retention of conformation-dependent neutralization epitopes was examined, and exposure of CD4BS epitopes was found to be enhanced (MAbs IgG1b12, 205-46-9, and 205-43-1) -- binding to 2G12 and 447-52D epitopes was essentially unaltered -- the 17b CD4i epitope was also exposed. Grovit-Ferbas2000 (vaccine antigen design)
17b: The MAbs with the broadest neutralizing activity, IgG1b12, 2G12 and 2F5, all have high affinity for the native trimer, indicating that they were raised in an immune response to the oligomer on the virion surface rather than dissociated subunits -- a disulfide linked gp120-gp41 (SOS gp140) was created to mimic the native conformation of Env and explore its potential as an immunogen -- SOS gp140 is recognized by NAbs IgG1b12, 2G12, and CD4-IgG2, and also by anti-V3 MAbs 19b and 83.1 -- SOSgp140 is not recognized by C4 region MAbs that neutralize only TCLA strains, G3-42 and G3-519 -- nor did it bind C11, 23A, and M90, MAbs that bind to gp120 C1 and C5, where it interacts with gp41 -- MAbs that bind CD4 inducible epitopes, 17b and A32 were very strongly induced by CD4 in SOS gp140 -- anti-gp41 MAbs that bind in the region that interacts with gp120, 7B2, 2.2B, T4, T15G1 and 4D4, did not bind to SOSgp140, in contrast to 2F5, which binds to the only gp41 epitope that is well exposed in native gp120-gp41 complexes. Binley2000 (vaccine antigen design)
17b: A CD4-independent viral variant of IIIB, IIIBx, was generated on CXCR4-expressing cells -- IIIBx exhibited greater exposure of the 17b and 48d epitopes and enhanced neutralization by CD4i MAbs and by polyclonal human sera -- the 17b epitope has significant overlap with the CCR5 coreceptor binding site. Hoffman1999 (antibody binding site, variant cross-reactivity)
17b: Deleting the V2 loop of neutralization-resistant HIV-1 isolate SF162 does not abrogate its replication in PBMC or macrophages, but it enhances its neutralization sensitivity to sera from patients with B clade infection up to 170-fold, and also enhances sensitivity to sera from clades A through F -- deletion of V2 but not V1 enabled neutralization by CD4i MAbs 17b and 48d. Stamatatos1998 (antibody binding site, vaccine antigen design)
17b: A panel of MAbs was shown to bind with similar or greater affinity and similar competition profiles to a deglycosylated or variable loop deleted core gp120 protein (Delta V1, V2, and V3), thus such a core protein produces a structure closely approximating full length folded monomer -- CD4i MAbs 17b and 48d bound better to the deleted protein than to wild type. Binley1998 (antibody binding site)
17b: The HIV-1 virus YU2 entry can be enhanced by MAbs binding to the CD4BS, V3 loop, and CD4i epitopes -- the activation for this enhanced entry state could be conferred on HxB2 by introducing the YU2 V3 loop, or the YU2 V3 and V1/V2 loops, and the presence of V1/V2 increased the enhancement -- a similar effect is observed by sub-neutralizing concentrations of sCD4 and the effect is dependent of CCR5 -- 17b enhances YU2 enhanced viral entry 10-fold, whereas HXBc2 was neutralized. Sullivan1998b
17b: sCD4 induces 17b binding in primary isolates and TCLA strains -- amino acids that reduce the efficiency of binding were determined and found also to compromise syncytia formation and viral entry -- V1V2 deletion or sCD4 binding can expose the 17b epitope for both HXBc2 and macrophage tropic YU2 -- neutralizing potency of 17b is probably weak due to poor exposure of the epitope -- 17b epitope exposure upon sCD4 binding can occur over a wide range of temperatures, consistent with the energy of CD4 binding being sufficient to drive the V1/V2 loop into a new conformation. Sullivan1998 (antibody binding site, variant cross-reactivity)
17b: Site directed mutagenesis of a WU2 protein with the V1-V2 loops deleted revealed key residues for 17b-gp120 interaction and interaction of gp120 and CCR5 -- mutations in residues that reduced 17b by 70% were R/D 419, I/R 420, Q/L 422, Y/S 435, I/S 423, K/D 121 and K/D 421-- 17b can neutralize HIV-1 strains that use different chemokine receptors, supporting a common region in gp120 in chemokine-receptor interaction. Rizzuto1998 (antibody binding site, variant cross-reactivity)
17b: Moore and Binley provide a commentary on the papers by Rizzuto1998, Wyatt1998 and Kwong1998 -- they point out 17b shares binding elements in gp120 with chemokine receptor molecules, and that CD4 needs to bind to gp120 first to make the 17b epitope accessible and it may be sterically blocked in the CD4 bound virus, thus making it a poor NAb for primary isolates Moore1998. Kwong1998,Moore1998,Rizzuto1998,Wyatt1998 (review, structure)
17b: Summary of the implications of the crystal structure of a gp120 core bound to C