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MAb ID	19b (N70-1.9b, N701.9b, 1.9B)
HXB2 Location	gp160(309-320) DNA(7149..7184)	gp160 Epitope Map
Author Location	gp120
Research Contact	James Robinson, University of Connecticut, Storrs
Epitope	`[S/R][I/V/T][H/R/T][I/L]GP[G/Q][Q/R/A][A/T/L/V][F/Y][Y/T][A/T/R/-]T`	Epitope Alignment
Ab Type	gp120 V3 // V3 glycan (V3g)
Neutralizing	L
Species (Isotype)	human(IgG1κ)
Patient	N70
Immunogen	HIV-1 infection
Keywords	ADCC, antibody binding site, antibody generation, antibody interactions, antibody polyreactivity, assay or method development, autoantibody or autoimmunity, binding affinity, broad neutralizer, glycosylation, neutralization, novel epitope, optimal epitope, review, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity

Notes

Showing 65 of 65 notes.

19b: 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. 19b targeted gp120 V3 loop and exhibited poor neutralization against HIV-1AD8 full-length and cytoplasmic tail-deleted Envs. Castillo-Menendez2019 (vaccine antigen design, structure)
19b: 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 19b recognized L193A variants of CH58 and CH77 IMCs with a significant increase compared to the WT. Prevost2018 (ADCC)
19b: The first cryo-EM structure of a cross-linked vaccine antigen was solved. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a bNAb PGV04 Fab fragment revealed how cross-linking affects key properties of the trimer. SOSIP and GLA-SOSIP trimers were compared for antigenicity by ELISA, using a large panel of mAbs previously determined to react with BG505 Env. Non-NAbs like 19b globally lost reactivity (7-fold median loss of binding), likely because of covalent stabilization of the cross-linked ‘closed’ form of the GLA-SOSIP trimer that binds non-NAbs weakly or not at all. V3-specific non-NAbs showed 2.1–3.3-fold reduced binding. Three autologous rabbit monoclonal NAbs to the N241/N289 ‘glycan-hole’ surface, showed a median ˜1.5-fold reduction in binding. V3 non-NAb 4025 showed residual binding to the GLA-SOSIP trimer. By contrast, bNAbs broadly retained reactivity significantly better than non-NAbs, with the exception of PGT145 (3.3-5.3 fold loss of binding in ELISA and SPR). Schiffner2018 (vaccine antigen design, binding affinity, structure)
19b: Assays of poly- and autoreactivity demonstrated that broadly neutralizing NAbs are significantly more poly- and autoreactive than non-neutralizing NAbs. 19b is neither autoreactive nor polyreactive. Liu2015a (autoantibody or autoimmunity, antibody polyreactivity)
19B: 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)
19b: 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. For 19b the non-NAb epitope did not depend on residues 306 and 308. deTaeye2018 (broad neutralizer)
19b: 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 non-NAb 19b, 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)
19b: 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)
19b: 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 19b and GE2-JG8 were used as anti-V3 Abs; they did not mediate strong ADCC activity. Ding2015 (ADCC)
19b: 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. 19b 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)
19B: LANL database note: This monoclonal antibody is a CHAVI reagent (http://chavi.org/); Species: human; Category: V3 MAbs; Contact person: James Robinson
19b: 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 V3 Ab, 19b did not bind cell surface or neutralize 92UG037.8 HIV-1 isolate though it did bind gp160 minus its C-terminus (gp160ΔCT) moderately, and was able to bind in the presence of sCD4. Chen2015 (neutralization, binding affinity)
19b: 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
19b: 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 non-NAb, 19b. Julien2015 (assay or method development, structure)
19b: 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 anti-V3 non-NAb 19b to trimers was reduced by trimer cross-linking. Schiffner2016 (assay or method development, binding affinity, structure)
19b: 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 non-NAb 19b did not neutralize BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, but did recognize and bind the immunogen itself. Sanders2013 (assay or method development, neutralization, binding affinity)
19b: 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. 19b was compared to the newly-derived mAbs; it tested positive in one assay of cross-reactivity with gut bacteria, and positive in one test of autoreactivity. Jeffries2016 (antibody polyreactivity)
19b: 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). V3-specific 19b does not neutralize BG505.T332N pseudovirus, but binds strongly to monomer, substantially less to protomer, and negligibly to trimer. Yasmeen2014 (antibody binding site, assay or method development)
19b: 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)
N70-1.9b: This review provides summaries of Abs that bind to HIV-1 Env. There are many V3 MAbs, many neutralize some TCLA strains, and a subset can also neutralize some primary isolates. Gorny2003 (review)
N70-1.9b: Type specificity. Antibody generation. Robinson1990c (antibody generation, variant cross-reactivity)
Lists 7 mAbs derived from patient N70: 15E, 1.9B, 2.3A, 2.3B, 2.1H, F91, 1.7B. Robinson1992
N70-1.9b: Type specific neutralization, ADCC directed against MN infected cells. Scott1990 (ADCC, variant cross-reactivity)
19b: 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. MAb 19b bound more strongly to deglycosylated trimers than untreated ones. Depetris2012 (glycosylation, binding affinity)
19b: 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 19b to gp120 was enhanced by B40t77, which is suggested to be due to distant conformational changes of gp120 induced by the aptamer. Joubert2010 (binding affinity, structure)
19b: 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. 19b bound better to all uncleaved ΔV1V2 variants than to the full-length trimer, and bound similarly to the cleaved ΔV1V2 and full-length variants. Bontjer2010 (binding affinity)
19b: 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. Binding of 19b to gp120 or to the V3 peptide alone of CC101.19 was greater than to gp120 or the V3 peptide of the three other viruses. 19b neutralized CC101.19 but did not neutralize the other three viruses. This indicates that the V3 region of CC101.19 has become unusually accessible to V3 Abs. Berro2009 (neutralization, binding affinity)
19b: This review summarizes 19b Ab epitope, properties and neutralization activity. Kramer2007 (review)
19b: Similarity level of the 19b binding site pentapeptide -I----G--FY-T to the host proteome was low, with the low-similarity 5-mer occurring in the host proteome 4 times, indicating that this peptide can be used to elicit Abs for active/passive immunotherapy with low risk of cross-reaction with the host proteome. Kanduc2008
19b: To examine sequence and conformational differences between subtypes B and C, several experiments were performed with 11 MAbs regarding binding and neutralization. Both binding and neutralization studies revealed that the 11 MAbs could be divided in three different groups, and that the most differences between the subtypes were located in the stem and turn regions of V3. 19b belonged to the group 1 MAbs, which are able to bind both subtype B and C gp120 proteins and peptides. 19b bound to B gp120 and C gp120 with low avidity. Furthermore, 19b was able to bind both subtype C V3 in the subtype B Env backbone chimera, and reverse, indicating that 19b binds to V3 in a way that is not affected by the gp120 backbone. For subtype B, changes in the position 13 (H13R) and/or position 18 (R18Q) showed no difference of 19b binding compared to wildtype. For subtype C, H13 residue enhanced binding of 19b, but the R18 mutation reduced binding, indicating that R18 affects the conformation of V3 subtype C. Although 19b bound to JR-FL V3, this isolate was resistant to neutralization by 19b, as was SF162. However, a chimeric SF162 variant with a JR-FL-like V3 sequence was hypersensitive to neutralization by 19b, suggesting an important role of one or more of the three V3 amino acids that differ between these two isolates in defining the epitope and/or structure of the protein. Patel2008 (neutralization, binding affinity, subtype comparisons)
19b: 19b neutralized two of the 15 subtype B isolates tested, 5768-p27 and 92BR020c. Binding affinity of MAb 19b to gp120 was strongly reduced (>10-fold) upon substitutions of Arg304, Ile307, Pro313, Arg315, Phe317, or Tyr318 to Ala. The affinity was moderately reduced (˜4-fold) upon substitution of Lys305. Thr320 was not important for 19b binding. Substituting Asp325 with Ala increased the binding affinity of 19b by 2-fold, suggesting that Ala at this position prevents formation of a salt bridge thus allowing for a better presentation of 19b epitope. 19b neutralized 5768-p27 more potently than 92BR020c although the viruses have same V3 residues important for 19b binding. 5768-p27 has a Met at position 309 and 92BR020c has Ile, indicating that 19b requires an aliphatic side chain at position 309. The inability of 19b to neutralize 6 of the 15 viruses tested could be explained by substitutions at important contact residues, while its inability to neutralize the remaining 6 viruses could not be explained by this. The fine specificity of 19b was mapped onto V3 in the structural context of gp120. Binding site was formed by Arg304 in the N-terminal V3 stem, and Arg315, Phe317, and Tyr318 were in the C-terminal half of the V3 tip. The presence of Pro313 and Arg315 is required to form the V3 tip hairpin turn and juxtapose the true contact residues. Thus, 19b may need to interact with V3 from an angle, which does not permit access to V3 on many different primary viruses. Pantophlet2008 (antibody binding site, neutralization, variant cross-reactivity, binding affinity, structure)
19b: 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 19b and other MAbs. Gao2007 (antibody binding site, review)
19b: This Ab was used in the analysis of clade C gp140 (97CN54) antigenicity and was shown to bind with relatively high avidity. Sheppard2007a (variant cross-reactivity)
19b: 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 (neutralization, variant cross-reactivity, review, subtype comparisons)
19b: This review focuses on the importance of neutralizing Abs in protecting against HIV-1 infection, including mechanisms of Ab interference with the viral lifecycle, Ab responses elicited during natural HIV infection, and use of monoclonal and polyclonal Abs in passive immunization. In addition, vaccine design strategies for eliciting of protective broadly neutralizing Abs are discussed. MAbs included in this review are: 2F5, Clone 3 (CL3), 4E10, Z13, IgG1b12, 2G12, m14, 447-52D, 17b, X5, m16, 47e, 412d, E51, CM51, F105, F425, 19b, 2182, DO142-10, 697-D, 448D, 15e and Cβ1. McCann2005 (antibody binding site, review)
19b: This Ab was shown to infrequently neutralize cloned Envs (clades A, B, C, D, F1, CRF01_AE, CRF02_AG, CRF06_cpx and CRF11_cpx) derived from donors with and without broadly cross-reactive neutralizing antibodies. Cham2006 (neutralization, variant cross-reactivity, subtype comparisons)
19b: 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. 19b was shown to bind specifically to all the recombinant proteins as well as to the gp120 from two subtype B isolates. 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)
19b: 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. V3 MAbs (447-52D, 19b, F245-B4e8 and 39F) bound to the GDMR antigen, but either did not bind or had diminished binding to mCHO. Selvarajah2005 (vaccine antigen design, vaccine-induced immune responses)
19b: This review provides summaries of Abs that bind to HIV-1 Env. There are many V3 MAbs, many neutralize some TCLA strains, and a subset also neutralize some primary isolates. Gorny2003 (review)
19b: This paper attempts to engineer a gp120 molecule that would focus the immune response onto the IgG1b12 epitope. Adding a glycosylation sequon (P313N) to the V3 loop knocked out binding to anti-V3 MAbs loop 2, 19b and 447-52-D. Pantophlet2003b (vaccine antigen design)
19b: scFv 4KG5 reacts with a conformational epitope that is formed by the V1V2 and V3 loops and the bridging sheet (C4) region of gp120 and is influenced by carbohydrates. Of a panel of MAbs tested, only NAb b12 enhanced 4KG5 binding to gp120 JRFL. MAbs to the following regions diminished 4KG5 binding: V2 loop, V3 loop, V3-C4 region, CD4BS. MAbs directed against C1, CD4i, C5 regions didn't impact 4KG5 binding. These results suggest that the orientation or dynamics of the V1/V2 and V3 loops restricts CD4BS access on the envelope spike, and IgG1b12 can uniquely remain unaffected by these loops. This was one of the V3 MAbs used. Zwick2003a (antibody interactions)
19b: 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, and 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 had large entropy contributions to free energy (mean: 26.1 kcal/mol) of binding to the gp120 monomer, except the potent CD4BS neutralizing MAb b6 had a much smaller value of 5.7 kcal/mol. High values suggest surface burial or protein folding and ordering of amino acids. Variable loop MAbs (L17, L78, 19b, 39F, Ag1211, D0142, and G3-2999) MAbs that bind to the N and C termini (211/c, A32, L100, P35, and C11) do not have dramatic entropy changes. 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)
19b: Virion capture assays are not a good predictor of neutralization, and the presentation of epitopes using this assay seems to be different from that of functional Envelope spikes on primary isolates -- F105 and b6 could efficiently block the b12-mediated capture of infectious virions in a virus capture, but did not inhibit b12 neutralization -- while b12 was potent at neutralizing the three primary virions JR-CSF, A DA, and 89.6, the Abs F105, 19b, and Fab b6 were overall very poor neutralizers. Poignard2003
19b: 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
19b: 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
19b: 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 19b. Kolchinsky2001
19b: 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 but 19b was an exception and required around 950 ng/ml to neutralize either form. Park2000
19b: 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
19b: No detectable neutralizing activity among primary isolates with different co-receptor usage -- some neutralization of TCLA strains. Trkola1998
19b: The MAb and Fab binding to the oligomeric form of gp120 and neutralization were highly correlated -- authors suggest that neutralization is determined by the fraction of Ab sites occupied on a virion irrespective of the epitope. Parren1998
19b: Used as a control in this Hx10 binding and neutralizing MAb study because 19b does not bind to Hx10. Mondor1998
19b: Neutralizes TCLA strains but not primary isolates. Parren1997
19b: Abs that recognize discontinuous epitopes can identify mimotopes from a phage peptide display library -- 19b has an epitope involving the tip of the V3 loop, with 5 or 6 essential amino acids distributed within a 12 amino acid stretch -- the previously determined binding site was confirmed -I----G--FY-T and some tolerated variants described, the I can be I, V, or L, the Y can be Y, F, or W -- probably a beta-turn is required for FY or FF binding, but WY can bind without the context of the turn. Boots1997
19b: Viral binding inhibition by 19b was weakly correlated with neutralization (all other neutralizing MAbs tested showed some correlation except 2F5) Ugolini1997
19b: Study shows neutralization is not predicted by MAb binding to JRFL monomeric gp120, but is associated with oligomeric Env binding -- 19b bound monomer, did not bind oligomer or neutralize JRFL. Fouts1997
19b: In a multilaboratory blinded study, failed to consistently neutralize any of nine B clade primary isolates -- there were four sequences with variations in the defined epitope among the 9 isolates tested. DSouza1997
19b: Inhibits gp120 interaction with CCR-5 in a MIP-1beta-CCR-5 competition study. Trkola1996b
19b: MIP-1alpha binding to CCR-5 expressing cells can be inhibited by gp120-sCD4 -- binding of 19b blocks this inhibition. Wu1996
19b: Not as effective as IgG1b12 at neutralization ex vivo of virus direct from plasma of HIV-1 infected individuals. Gauduin1996
19b: Review: more broadly cross-reactive than anti-V3 tip MAb 447-D. Moore1995c
19b: Despite broad gp120 binding reactivity, not broadly neutralizing. Moore1995b
19b: Binds to gp120 epitopes from clades A,B,C,E, and F -- weakly neutralized some B and one C clade virus. Epitope is -I----G--FY-T according to authors, with invariant contacts reported while variable residues are signified by dashes. Consensus sequences for each clade are as follows, where the underlined residues contribute to Ab 19b binding: SVHIGPGQAFYAT (Clade A), SIHIGPGRAFYTT (Clade B), SIRIGPGQTFYAT (Clade C), RTHIGPQALYT-T (Clade D), SITIGPGQVFYRT (Clade E), SIHIGPGQAFYAT (Clade F). This would be the same as writing the epitope as (----GP------T). Author reported HXB2 numbering is gp160(309-320). Moore1995a (antibody binding site, optimal epitope, novel epitope)
19b: Formalin inactivation of virus at 0.1% formalin for 10 hours at 4 degrees was optimal for inactivation of virus while maintaining epitope integrity. Sattentau1995
19b: Competition studies with human sera from seroconverting individuals showed that anti-CD4 BS antibodies can arise very early in infection, comparable or prior to anti-V3 antibodies. Moore1994d
19b: V3 loop binding MAb that is more broadly clade cross-reactive than most (binds to 19/29 clade B and 10/12 clade E gp120s). Novel, optimal epitope is reported as -I----G--FY-T. While several changes are tolerated, the following are inhibitory -I---PG--FY-T, -S---RG--YH-T, -I----G--LV-T, -I----G--FL-T. Moore1994b (optimal epitope, novel epitope)

References

Showing 65 of 65 references.

Isolation Paper
Robinson1990c J. E. Robinson, D. Holton, S. Pacheco-Morell, J. Liu, and H. McMurdo. Identification of Conserved and Variable Epitopes of Human Immunodeficiency Virus Type-1 (HIV-1) gp120 by Human Monoclonal Antibodies Produced by EBV Transformed Cell Lines. AIDS Res. Hum. Retroviruses, 6:567-579, 1990. PubMed ID: 1694449. Show all entries for this paper.

Berro2009 Reem Berro, Rogier W. Sanders, Min Lu, Per J. Klasse, and John P. Moore. Two HIV-1 Variants Resistant to Small Molecule CCR5 Inhibitors Differ in How They Use CCR5 for Entry. PLoS Pathog., 5(8):e1000548, Aug 2009. PubMed ID: 19680536. Show all entries for this paper.

Binley1997 J. M. Binley, H. Arshad, T. R. Fouts, and J. P. Moore. An investigation of the high avidity antibody response to gp120 of human immunodeficiency virus type 1. AIDS Res. Hum. Retroviruses, 13:1007-1015, 1997. PubMed ID: 9264287. Show all entries for this paper.

Binley2000 J. Binley, R. Sanders, B. Clas, N. Schuelke, A. Master, Y. Guo, F. Kajumo, D. Anselma, P. Maddon, W. Olson, and J. Moore. A Recombinant Human Immunodeficiency virus type 1 envelope glycoprotein complex stabilized by an intramolecular disulfide bond between the gp120 and gp41 subunits is an antigenic mimic of the trimeric virion associated structure. J. Virol., 74:627-43, 1999. PubMed ID: 10623724. Show all entries for this paper.

Bontjer2010 Ilja Bontjer, Mark Melchers, Dirk Eggink, Kathryn David, John P. Moore, Ben Berkhout, and Rogier W. Sanders. Stabilized HIV-1 Envelope Glycoprotein Trimers Lacking the V1V2 Domain, Obtained by Virus Evolution. J. Biol. Chem, 285(47):36456-36470, 19 Nov 2010. PubMed ID: 20826824. Show all entries for this paper.

Boots1997 L. J. Boots, P. M. McKenna, B. A. Arnold, P. M. Keller, M. K. Gorny, S. Zolla-Pazner, J. E. Robinson, and A. J. Conley. Anti-human immunodeficiency virus type 1 human monoclonal antibodies that bind discontinuous epitopes in the viral glycoproteins can identify mimotopes from recombinant phage peptide display libraries. AIDS Res. Hum. Retroviruses, 13:1549-59, 1997. PubMed ID: 9430247. Show all entries for this paper.

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.

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.

Cham2006 Fatim Cham, Peng Fei Zhang, Leo Heyndrickx, Peter Bouma, Ping Zhong, Herman Katinger, James Robinson, Guido van der Groen, and Gerald V. Quinnan, Jr. Neutralization and Infectivity Characteristics of Envelope Glycoproteins from Human Immunodeficiency Virus Type 1 Infected Donors Whose Sera Exhibit Broadly Cross-Reactive Neutralizing Activity. Virology, 347(1):36-51, 30 Mar 2006. PubMed ID: 16378633. Show all entries for this paper.

Chen2015 Jia Chen, James M. Kovacs, Hanqin Peng, Sophia Rits-Volloch, Jianming Lu, Donghyun Park, Elise Zablowsky, Michael S. Seaman, and Bing Chen. Effect of the Cytoplasmic Domain on Antigenic Characteristics of HIV-1 Envelope Glycoprotein. Science, 349(6244):191-195, 10 Jul 2015. PubMed ID: 26113642. Show all entries for this paper.

Depetris2012 Rafael S Depetris, Jean-Philippe Julien, Reza Khayat, Jeong Hyun Lee, Robert Pejchal, Umesh Katpally, Nicolette Cocco, Milind Kachare, Evan Massi, Kathryn B. David, Albert Cupo, Andre J. Marozsan, William C. Olson, Andrew B. Ward, Ian A. Wilson, Rogier W. Sanders, and John P Moore. Partial Enzymatic Deglycosylation Preserves the Structure of Cleaved Recombinant HIV-1 Envelope Glycoprotein Trimers. J. Biol. Chem., 287(29):24239-24254, 13 Jul 2012. PubMed ID: 22645128. 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.

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.

Ding2015 Shilei Ding, Maxime Veillette, Mathieu Coutu, Jérémie Prévost, Louise Scharf, Pamela J. Bjorkman, Guido Ferrari, James E. Robinson, Christina Stürzel, Beatrice H. Hahn, Daniel Sauter, Frank Kirchhoff, George K. Lewis, Marzena Pazgier, and Andrés Finzi. A Highly Conserved Residue of the HIV-1 gp120 Inner Domain Is Important for Antibody-Dependent Cellular Cytotoxicity Responses Mediated by Anti-cluster A Antibodies. J. Virol., 90(4):2127-2134, Feb 2016. PubMed ID: 26637462. Show all entries for this paper.

DSouza1997 M. P. D'Souza, D. Livnat, J. A. Bradac, S. H. Bridges, the AIDS Clinical Trials Group Antibody Selection Working Group, and Collaborating Investigators. Evaluation of monoclonal antibodies to human immunodeficiency virus type 1 primary isolates by neutralization assays: performance criteria for selecting candidate antibodies for clinical trials. J. Infect. Dis., 175:1056-1062, 1997. Five laboratories evaluated neutralization of nine primary B clade isolates by a coded panel of seven human MAbs to HIV-1 subtype B envelope. IgG1b12, 2G12, 2F5 showed potent and broadly cross-reactive neutralizing ability; F105, 447/52-D, 729-D, 19b did not neutralize the primary isolates. PubMed ID: 9129066. Show all entries for this paper.

Fouda2013 Genevieve G. Fouda, Tatenda Mahlokozera, Jesus F. Salazar-Gonzalez, Maria G. Salazar, Gerald Learn, Surender B. Kumar, S. Moses Dennison, Elizabeth Russell, Katherine Rizzolo, Frederick Jaeger, Fangping Cai, Nathan A. Vandergrift, Feng Gao, Beatrice Hahn, George M. Shaw, Christina Ochsenbauer, Ronald Swanstrom, Steve Meshnick, Victor Mwapasa, Linda Kalilani, Susan Fiscus, David Montefiori, Barton Haynes, Jesse Kwiek, S. Munir Alam, and Sallie R. Permar. Postnatally-Transmitted HIV-1 Envelope Variants Have Similar Neutralization-Sensitivity and Function to That of Nontransmitted Breast Milk Variants. Retrovirology, 10:3, 2013. PubMed ID: 23305422. Show all entries for this paper.

Fouts1997 T. R. Fouts, J. M. Binley, A. Trkola, J. E. Robinson, and J. P. Moore. Neutralization of the Human Immunodeficiency Virus Type 1 Primary Isolate JR-FL by Human Monoclonal Antibodies Correlates with Antibody Binding to the Oligomeric Form of the Envelope Glycoprotein Complex. J. Virol., 71:2779-2785, 1997. To test whether antibody neutralization of HIV-1 primary isolates is correlated with the affinities for the oligomeric envelope glycoproteins, JRFL was used as a model primary virus and a panel of 13 human MAbs were evaluated for: half-maximal binding to rec monomeric JRFL gp120; half-maximal binding to oligomeric - JRFL Env expressed on the surface of transfected 293 cells; and neutralization of JRFL in a PBMC-based neutralization assay. Antibody affinity for oligomeric JRFL Env but not monomeric JRFL gp120 correlated with JRFL neutralization. PubMed ID: 9060632. Show all entries for this paper.

Gao2007 Feng Gao, Hua-Xin Liao, Beatrice H. Hahn, Norman L. Letvin, Bette T. Korber, and Barton F. Haynes. Centralized HIV-1 Envelope Immunogens and Neutralizing Antibodies. Curr. HIV Res., 5(6):572-577, Nov 2007. PubMed ID: 18045113. Show all entries for this paper.

Gauduin1996 M.-C. Gauduin, G. P. Allaway, P. J. Maddon, C. F. Barbas III, D. R. Burton, and R. A. Koup. Effective Ex Vivo Neutralization of Human Immunodeficiency Virus Type 1 in Plasma by Recombinant Immunoglobulin Molecules. J. Virol., 70:2586-2592, 1996. Virus direct from plasma from six HIV-1 infected individuals was used for neutralization assay. MAb 19b could neutralize 2/6 plasma samples, while MAb IgG1b12 could neutralize 5/6 plasma samples. CD4-based molecules were also tested: CD4-IgG2 was effective in the it ex vivo assay, but sCD4 was not. Thus, MAbs IgG1b12 and CD4-IgG2 have broad and potent it in vitro and it ex vivo neutralizing activities. PubMed ID: 8642690. Show all entries for this paper.

Gorny2003 Miroslaw K. Gorny and Susan Zolla-Pazner. Human Monoclonal Antibodies that Neutralize HIV-1. In Bette T. M. Korber and et. al., editors, HIV Immunology and HIV/SIV Vaccine Databases 2003. pages 37--51. Los Alamos National Laboratory, Theoretical Biology \& Biophysics, Los Alamos, N.M., 2004. URL: http://www.hiv.lanl.gov/content/immunology/pdf/2003/zolla-pazner_article.pdf. LA-UR 04-8162. Show all entries for this paper.

Jeffries2016 T. L. Jeffries, Jr., C. R. Sacha, J. Pollara, J. Himes, F. H. Jaeger, S. M. Dennison, E. McGuire, E. Kunz, J. A. Eudailey, A. M. Trama, C. LaBranche, G. G. Fouda, K. Wiehe, D. C. Montefiori, B. F. Haynes, H.-X. Liao, G. Ferrari, S. M. Alam, M. A. Moody, and S. R. Permar. The Function and Affinity Maturation of HIV-1 gp120-Specific Monoclonal Antibodies Derived from Colostral B Cells. Mucosal. Immunol., 9(2):414-427, Mar 2016. PubMed ID: 26242599. 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.

Joubert2010 Marisa K. Joubert, Nichole Kinsley, Alexio Capovilla, B. Trevor Sewell, Mohamed A. Jaffer, and Makobetsa Khati. A Modeled Structure of an Aptamer-gp120 Complex Provides Insight into the Mechanism of HIV-1 Neutralization. Biochemistry, 49(28):5880-5890, 20 Jul 2010. PubMed ID: 20527993. 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.

Kanduc2008 Darja Kanduc, Rosario Serpico, Alberta Lucchese, and Yehuda Shoenfeld. Correlating Low-Similarity Peptide Sequences and HIV B-Cell Epitopes. Autoimmun. Rev., 7(4):291-296, Feb 2008. PubMed ID: 18295732. Show all entries for this paper.

Kolchinsky2001 P. Kolchinsky, E. Kiprilov, P. Bartley, R. Rubinstein, and J. Sodroski. Loss of a single N-linked glycan allows CD4-independent human immunodeficiency virus type 1 infection by altering the position of the gp120 V1/V2 variable loops. J. Virol., 75(7):3435--43, Apr 2001. URL: http://jvi.asm.org/cgi/content/full/75/7/3435. PubMed ID: 11238869. Show all entries for this paper.

Kramer2007 Victor G. Kramer, Nagadenahalli B. Siddappa, and Ruth M. Ruprecht. Passive Immunization as Tool to Identify Protective HIV-1 Env Epitopes. Curr. HIV Res., 5(6):642-55, Nov 2007. PubMed ID: 18045119. Show all entries for this paper.

Kwong2002 Peter D. Kwong, Michael L. Doyle, David J. Casper, Claudia Cicala, Stephanie A. Leavitt, Shahzad Majeed, Tavis D. Steenbeke, Miro Venturi, Irwin Chaiken, Michael Fung, Hermann Katinger, Paul W. I. H. Parren, James Robinson, Donald Van Ryk, Liping Wang, Dennis R. Burton, Ernesto Freire, Richard Wyatt, Joseph Sodroski, Wayne A. Hendrickson, and James Arthos. HIV-1 Evades Antibody-Mediated Neutralization through Conformational Masking of Receptor-Binding Sites. Nature, 420(6916):678-682, 12 Dec 2002. Comment in Nature. 2002 Dec 12;420(6916):623-4. PubMed ID: 12478295. Show all entries for this paper.

Liao2006 Hua-Xin Liao, Laura L. Sutherland, Shi-Mao Xia, Mary E. Brock, Richard M. Scearce, Stacie Vanleeuwen, S. Munir Alam, Mildred McAdams, Eric A. Weaver, Zenaido Camacho, Ben-Jiang Ma, Yingying Li, Julie M. Decker, Gary J. Nabel, David C. Montefiori, Beatrice H. Hahn, Bette T. Korber, Feng Gao, and Barton F. Haynes. A Group M Consensus Envelope Glycoprotein Induces Antibodies That Neutralize Subsets of Subtype B and C HIV-1 Primary Viruses. Virology, 353(2):268-282, 30 Sep 2006. PubMed ID: 17039602. Show all entries for this paper.

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.

McCann2005 C. M. Mc Cann, R. J. Song, and R. M. Ruprecht. Antibodies: Can They Protect Against HIV Infection? Curr. Drug Targets Infect. Disord., 5(2):95-111, Jun 2005. PubMed ID: 15975016. Show all entries for this paper.

Mondor1998 I. Mondor, S. Ugolini, and Q. J. Sattentau. Human Immunodeficiency Virus Type 1 Attachment to HeLa CD4 Cells Is CD4 Independent and Gp120 Dependent and Requires Cell Surface Heparans. J. Virol., 72:3623-3634, 1998. PubMed ID: 9557643. Show all entries for this paper.

Moore1994b J. P. Moore, F. E. McCutchan, S.-W. Poon, J. Mascola, J. Liu, Y. Cao, and D. D. Ho. Exploration of Antigenic Variation in gp120 from Clades A through F of Human Immunodeficiency Virus Type 1 by Using Monoclonal Antibodies. J. Virol., 68:8350-8364, 1994. Four of five anti-V3 MAbs were slightly cross-reactive within clade B, but not very reactive outside clade B. Two discontinuous CD4 binding site Mabs appear to be pan-reactive. Anti-V2 MAbs were only sporadically reactive inside and outside of clade B. PubMed ID: 7525988. Show all entries for this paper.

Moore1994d J. P. Moore, Y. Cao, D. D. Ho, and R. A. Koup. Development of the anti-gp120 antibody response during seroconversion to human immunodeficiency virus type 1. J. Virol., 68:5142-5155, 1994. Three seroconverting individuals were studied. The earliest detectable anti-gp120 antibodies were both conformational and anti-V3 loop, and could be detected only after the peak viremia has passed. No uniform pattern of autologous neutralizing anti-CD4BS or anti-V3 MAbs was observed. PubMed ID: 8035514. Show all entries for this paper.

Moore1995a J. P. Moore, A. Trkola, B. Korber, L. J. Boots, J. A. Kessler II, F. E. McCutchan, J. Mascola, D. D. Ho, J. Robinson, and A. J. Conley. A Human Monoclonal Antibody to a Complex Epitope in the V3 Region of gp120 of Human Immunodeficiency Virus Type 1 Has Broad Reactivity within and outside Clade B. J. Virol., 69:122-130, 1995. The epitope was defined as including amino acids on both sides of the loop of the V3 loop: -I----G--FY-T, where the G is the second G of the GPGR tip of the loop. This antibody bound well to gp120 molecules from clades A,B,C,E, and F, when the critical amino acids were present. Binding did not parallel neutralization however; 19b could produce a 50-fold reduction of infectivity in some primary B isolates, and in C clade isolates at low virus input concentrations, but not in isolates from all clades where binding could occur (A,E, and F). PubMed ID: 7527082. Show all entries for this paper.

Moore1995b J. P. Moore, Y. Cao, L. Qing, Q. J. Sattentau, J. Pyati, R. Koduri, J. Robinson, C. F. Barbas III, D. R. Burton, and D. D. Ho. Primary Isolates of Human Immunodeficiency Virus Type I Are Relatively Resistant to Neutralization by Monoclonal Antibodies to gp120, and Their Neutralization Is Not Predicted by Studies with Monomeric gp120. J. Virol., 69:101-109, 1995. A panel of anti-gp120 MAbs and sera from HIV-1 infected individuals was tested for its ability to neutralize primary isolates. Most MAbs bound with high affinity to gp120 monomers from the various isolates, but were not effective at neutralizing. The MAb IgG1b12, which binds to a discontinuous anti-CD4 binding site epitope, was able to neutralize most of the primary isolates. PubMed ID: 7527081. Show all entries for this paper.

Moore1995c J. P. Moore and D. D. Ho. HIV-1 Neutralization: The Consequences of Adaptation to Growth on Transformed T-Cells. AIDS, 9(suppl A):S117-S136, 1995. This review considers the relative importance of a neutralizing antibody response for the development of a vaccine, and for disease progression during the chronic phase of HIV-1 infection. It suggests that T-cell immunity may be more important. The distinction between MAbs that can neutralize primary isolates, and those that are effective at neutralizing only laboratory adapted strains is discussed in detail. Alternative conformations of envelope and non-contiguous interacting domains in gp120 are discussed. The suggestion that soluble monomeric gp120 may serve as a viral decoy that diverts the humoral immune response it in vivo is put forth. PubMed ID: 8819579. Show all entries for this paper.

Pantophlet2003b Ralph Pantophlet, Ian A. Wilson, and Dennis R. Burton. Hyperglycosylated Mutants of Human Immunodeficiency Virus (HIV) Type 1 Monomeric gp120 as Novel Antigens for HIV Vaccine Design. J. Virol., 77(10):5889-8901, May 2003. PubMed ID: 12719582. Show all entries for this paper.

Pantophlet2008 Ralph Pantophlet, Terri Wrin, Lisa A. Cavacini, James E. Robinson, and Dennis R. Burton. Neutralizing Activity of Antibodies to the V3 Loop Region of HIV-1 gp120 Relative to Their Epitope Fine Specificity. Virology, 381(2):251-260, 25 Nov 2008. PubMed ID: 18822440. Show all entries for this paper.

Park2000 E. J. Park, M. K. Gorny, S. Zolla-Pazner, and G. V. Quinnan. A global neutralization resistance phenotype of human immunodeficiency virus type 1 is determined by distinct mechanisms mediating enhanced infectivity and conformational change of the envelope complex. J. Virol., 74:4183-91, 2000. PubMed ID: 10756031. Show all entries for this paper.

Parren1997 P. W. Parren, M. C. Gauduin, R. A. Koup, P. Poignard, Q. J. Sattentau, P. Fisicaro, and D. R. Burton. Erratum to Relevance of the Antibody Response against Human Immunodeficiency Virus Type 1 Envelope to Vaccine Design. Immunol. Lett., 58:125-132, 1997. corrected and republished article originally printed in Immunol. Lett. 1997 Jun;57(1-3):105-112. PubMed ID: 9271324. Show all entries for this paper.

Parren1998 P. W. Parren, I. Mondor, D. Naniche, H. J. Ditzel, P. J. Klasse, D. R. Burton, and Q. J. Sattentau. Neutralization of human immunodeficiency virus type 1 by antibody to gp120 is determined primarily by occupancy of sites on the virion irrespective of epitope specificity. J. Virol., 72:3512-9, 1998. The authors propose that the occupancy of binding sites on HIV-1 virions is the major factor in determining neutralization, irrespective of epitope specificity. Neutralization was assayed T-cell-line-adapted HIV-1 isolates. Binding of Fabs to monomeric rgp120 was not correlated with binding to functional oligomeric gp120 or neutralization, while binding to functional oligomeric gp120 was highly correlated with neutralization. The ratios of oligomer binding/neutralization were similar for antibodies to different neutralization epitopes, with a few exceptions. PubMed ID: 9557629. Show all entries for this paper.

Patel2008 Milloni B Patel, Noah G. Hoffman, and Ronald Swanstrom. Subtype-Specific Conformational Differences within the V3 Region of Subtype B and Subtype C Human Immunodeficiency Virus Type 1 Env Proteins. J. Virol., 82(2):903-916, Jan 2008. PubMed ID: 18003735. Show all entries for this paper.

Poignard2003 Pascal Poignard, Maxime Moulard, Edwin Golez, Veronique Vivona, Michael Franti, Sara Venturini, Meng Wang, Paul W. H. I. Parren, and Dennis R. Burton. Heterogeneity of Envelope Molecules Expressed on Primary Human Immunodeficiency Virus Type 1 Particles as Probed by the Binding of Neutralizing and Nonneutralizing Antibodies. J. Virol., 77(1):353-365, Jan 2003. PubMed ID: 12477840. 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.

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.

Robinson1992 J. Robinson, H. Yoshiyama, D. Holton, S. Elliot, and D.D. Ho. Distinct Antigenic Sites on HIV gp120 Identified by a Panel of Human Monoclonal Antibodies. J. Cell Biochem., Suppl 16E:71, 1992. Show all entries for this paper.

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.

Sattentau1995 Q. J. Sattentau, S. Zolla-Pazner, and P. Poignard. Epitope Exposure on Functional, Oligomeric HIV-1 gp41 Molecules. Virology, 206:713-717, 1995. Most gp41 epitopes are masked when associated with gp120 on the cell surface. Weak binding of anti-gp41 MAbs can be enhanced by treatment with sCD4. MAb 2F5 binds to a membrane proximal epitope which binds in the presence of gp120 without sCD4. PubMed ID: 7530400. Show all entries for this paper.

Sattentau1995b Q. J. Sattentau. Conservation of HIV-1 gp120 Neutralizing Epitopes after Formalin Inactivation. AIDS, 9:1383-1385, 1995. PubMed ID: 8605064. 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.

Schulke2002 Norbert Schulke, Mika S. Vesanen, Rogier W. Sanders, Ping Zhu, Min Lu, Deborah J. Anselma, Anthony R. Villa, Paul W. H. I. Parren, James M. Binley, Kenneth H. Roux, Paul J. Maddon, John P. Moore, and William C. Olson. Oligomeric and Conformational Properties of a Proteolytically Mature, Disulfide-Stabilized Human Immunodeficiency Virus Type 1 gp140 Envelope Glycoprotein. J. Virol., 76(15):7760-76, Aug 2002. PubMed ID: 12097589. Show all entries for this paper.

Scott1990 C. F. Scott, Jr., S. Silver, A. T. Profy, S. D. Putney, A. Langlois, K. Weinhold, and J. E. Robinson. Human Monoclonal Antibody That Recognizes the V3 Region of Human Immunodeficiency Virus gp120 and Neutralizes the Human T-Lymphotropic Virus Type IIIMN Strain. Proc. Natl. Acad. Sci. U.S.A., 87:8597-8601, 1990. PubMed ID: 1700435. Show all entries for this paper.

Selvarajah2005 Suganya Selvarajah, Bridget Puffer, Ralph Pantophlet, Mansun Law, Robert W. Doms, and Dennis R. Burton. Comparing Antigenicity and Immunogenicity of Engineered gp120. J. Virol., 79(19):12148-12163, Oct 2005. PubMed ID: 16160142. Show all entries for this paper.

Sheppard2007a Neil C. Sheppard, Sarah L. Davies, Simon A. Jeffs, Sueli M. Vieira, and Quentin J. Sattentau. Production and Characterization of High-Affinity Human Monoclonal Antibodies to Human Immunodeficiency Virus Type 1 Envelope Glycoproteins in a Mouse Model Expressing Human Immunoglobulins. Clin. Vaccine Immunol., 14(2):157-167, Feb 2007. PubMed ID: 17167037. Show all entries for this paper.

Srivastava2005 Indresh K. Srivastava, Jeffrey B. Ulmer, and Susan W. Barnett. Role of Neutralizing Antibodies in Protective Immunity Against HIV. Hum. Vaccin., 1(2):45-60, Mar-Apr 2005. PubMed ID: 17038830. Show all entries for this paper.

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Trkola1998 A. Trkola, T. Ketas, V. N. Kewalramani, F. Endorf, J. M. Binley, H. Katinger, J. Robinson, D. R. Littman, and J. P. Moore. Neutralization Sensitivity of Human Immunodeficiency Virus Type 1 Primary Isolates to Antibodies and CD4-Based Reagents Is Independent of Coreceptor Usage. J. Virol., 72:1876-1885, 1998. PubMed ID: 9499039. Show all entries for this paper.

Ugolini1997 S. Ugolini, I. Mondor, P. W. H. I Parren, D. R. Burton, S. A. Tilley, P. J. Klasse, and Q. J. Sattentau. Inhibition of Virus Attachment to CD4+ Target Cells Is a Major Mechanism of T Cell Line-Adapted HIV-1 Neutralization. J. Exp. Med., 186:1287-1298, 1997. PubMed ID: 9334368. 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.

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Yasmeen2014 Anila Yasmeen, Rajesh Ringe, Ronald Derking, Albert Cupo, Jean-Philippe Julien, Dennis R. Burton, Andrew B. Ward, Ian A. Wilson, Rogier W. Sanders, John P. Moore, and Per Johan Klasse. Differential Binding of Neutralizing and Non-Neutralizing Antibodies to Native-Like Soluble HIV-1 Env Trimers, Uncleaved Env Proteins, and Monomeric Subunits. Retrovirology, 11:41, 2014. PubMed ID: 24884783. Show all entries for this paper.

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MAb ID	447-52D (447/52-DII, 447-52-D, 447d, 447-52-D, 447-D, 447, 447D, 447D-52)
HXB2 Location	gp160(312-315) DNA(7158..7169)	gp160 Epitope Map
Author Location	gp120( MN)
Research Contact	Dr. Susan Zolla-Pazner, NYU Med Center NY, NY; Veteran Affairs Med Center NY, NY; or Cellular Products Inc, Buffalo, NY,
Epitope	`GPGR`	Epitope Alignment
Subtype	B
Ab Type	gp120 V3 // V3 glycan (V3g)
Neutralizing	L P View neutralization details
Contacts and Features	View contacts and features
Species (Isotype)	human(IgG3λ)
Patient
Immunogen	HIV-1 infection
Keywords	acute/early infection, ADCC, antibody binding site, antibody generation, antibody interactions, antibody lineage, antibody sequence, assay or method development, binding affinity, broad neutralizer, co-receptor, complement, computational epitope prediction, dendritic cells, dynamics, elite controllers, enhancing activity, escape, genital and mucosal immunity, glycosylation, HIV-2, kinetics, mimics, mimotopes, neutralization, optimal epitope, polyclonal antibodies, review, SIV, structure, subtype comparisons, supervised treatment interruptions (STI), Th2, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity, viral fitness and reversion

Notes

Showing 219 of 219 notes.

447-52d: 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)
447-52D: 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 447-52D 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)
447-52D: 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)
447-52D: 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)
447-52D: 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)
447-52D: 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 V3 loop crown for 447-52D. Hogan2018 (vaccine antigen design)
447-52D: 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. With S306L plus R308L substitutions 447-52D did not bind to SOSIP.v5.2 and SOSIP.v5.2 constructs. deTaeye2018 (broad neutralizer)
447-52D: 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)
447-52D: 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 447-52D), 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)
447-52D: 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
447-52D: 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 non-NAb 447-52D 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)
447-52D: 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)
447D: 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. The V3 MAbs tested were: 447, 2219, and 2557. Upadhyay2014 (glycosylation, neutralization)
447-52D: A computational method, MDE, predicts the presence of neutralization epitopes in the V3 loop solely from the viral sequence and the crystal structure of the antibody. For V3-specific mAbs 2219 and 447-52D, the method accurately predicted the presence of neutralization epitopes in diverse strains of HIV-1. Identification of Ab-targeted neutralization epitopes in silico enables easy prediction of the reactivity of specific mAbs across diverse variants, and facilitates rational design of immunogens. Shmelkov2014 (computational epitope prediction)
447-52D: This study proposes a mimotope model of the V3 crown epitope in which the PR-L and GPG sequences represent the two known epitope binding sites. Rabbit serum to these mimotopes recognized the V3 peptides and moderately decreased the fusion between HIV-1 Env- and CD4-expressing Jurkat cells. MAb 447-52D has been used as V3 epitope core recognizing Ab. The most intriguing characteristic of this mimotope model of the V3 epitope is the absence of the arginine at the position next to the GPG, which offers the flexibility of this phage-displayed linear peptide affecting the correct interaction between the epitope and the antibody tolerating substitutions of the GPG amino acids. Gazarian2013 (mimotopes)
447-52D: 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. 447-52D bound to all 4 trimeric Env. Carbonetti2014 (elite controllers, vaccine-induced immune responses)
447-52D: 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. 447-52D bound to all the Envs tested except the clade B REJO, the consensus A1 sequence, the clade 405c, and the clade A/E A244. The predicted germ line version of 447-52D did not exhibit any detectable binding against these Envs. Ca²⁺ influx through the 447-52D BCR was also tested as a function of binding affinity. Removal of selected N-linked glycosylaion sites on Env did not confer binding to the predicted germline 447-52D. McGuire2014 (antibody interactions, antibody lineage)
447-52D: Describes the mutagenesis of plasmid P5Q (a scFv antibody derived from mAb 447). Cites the original mAb 447 as first described by Buchbinder et al. 1992. Lewis1995 (binding affinity, antibody sequence)
447-52D: 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. 447-52D was used as an anti-V3 Ab to study effects of Ab specificity and affinity on ADCC against HIV-1 infected targets. Smalls-Mantey2012 (ADCC, assay or method development)
447-52D: 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. 447-52D had limited neutralizing activity recognizing the V3 loop and carried fewer somatic mutations than bnAbs. Fig S4C described the comparison of Ab framework amino acid replacement vs. interactive surface area on 447-52D. Klein2013 (neutralization, structure, antibody lineage)
447-52D: Polyclonal B cell responses to conserved neutralization epitopes are reported. Cross-reactive plasma samples were identified and evaluated from 308 subjects tested. 447-52D was used as a control mAb in the comprehensive set of assays performed. Tomaras2011 (neutralization, polyclonal antibodies)
447-52D: The role of V1V2 in the resistance of HIV-1 to neutralizing Abs was studied using a panel of neutralization-sensitive and -resistant HIV-1 variants and through exchanging regions of Env between neutralization-sensitive and -resistant viruses. An increase in the length of the V1V2 loop and/or the number of potential N-linked glycosylation sites (PNGS) in that same region of Env was directly involved in the neutralization resistance. The introduction of a shorter V1V2 loop from historical seroconverters into the background of Env of HIV-1 from contemporary seroconverters resulted in significant increase in neutralization sensitivity to MAb 447-52D. vanGils2011 (glycosylation, neutralization, escape)
447-52D: The inhibitory activity of HIV-1-specific Abs against HIV-1 replication in langerhans cells (LCs) and interstitial dendritic cells (IDCs) was analyzed. Five well-known NAbs 447-52D, 4E10, b12, 2G12, 2F5 strongly inhibited HIV-1BaL and HIV-1TV1 replication in LCs and IDCs, and their inhibitory activities were stronger than those measured on PBMCs. Inhibition was more efficient by IgGs than corresponding IgAs, due to an Fc receptor-dependent mechanism, where HIV-1 inhibition occurs by binding of the Fc portion of IgGs to Fc receptors. Blocking the binding of the NAb to the FcRs present on the cell surface of the DCs reduced the inhibitory activity of the IgG 447-52D. Finally, nonneutralizing inhibitory action of 447-52D Fab fragments 240D and 246D 246D, which do not exhibit neutralizing activity on PBMCs, reduced the number of HIV-1BaL-infected LCs and IDCs by 90%. Peressin2011 (genital and mucosal immunity, dendritic cells)
447-52D: 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 was used to analyze the antigenic integrity of the covalent complexes using capture ELISA. Binding of the cross-linked complex on 447-52D or MN 215 was increased compared with that of gp140 alone. Martin2011 (mimics, binding affinity)
447-52D: Signature motifs specific for neutralization epitopes present in the V3 loop crown were used to determine the presence or absence of MAb-specific epitopes in vaccine immunogens and in break-through viruses infecting vaccine and placebo recipients in the VAX003 and VAX004 Phase III clinical trials. Of the six epitopes present in the immunogens and targeted by known NAbs, only the one targeted by anti-V3 NAb 2219 exhibited a significant reduction in occurrence in vaccinated subjects from VAX003 Thailand cohort compared to the placebo group. The signature motif used for MAb 447-52D is P16, R18 in V3-loop position numbers. Shmelkov2011 (vaccine-induced immune responses)
447-52D: 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. 447-52D induced potent shedding that correlated with its neutralization activity. Ruprecht2011 (neutralization, kinetics)
447-52D: Closely related HIV-1 B clade Envs from a pediatric subject in a late disease differed in their capacity to infect primary macrophages. E153G conferred high levels of macrophage infectivity for several heterologous R5 envelopes, while the reciprocal G153E substitution abrogated infection. Shifts in macrophage tropism were associated with dramatic shifts in sensitivity to the V3 loop MAb 447-52D and soluble CD4, as well as more modest changes in sensitivity to the CD4bs MAb, b12. Musich2011 (escape)
447-52D: This study analyzed the neutralization sensitivity of sequential HIV-1 primary isolates during their natural evolution in 5 subtype B and CRF02_AG HIV-1 infected drug naive individuals to 13 anti-HIV-1 MAbs (including this MAb) directed at epitopes in the V2, V3, CD4bd and carbohydrates. Patient viruses evolved to become more sensitive to neutralization by MAbs directed at epitopes at V2, V3 and CDbd, indicating that cross sectional studies are inadequate to define the neutralization spectrum of MAb neutralization with primary HIV-1 isolates. Haldar2011 (neutralization)
447-52D: 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. MAb 447–52D bound more strongly to deglycosylated trimers than untreated ones. Depetris2012 (glycosylation, binding affinity)
447-52D: Masking signatures were developed and analyzed for 4 anti-HIV V3 loop MAbs, 2219, 3074, 2557, 447-52D. The epitopes were classified as "masked" if their signature motifs were present in a virus, but there was no detectible neutralization by the MAb of the same virus in vitro. The signature motif for MAb 2219 used in the study was R9+K10+[l,V]12+[Y,F]21. Of the 4 MAbs, 2219 neutralized the largest number of pseudoviruses containing its epitope. The 2219 neutralization epitope is unmasked in 25/68 (36.8%) of the viruses containing the 2219 epitope. Agarwal2011 (neutralization)
447-52D: 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. The effect of I424M substitution in three clade B Envs (RHPA4259.7, JRFL and YU2) was tested and 2-45-fold increase was found in their sensitivities to anti-V3 MAbs including 447-52D. Ringe2011 (neutralization)
447-52D: 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. In some cases the affinities of PG9/PG16 binding were comparable to those of 447-52D. Lower binding affinity of gp140 ligands to PG9/PG16 than 447D was observed. 447-52D binds to an epitope within the V3 loop of gp120 and interacts very efficiently with monomeric gp120. 447-52D also bound to all clade A Env gp140s tested. The anti-SF162 neutralizing activity of 447-52D decreased when the lysine at position 160 was replaced by an asparagine. Davenport2011 (neutralization, binding affinity)
447-52D: The location and extent of conservation of eight protease cleavage sites on HIV-1 gp120 recognized by 3 major human proteases (cathepsins L, S and D) are described along with the effect of cathepsin cleavage on gp120 binding to CD4-IgG and NAbs. 447-52D binding was destroyed with cathepsin L-treated gp120 but preserved with cathepsin D-treated gp120. Yu2010 (binding affinity)
447-52D: 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)
447-52D: 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 predominantly neutralizes clade B viruses and occasionally neutralizes some viruses from non-B clades. Gonzalez2010 (neutralization, variant cross-reactivity, escape, review)
447-52D: The expression and characterization of different glycoforms of V3-Fc fusion protein along with its binding to HIV-neutralizing Abs 2G12 and 447-52D was examined. The binding affinity of 447-52D was high for complex type glycoform V3-Fc-CT and high-mannose type glycoforms of V3-Fc (V3-Fc-HM, V3-Fc-M9 and the two mutants:N301A and Fc-N297A) following a quick association/dissociation kinetic process but it was higher for gp120 with extremely slow dissociation process. The affinity to 447-52D was not significantly affected by removal of the N-glycans at the N297, N301 and N332 sites. Yang2010a (glycosylation, binding affinity)
447-D52: 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 for several antibodies. 447D-52, however, did not neutralize any of the mutants tested. ORourke2010 (neutralization, variant cross-reactivity)
447-52D: 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. V3 Abs with specificities similar to that of 447-52D were elicited nearly ubiquitously in all of the vaccine sera tested, where the sera were able to outcompete binding to 447-52D. Vaine2010 (antibody interactions)
447-52D: Structure of 447-52D bound to a peptide containing the sequence of the V3 loop was used to derive sensitive and specific signature motifs for its neutralization epitope. 447-52D epitope (¹⁶PxR¹⁸) was found conserved in 11% of circulating HIV-1 strains, and was highly restricted to subtype B strains. 447-52D neutralized 9% of subtype A pseudovirions, 47% of subtype B, 4% of subtype C, 10% of subtype D and 0% of CRF02_AG. Swetnam2010 (antibody binding site, neutralization, variant cross-reactivity, subtype comparisons, structure)
447-52D: Peptide ligands for CD4i epitopes on native dualtropic Envs were selected by phage display. The correct exposure of CD4i epitopes was detected by binding with MAb 447-52D, which bound both in the presence or absence of sCD4. Dervillez2010 (binding affinity)
447-52D: 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. V3-directed MAb 447-52D bound similarly to all three trimer variants: WT and 368D/R, and 423/425/431. Douagi2010 (binding affinity)
447-52D: The effect of presence and absence of V1 loop was assessed using two approaches: remove V1 loop from the soluble trimeric gp140 construct (ΔV1SF162gp140) and second, substitute the V1 loop on SF162gp140 construct with four different V1 loops from 89.6, YU2, JRFL, and HxB2 (heterologous HIV-1 viruses). Deletion or substitution of V1 loop increased resistance to neutralization by 447-52D in 3 out of 5 V1-modified gp140 constructs, although it did not affect the binding to 447-52D. D368R modification to SF162gp120 did not affect the binding to 447-52D but there was a decrease in neutralization activity by 447-52D. Ching2010 (neutralization, binding affinity)
447-52d: Clustering analysis was performed to find patterns of neutralization reactivity for the dataset of 103 patients sera against 20 viruses. The clustering by five MAbs (including 447-52d) against the 20 isolates was less statistically robust than that with serum titers, resulting in three clusters for both cases. The membership in an isolate cluster defined by serum titers was compared with its sensitivity to every MAb to understand the relationship of serum and MAb reactivity. Membership in two out of three clusters did not correlate with sensitivity to 447-52d. Doria-Rose2010 (neutralization)
447: 447 neutralizing activity was assessed against pseudoviruses expressing Envs of diverse HIV-1 subtypes from subjects with acute and chronic infection. IC50 neutralization activity was also statistically assessed based on the area under the neutralization curves (AUC). 447 was able to neutralize 6/57 viruses in U87-based assay and 12/41 viruses in TZM-based assay, including Tier 1 and Tier 2 viruses, viruses of subtypes A, B, C, AG, and viruses from both chronic and acute infections. AUC analysis revealed that 15/57 viruses in the U87-based assay, and 12/41 viruses in the TZM-based assay, were significantly neutralized by this Ab. Thus, the AUC method has the ability to detect low levels of neutralizing activity that otherwise may be missed. Hioe2010 (assay or method development, neutralization, variant cross-reactivity)
447-52D: 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. 447-52D neutralized all ΔV1V2 variants more potently than wild type virus, indicating better exposure of the 447-52D epitope when V1V2 domain is removed. Bontjer2010 (neutralization)
447-52D: This review discusses recent research done to improve the production, quality, and cross-reactivity of binding Abs, neutralizing Abs, monoclonal Abs with broad neutralizing activity, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated viral inhibition (ADCVI), and catalytic Abs. Studies focusing on several aspects of BNAb roles in vaccine development, and studies done to better understand the broad binding capacity of BNAbs are reviewed. Baum2010 (ADCC, neutralization, review)
447-52D: GnTI virus (complex glycans of the neutralizing face are replaced by fully trimmed oligomannose stumps), and the N301Q mutant virus (glycan at position 301 is removed), were both significantly more sensitive to neutralization by 447-52D compared to the parental virus. This suggests that the antennae of the complex glycans play a significant role in protecting the V3 loop from Ab binding. Binley2010 (glycosylation, neutralization)
447: This human Ab was compared to MAbs 2.2G, 2.3E, 2.5B derived from B-cell cultures from SHIV-infected rhesus macaques and human MAbs 2909, 830A and sCD4. 447 blocked the capture of virions by MAbs 2.2G, 2.3E, 2.5B and human MAb 2909. 447 capture of virions was partially blocked by 2909 and 830A and not blocked by sCD4. Robinson2010 (binding affinity)
447: Two V3-scaffold immunogen constructs were designed and expressed using 3D structures of cholera toxin B (CTB), V3 in the gp120 context, and V3 bound to 447-52D MAb. The construct (V3-CTB) presenting the complete V3 was recognized by 447-52D and by the large majority of other MAbs (18/24), indicating correctly folded and exposed MAb epitopes. V3-CTB induced V3-binding Abs and Abs displaying cross-clade neutralizing activity in immunized rabbits. Short V3-CTB construct, presenting a V3 fragment in conformation observed in complex with 447-52D, showed high affinity binding to 447-52D. Few other MAbs retained the same binding affinities for this construct as for the V3-CTB, indicating that they utilize a binding mode similar to that of 447-52D. Totrov2010 (vaccine antigen design, binding affinity, structure)
447-52D: A panel of 109 HIV-1 pseudoviruses was assessed for neutralization sensitivities to 447-52D 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, 7 Tier 1B, 3 Tier 2 and 1 Tier 3 viruses were found to be sensitive to neutralization by 447-52D. Seaman2010 (neutralization)
447-52D: Neutralizing sensitivity of L669S gp41 mutant virus to 447-52D increased ∼169-fold compared to the wild type virus, indicating that conformational changes in the MPER could alter the exposure of neutralization epitopes in other regions of HIV-1 Env. Shen2010 (neutralization)
447-52D: Neutralization potency of 447-52D was compared to that of HK20 scFv in TZM-based assay using 45 Tier 1 and Tier 2 HIV isolates. 447-52D neutralized 6/45 isolates. Sabin2010 (neutralization, variant cross-reactivity)
447-52D: Crystal structures of 2219, 2557, 1006-15D and 3074 MAbs in complex with V3 peptides revealed that these MAbs bind to conserved elements in four regions of the V3: the arch, the circlet, the band, and the V3 peptide main chain backbone. A mimotope that preserved the key structural elements in the circlet and band regions, but with GPG of the arch replaced by a disulfide bond, interacted with broadly reactive MAbs 2557, 1006 and 2219. It did not react with 447-52D nor 268-D, which are dependent on the Arg in the arch. Thus, mimotopes can be constructed that may focus the immune response on structurally conserved elements. Jiang2010 (antibody binding site, mimotopes, structure)
447-52D: B cell depletion in an HIV-1 infected patient using rituximab led to a decline in NAb titers and rising viral load. Recovery of NAb titers resulted in control of viral load, and the newly emerged virus population was examined. Strong binding competition between patient sera and 447-52D was observed. Huang2010 (antibody interactions)
447-52D: Binding affinity of 447-52D to a minimal peptide was 2-fold weaker than binding of this Ab to gp140 monomers and trimers. The opposite was observed for MAb 4E10. Xu2010 (binding affinity)
447-52D: 447-52D ability to bind different Env trimers and its neutralization breadth are 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)
447-52D: 58 mAbs, including 3 broadly neutralizing mAbs, were isolated from memory B cells of HIV-1 infected donors using an improved EBV immortalization method combined with a broad screening strategy. 447-52D neutralization activity was compared to the three new broadly neutralizing mAbs. 447-52D neutralized 88% of Tier 1 and 4% of Tier 2 viruses, the neutralization of Tier 2 viruses being inferior to that of the new mAbs HGN194 and HJ16. Corti2010 (neutralization)
447-52D: 433 Abs were cloned from HIV envelope-binding memory B cells from 6 patients with broadly neutralizing sera. The Abs had neutralizing activity directed against several epitopes on gp120 and the majority neutralized Tier 1 viruses. Tier-2 neutralization was observed only with mixtures of MAbs, but only at high concentrations. 447-52D was used as a control and it neutralized 5/5 Tier 1 and 2/5 Tier 2 viruses. Scheid2009 (neutralization)
447-52D: NAb specificities of a panel of HIV sera were systematically analyzed by selective adsorption with native gp120 and specific mutant variants. The integrity and specificity of gp120 beads in adsorption assay were validated by their ability to adsorb binding activity of 447-52D. 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 447-52D. To test for presence of coreceptor binding region MAbs in sera, gp120 I420 mutant was used. This mutant was recognized by 447-52D at equal levels as the wild type. To test sera for presence of V3 neutralizing activity, V3 peptides were used. These peptides inhibited neutralization mediated by 447-52D. 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)
447-52D: 447-52D sequence-independent mode of epitope recognition is reviewed in detail. The review also summarizes on how different modes of Ab binding and recognition are used to overcome viral evasion tactics and how this knowledge may be used to re-elicit responses in vivo. Kwong2009a (antibody binding site, review)
447-52D: 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)
447-52D: 447-52D bound to both SF162 wild type and SF162 mutant, carrying only the monomeric form of the Env protein, virions and transfected cells. 447-52D exhibited higher binding activity to SF162 wild type compared to 2909, suggesting that 2909 epitope may not be formed on each trimer. Kimura2009 (antibody binding site, binding affinity)
447-D: FcγR-mediated inhibition and neutralization of HIV by 447-D and other MAbs is reviewed. The review also summarizes the role of ADCC and ADCVI Abs on HIV infection inhibition and neutralization. Forthal2009 (review)
447-52D: 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. The number of mutations from the germline and the number of mutated contact residues for 447-52D were smaller than those for VRC01. Zhou2010 (neutralization, structure)
447-52D: 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 447-52D. Memory B cells were selected that bound to RSC3 and full IgG mAbs were expressed. Three newly detected MAb VRC1 did not enhance neutralization by 447-52D. Addition of RSC3 had no effect on 447-52D neutralization of HXB2. Wu2010 (neutralization, binding affinity)
447-52d: Insertion of one or two disulfide bonds at specific residues in a V3 MN peptide sequence was used to constrain the conformations of the peptides to β-hairpin structures recognized by the 447-52d (postulated R5 V3 conformation). Insertion of two disulfide bonds increased the tendency of the peptides to form β-hairpin structures but it required replacement of residues reacting strongly with 447-52d Ab. Thus, peptides constrained by one disulfide bond are suggested to be more attractive candidates for immunogens that could elicit neutralizing Abs. Mor2009 (antibody binding site)
447-52d: The epitope sequence motif of 447-52d was precisely defined based on the 3D structure of the MAb complexed with V3MN peptide. Depending on how snugly V3 loop side chains are bound by the Ab, the complex can be divided into 3 subdomains. The specific epitope motif suggested by the complex structure was shown to be R315. 93% of HIV sequences with R315 in the Los Alamos HIV database fit the ag-binding site of MAb 447-52d. A set of V3 chimeric pseudoviruses, carrying either R315 or Q315, were tested for their sensitivity to neutralization by 447-52d. R315 viruses were neutralized very well while Q315 viruses were neutralized much more weakly. Thus, the sequence motif for the neutralization epitope recognized by 447-52d is R315. The neutralization-relevant epitope sequence motif of 447-52d was calculated to be present in approximately 13% of worldwide HIV isolates, predominating in subtype B isolates. Cardozo2009 (neutralization, optimal epitope)
447-52D: NL4.3 virus was cultured with cyclotriazadisulfonamide (CADA) and CADA-resistant virus was selected. 447-52D MAb showed enhanced binding to the CADA-resistant virus compared to wildtype. In addition, CADA-resistant virus was more susceptible to neutralization by this MAb. The mutations in CADA-resistant virus are suggested to stabilize the conformation of gp120 and reduce glycosylation. Vermeire2009 (neutralization, binding affinity)
447-52D: C2EB5 MAb was isolated from mice immunized with a peptide from C2 region. C2EB5 neutralization and binding affinity to virions of clades A, B, C, D and CRF01_AE was compared to that of 447-52D. Sreepian2009 (neutralization, variant cross-reactivity, binding affinity)
447-52D: Binding of 447-52D 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
447-52D: V3 peptides were constrained in various ways to stabilize the β-hairpin conformation. This study showed that it is possible to constrain V3 peptides to this conformation that is recognized by 447-52D while maintaining high-affinity binding to this Ab. Peptides designed to mimic either the R5A or R5B conformation had higher affinity to 447-52D than peptides designed to mimic X4 conformation. Mester2009 (antibody binding site, kinetics, binding affinity)
447-52D: This Ab neutralized JRFL strain but many folds higher concentrations of the Ab were needed compared to neutralization of SF162 and SS1196 by 447-52D. 447-52D did not neutralize strain 3988.25. Hioe2009 (neutralization)
447-52D: The Ig usage for variable heavy chain of this Ab was as follows: IGHV:3-15*07, IGHD:3-10, D-RF:3, IGHJ:6. There was a preferential usage of the VH5-51 gene segment for V3 Abs. The usage of the VH4 family for the V3 Abs was restricted to only one gene segment, VH4-59, and the VH3 gene family was used at a significantly lower level by these Abs. The V3 Abs preferentially used the JH3 and D2-15 gene segments. Gorny2009 (antibody sequence)
447-52D: An international collaboration (NeutNet) was organized to compare the performance of a wide variety of HIV-1 neutralization assays performed in different laboratories. Four neutralizing agents were evaluated: 4E10, 447-52D, sCD4 and TriMab (equal mixture of 2F5, 2G12 and 4E10). In general, there were clear differences in assay sensitivities that were dependent on both the neutralizing agent and the virus. No single assay was capable of detecting the entire spectrum of neutralizing activities. Fenyo2009 (assay or method development, neutralization)
447-52D: 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 were sensitive to neutralization by 447-52D, while the wildtype derived viruses HIV-2KR.X4 and HIV-2KR.X7 were completely resistant. A V3 linear peptide from HIV-1 JR-FL was able to absorb all 447-52D neutralizing activity and a peptide from HIV-1 YU2 removed most of the 447-52D neutralizing activity. Fc-V3 fusion proteins from subtypes B and C completely eliminated 447-52D-mediated neutralization. However, 447-52D was unable to neutralize the primary HIV-1 BORI virus while it neutralized the HIV-2-BORI V3 chimera. Competition assays showed that most of the plasmas derived from subtype B and C chronically infected individuals had neutralizing activity that was V3 specific and dependent upon residued in the V3 crown that overlap 447-52D and F425 B4e8 epitopes. Also, 55 early founder viral Env proteins from 47 subjects acutely infected with subtype B virus were tested for susceptibility to 447-52D. 51 viruses were resistant to neutralization by 447-52D, but many showed sensitivity to this Ab once conformational changes were induced with sCD4. This indicates that the V3 region in primary HIV-1 Envs is highly conserved but is shielded from Ab recognition. Davis2009 (HIV-2, neutralization, acute/early infection)
447-52D: 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. 447-52D bound detectably to gp120 of CC101.19 but this was greatly reduced compared to the binding of 447-52D to gp120 of the other three viruses. The opposite was true for 447-52D binding to the V3 peptide alone of the four viruses. 447-52D neutralized CC101.19 but did not neutralize the other three viruses. This indicates that the V3 region of CC101.19 has become unusually accessible to V3 Abs. Berro2009 (neutralization, binding affinity)
447-52D: 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. 447-52D 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)
447-52D: Reactivity and structure of 447-52D and 537-10D MAbs was compared. 447-52D was able to bind 22/24 V3 peptides from a panel of clades A, B and C, including peptides with both GPGR and GPGQ motifs, while 537-10D only reacted with peptides containing the GPGR motif. Crystal structures of the Fab fragments of 447-52D and 537-10D in complex with 23-mer peptides derived from clades A and B viruses, respectively, was determined. Although both MAbs had highly similar antigen binding sites, differences in their binding and neutralization activities were found to be due to subtile differences in their structures. The structure analyses explained the ability of 447-52D to bind to both GPGR and GPGQ motifs. Burke2009 (antibody binding site, neutralization, structure)
447-52D: Data is summarized on the X-ray crystal structures resolution and NMR studies of 447-52D. Sirois2007 (review, structure)
447-52D: 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. Also, a summary of the neutralizing activity of MAb 447-52D in different HIV-1 clades is provided. McKnight2007 (variant cross-reactivity, review)
447-52D: This review provides information on the HIV-1 glycoprotein properties that make it challenging to target with neutralizing Abs. 447-52D 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, such as 447-52D, are discussed. In addition, approaches to target cellular molecules, such as CD4, CCR5, CXCR4, and MHC molecules, with therapeutic Abs are reviewed. Phogat2007 (review)
447-52D: This review summarizes current knowledge on the various functional properties of antibodies in HIV-1 infection, including 447-52D MAb, in vivo and in vitro activity of neutralizing Abs, the importance and downfalls of non-neutralizing Abs and antibodies that mediate antibody-dependent cellular cytotoxicity and the complement system, and summarizes data on areas that need future investigation on Ab-mediated immune control. Huber2007 (review)
447-52D: 447-52D structure, binding, neutralization, and strategies that can be used for vaccine antigen design to elicit anti-V3 Abs, are reviewed in detail. Lin2007 (review, structure)
447/52D: This review summarizes 447-52D Ab epitope, properties and neutralization activity. Kramer2007 (review)
447-52D: Current insights into CTLs and NAbs, and their possible protective mechanisms against establishment of persistent HIV/SIV infection are discussed. Pre- and post-infection sterile and non-sterile protection of NAbs against viral challenge, and potential role of NAbs in antibody-mediated antigen presentation in modification of cellular immunity, are reviewed. 447-52D anti-viral activity in suppression of viral rebound in HIV-1 infected humans undergoing structured treatment interruptions is described. Yamamoto2008 (supervised treatment interruptions (STI), review)
447-52D: A mathematical model was developed and used to derive transmitted or founder Env sequences from individuals with acute HIV-1 subtype B infection. All but three of the transmitted or early founder Envs were resistant to neutralization by 447-52D, indicating that the coreceptor binding surfaces on transmitted/founder Envs are conformationally masked. sCD4 could trigger a conformational change in gp120 of these Envs and render the virus susceptible to neutralization by 447-52D. Keele2008 (neutralization, acute/early infection)
447-52D: A significantly higher level of 447-52D bound to gp120 complexed with anti-CD4bs mAbs than to gp120 alone or in complex with other non-CD4bs Abs, indicating that binding of anti-CD4bs Abs to gp120 increases exposure of specific V3 MAb epitopes. Visciano2008 (antibody binding site)
447D: Trimeric envelope glycoproteins with a partial deletion of the V2 loop derived from subtype B SF162 and subtype C TV1 were compared. 447D recognized both B and C trimers with similar efficiency, indicating that the epitope recognized by this Ab is exposed and preserved in the subtype C trimers. 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)
447-52D: 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 447-52D, 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 for neutralization by 447-52D, although 447-52D bound strongly to gp120 from CC1/85 and CC101.19. These results indicate that V3-dependent and -independent changes responsible for CCR5 inhibitor resistance do not necessarily alter the exposure of V3 to some of the V3 Abs. Pugach2008 (co-receptor, neutralization, binding affinity)
447-52D: To examine sequence and conformational differences between subtypes B and C, several experiments were performed with 11 MAbs regarding binding and neutralization. Both binding and neutralization studies revealed that the 11 MAbs could be divided in three different groups, and that the most differences between the subtypes were located in the stem and turn regions of V3. 447-52D belonged to the group 2 MAbs, which are able to bind subtype B but not subtype C gp120, and are able to bind both V3 peptides. 447-52D was able to bind subtype B V3 in the subtype C Env backbone chimera, but not the reverse, indicating that 447-52D binds to a structure created by the subtype B V3 sequence that is not impacted by the gp120 backbone. For subtype B, 447-52D required an R18 residue in order to bind, but the binding was not significantly affected by the H13R change. For subtype C, Q18R mutation did not restore binding to gp120, but the R13H-Q18R double mutation did. Peptide binding was affected only by the R13H mutation, indicating that the poor binding of Q18R gp120 mutant has a structural basis. 447-52D was not able to neutralize JR-FL isolate, and somewhat neutralized SF162. A chimeric SF162 variant with a JR-FL-like V3 sequence was hypersensitive to neutralization by this Ab. Patel2008 (neutralization, binding affinity, subtype comparisons)
447-52D: 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 used for the immunizations were inoculated with PBMCs, and CD4-specific binding to live CD3+/CD4+/CD8- cells was verified by recognition of the trimers by 447-52D. Forsell2008
447-52D: To test whether the conformation change of Env induced by CD4 affects the breadth and potency of 447-52D neutralization, 447-52D was tested in the presence or absence of sCD4 in neutralization of a panel of 12 subtype B and 12 subtype C Env-pseudoviruses. Without sCD4, 447-52D neutralized 2 subtype B and 0 subtype C viruses. With sCD4 present, 447-52D neutralized 7 subtype B and 1 subtype C virus, indicating that neutralization resistance of some viruses to 447-52D is due to a lack of exposure of the V3 loop. Neutralization of JRFL, ADA, and YU2 isolates by 447-52D increased with increased dose of sCD4. A virus with GPGG sequence at the tip of the V3 loop did not react with 447-52D, indicating that amino acid sequence variation may account for the neutralization resistance of other viruses. The presence of b12 and F105 did not induce 447-52D mediated neutralization of JRFL virus, indicating that b12 and F105 do not induce a conformation alternation in Env that exposes V3 loop to 447-52D. Wu2008 (neutralization, variant cross-reactivity)
447-52D: The neutralization profile of early R5, intermediate R5X4, and late X4 viruses from a rhesus macaque infected with SHIV-SF162P3N was assessed. The parental R5 virus was resistant to neutralization by 447-52D, while both the R5X4 intermediate and the late X4 viruses were sensitive to neutralization by 447-52D. The enhanced neutralization susceptibility of the dual-tropic and the X4 viruses to 447-52D suggests adoption of an increasingly open conformation of the Env gp120 over time. Tasca2008 (co-receptor, neutralization)
447D: 447D neutralized 6 of the 15 subtype B isolates tested, of which 5 were resistant to neutralization by MAbs 19b, 39F, CO11, F2A3, F530, LA21 and LE311. Angle of interaction between 447D and V3 was shown by superimposing the Fab fragment of the Ab with V3. 447D was shown to interact with V3 from a nearly identical angle as MAb 58.2. Pantophlet2008 (antibody binding site, neutralization, structure)
447-52D: 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 447-52D 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 447-52D epitope. gp140DF162ΔV2 was purified by the miniCD4 method to assess its ability to capture gp140 trimers. Purified gp140DF162ΔV2 was recognized by 447-52D, and the k-off value for 447-52D was reduced compared to gp120SF162 monomer, consistent with the gp140DF162ΔV2 trimeric conformation. Binding of 447-52D 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, kinetics, binding affinity)
447-52D: 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. 447-52D provided some inhibition of binding of the three neutralizing VHH Abs to gp120, suggesting that 447-52D imposes steric hinderance to binding of the VHH Abs to gp120. Forsman2008 (antibody interactions)
447-52D: 24 broadly neutralizing plasmas from HIV-1 subtype B and C infected individuals were investigated using a series of mapping methods to identify viral epitopes targeted by NAbs. V3 Ab activity was measured by three assays where 447-52D was used as a control. A V3 peptide derived from the N-terminal part of the V3 loop, including the crown, potently inhibited neutralization of several HIV-1 isolates by 447-52D, indicating that V3 Abs are commonly directed to the N-terminal part of the V3 loop. Binley2008 (neutralization)
447: 32 human HIV-1 positive sera neutralized most viruses from clades A, B, and C. Two of the sera stood out as particularly potent and broadly reactive. Two CD4-binding site defective mutant Env proteins were generated to evaluate whether Abs to the CD4-binding site are involved in the neutralizing activity of the two sera. The integrity of the wildtype and mutant proteins was tested to their reactivity to the 447 Ab. Li2007a (binding affinity)
447-52D: 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 were over 200 times more sensitive to 447-52D, indicating that deglycosylation in CV-N resistant viruses is likely to make the V3 loop more accessible to Abs. Hu2007 (antibody binding site, neutralization, escape)
447-52D: 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. 447-52D captured modestly (but not significantly) fewer mutant pseudovirions than wild type, neutralization was not tested. Dey2008 (binding affinity)
447D: The study explores how the V1 loop of Env influences the neutralization susceptibilities of heterologous viruses to antibodies elicited by the SF162gp140 immunogen. When the V1 loop of the heterologous isolates was replaced by the V1 loop present on the DF162go140 immunogen, these isolates became susceptible to neutralization by anti-V3 MAb 447D, indicating that the V1 loop plays an important role in the resistance of heterologous viruses to neutralization. Ching2008 (neutralization)
447-52D: The study determined a crystal structure of Fab 447-52D in complex with a V3 peptide NNTRKSIHLGPGRAFYATGDIIG at 2.1 A resolution. The structure revealed an extended CDR H3 loop that forms a β-sheet with the peptide, with predominantly main-chain hydrogen bonds contacts. There was high structural homology with reported structures of other Fab 447-52D complexes, indicating that the V3 loop may adopt a small set of conserved structures around the crown of the β-hairpin. Dhillon2008 (structure)
447-52D: 447-52D bound only to V3 peptides from the three isolates (MN, SHIVsf162p3 and clade B consensus) which contain GPGR motif. 447-52D did not recognize one B consensus peptide that did contain GPGR motif. Glycosylation of the position 154 in V1 was more important for the protection of the virus from this Ab than glycosylation of the position 195 in V2. 447-52D neutralized chimeric viruses 89.6/SF162V1, JRFL/SF162V1, YU2/SF162V1 and HxB2/SF162V1 more efficiently than their wildtype counterparts, indicating that the accessibility of the V3 loop is affected by the nature of the V1 loop. Derby2007 (neutralization, binding affinity)
447-52D: The epitope recognition sequence for this Ab was introduced into the corresponding region of SIVmac239 either alone or together with epitopes for Abs 2F5 and 4E10. The infectivity and replicative capacity of SIV239/447-52D and SIV239/447-52D/2F5/4E10 were, however, not detectable and too low, respectively, to be used for further analyses. Yuste2006 (SIV)
447-52D: The neutralizing capacity and binding of this Ab to the V3 region of gp120, as well as resistance to neutralization in different HIV-1 clades are reviewed. Pantophlet2006 (antibody binding site, neutralization, review, subtype comparisons, structure)
447-52D: This Ab was shown to neutralize SF162 and the neutralization sensitivity increased in the SF162 variant with a JR-FL V3 loop, SF162(JR-FL V3). In contrast, a great reduction in sensitivity to neutralization was observed in the SF162(JR-FL V1/V2) variant and was somewhat restored in the SF162(JR-FL V1/V2/V3) variant, indicating that the masking of the V1/V2 loop plays a much greater role in restricting neutralization sensitivity than the variations in V3. This Ab was shown to neutralize viruses with V3 sequences from several different subtypes (B, F, A1, CRF02_AG, H and CRF01_AE) except subtype C. This Ab failed to neutralize SF162(JR-FL V1/V2) with V3 derived from different HIV-1 clades indicating effective V1/V2-mediated masking of several HIV-1 clades. The effect on the neutralization sensitivity of the residue at the crown of the V3 loop (position 18) was shown to be great for this Ab. Krachmarov2006 (neutralization, variant cross-reactivity, subtype comparisons)
447-52D: The G314E escape variant highly resistant to KD-247 was shown to be more sensitive to 447-52D than the wildtype virus. 447-52D was shown to be able to bind well to both mutant and wildtype surface-expressed Envs. Yoshimura2006 (escape, binding affinity)
47-52D: Binding of this Ab to three V3 peptides was compared to binding of Ab 2219 to the same peptides. 447-52D was shown to bind to V3 MN and V3 UG1033 but not to V3 UR29. Stanfield2006 (variant cross-reactivity, binding affinity)
447-52D: This MAb was derived from plasma from a patient with env clade B virus with the GPGR V3 motif. When cross-reactivity was tested, this Ab bound to the V3subtypeB-fusion protein containing GPGR motif but not to the V3subtypeA-fusion protein containing GPGQ motif. This Ab was also shown to be able to neutralize both clade B psSF162 (GPGR) and clade C psMW965 (GPGQ) virus, and four of subtype B and two of non-B primary isolates. Gorny2006 (neutralization, variant cross-reactivity, binding affinity, subtype comparisons)
447-52D: Escape variants with the V3 P313L mutation, or V2 R166K, D167N and P175L mutations, were resistant or partially resistant, respectively, to 447-52D. Binding of 447-52D to surface-expressed Env proteins with the V2 mutations was lowered compared to the binding to viruses with no mutations. Binding to surface-expressed Env proteins with the V3 mutation was comparable to the negative control values. Binding affinity of this Ab for different combinations of V2 and V3 mutants was also tested. Shibata2007 (escape, binding affinity)
447-52D: This Ab was used in the analysis of clade C gp140 (97CN54) antigenicity and was shown to bind with relatively high avidity to the molecule and to dissociate substantially within 420 s. It was also used as a positive control in the neutralization assay. Sheppard2007a (neutralization, variant cross-reactivity, kinetics, binding affinity)
447-52D: Compared to the full-length Con-S gp160, chimeric VLPs containing Con-S ΔCFI gp145 with transmembrane (TM) and cytoplasmic tail (CT) sequences derived from the mouse mammary tumor virus (MMTV), showed higher binding capacity to 447-52D. Chimeric VLPs with only CT derived from MMTV also showed higher binding capacity to 447-52D than the full-length Con-S gp160, however, not as high as the chimeric CT-TM VLPs. Wang2007a (binding affinity)
447-52D: The major infectivity and neutralization differences between a PBMC-derived HIV-1 W61D strain and its T-cell line adapted counterpart were conferred by the interactions of three Env amino acid substitutions, E440G, D457G and H564N. Chimeric Env-pseudotyped virus Ch5, containing all three of the mutations, was more neutralization sensitive to 447-52D than Ch2, which did not contain any of these mutations. Env-pseudotyped viruses containing D457G mutation alone, or in combination with E440G or H564N, were also more sensitive to neutralization by 447-52D than Ch2. Beddows2005a (neutralization)
447-52D: The structure of the 447-52D MAb and its mechanisms of the V3 loop GPGR motif recognition and binding are reviewed. Engineering of Abs based on revealed structures of broadly neutralizing MAbs is discussed. Burton2005 (antibody binding site, review, structure)
447-52D: Monomeric gp120 and trimeric gp140CF proteins synthesized from an artificial group M consensus Env gene (CON6) bound well to 447-52D, indicating correct exposure of the 447-52D epitope. Gao2005a (antibody binding site)
447-D: This Ab was used as a control in a peptide adsorption assay. 447-D neutralized the SF162 primary isolate to 95%. When 447-D was pre-incubated with BaL or YU2 V3 loop peptides, nearly all neutralizing activity was inhibited. Grundner2005 (neutralization)
447-52D: The crystal and nuclear magnetic resonance structures of V3-reactive antibody-peptide complexes were examined. 447-52D completely surrounded V3, suggesting a high degree of accessibility for generating an immune response. Accessibility of V3 to this MAb is shown in a 3D figure. Huang2005 (antibody binding site, structure)
447-52D: 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 447-52D, five of the modified proteins expressed in insect cells, including 3G mutant (mutations in 3 glycosylation sites), dV1V2 mutant (V1V2 deletions), 3G-2G, 3G-dV2, and 3G-dV2-1G (1G being a mutation near the TM domain), showed higher binding than the wildtype. Of these, the 3G-dV2-1G mutant showed highest binding to 447-52D, indicating that glycosylation of the gp41 domain may affect exposure of the V3 loop. Expressed in animal cells, mutants dV2 and 3G-dV1V2 showed increased binding to 447-52D at relatively high Ab concentrations compared to the wildtype Env. Kang2005 (antibody binding site, binding affinity)
447D: Full-length gp160 clones were derived from acute and early human HIV-1 infections and used as env-pseudotyped viruses in neutralization assays for their characterization as neutralization reference agents. 2 out of 19 pseudoviruses were sensitive to neutralization by 447D, as was the SF162.LS strain. Li2005a (assay or method development, neutralization)
447: Pseudoviruses expressing HIV-1 envelope glycoproteins from BL01, BR07 and 89.6 strains were compared in neutralization assays to replication competent clone derived from transfection of 293T cells (IMC-293T) and to the IMC-293T derived from a single passage through PBMC (IMC-PBMC). The neutralization responses of pseudoviruses and corresponding IMC-293T to 447 were similar, while a significant decrease in viral neutralization sensitivity to 447 was observed for the BR07 and 89.6 IMC-PBMC viruses. The decrease was associated with an increase in average virion envelope glycoprotein content on the PBMC-derived virus. Louder2005 (assay or method development, neutralization)
447-52D: The structure of V3 HIV-1 peptides derived from IIIB and MN isolates when bound to 447-52D was determined by NMR. It was observed that the two different V3 peptides assumed same N-terminal strand conformation when bound to this Ab. V3 peptide IIIB bound to Ab 0.5β differed from the same peptide bound to 447-52D by 180 degrees N-terminal chain orientation. It is suggested that the conformation of an Ab-bound V3 peptide is dictated not only by the peptide sequence but also by an induced fit to the specific Ab. Dominant interactions of 447-52D with three conserved N-terminal residues may be responsible for the broadly neutralizing capability of this Ab. Rosen2005 (antibody binding site, co-receptor, variant cross-reactivity, structure)
447-52D: 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 (neutralization, variant cross-reactivity, review, subtype comparisons)
447-52D: gp120 alone and gp120 bound to CD4D12 (the first two domains of human CD4) or to M9 (a 27-residue CD4 analog) were used to immunize guinea pigs. Only sera from the gp120-CD4D12 immunized animals showed broadly neutralizing activity. Sera from gp120-CD4D12 and gp120 immunized animals competed equally well with 447-52D, indicating that the V3-loop was accessible in both immunogens. Varadarajan2005 (antibody binding site, vaccine antigen design)
447-52D: This review focuses on the importance of neutralizing Abs in protecting against HIV-1 infection, including mechanisms of Ab interference with the viral lifecycle, Ab responses elicited during natural HIV infection, and use of monoclonal and polyclonal Abs in passive immunization. In addition, vaccine design strategies for eliciting of protective broadly neutralizing Abs are discussed. MAbs included in this review are: 2F5, Clone 3 (CL3), 4E10, Z13, IgG1b12, 2G12, m14, 447-52D, 17b, X5, m16, 47e, 412d, E51, CM51, F105, F425, 19b, 2182, DO142-10, 697-D, 448D, 15e and Cβ1. McCann2005 (antibody binding site, neutralization, review, structure)
447-52D: MAbs were investigated in different neutralization formats, including the standard format that measures activity over the entire infection period and several formats that emphasize various stages of infection. Visualization of Env-Ab binding was conducted by BN-PAGE band shifts. 447-52D binding to trimer was completely dependent on sCD4, consistent with neutralization. Crooks2005 (antibody binding site, assay or method development, neutralization)
447-52D: This review summarizes data on 447-52D-V3 and 447-52D-V3 peptide X-ray crystallographic structures and NMRs and its neutralization capabilities. The binding mechanism of this Ab to V3 explains its ability to neutralize a wide array of viral isolates. Conformation of the V3 peptide bound to 447-52D is very similar to its conformation when bound to mouse Abs 50.1, 59.1 and 83.1. Stanfield2005 (antibody binding site, neutralization, variant cross-reactivity, review, structure)
447-52D: A T-cell line adapted strain (TCLA) of CRF01_AE primary isolate DA5 (PI) was more neutralization sensitive to 447-52D 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 447-52D then the PI strain. Mutants at positions 138 in V1 and 461/464 in V5 showed lower sensitivity to neutralization by 447-52D. Deglycosylated subtype B mutants at positions 197 and 234 were slightly more neutralizable by 447-52D. Teeraputon2005 (antibody binding site, neutralization, subtype comparisons)
447-52D: In addition to gp120-gp41 trimers, HIV-1 particles were shown to bear nonfunctional gp120-gp41 monomers and gp120-depleted gp41 stumps on their surface. 447-52D moderately neutralized wildtype virus particles. It effectively bound to nonfunctional monomers but not to gp120-gp41 trimers. Monomer binding did not correlate with neutralization, but it did correlate with virus capture. It is hypothesized that the nonfunctional monomers on the HIV-1 surface serve to divert the Ab response, helping the virus to avoid neutralization. Moore2006 (antibody binding site, neutralization)
447D: 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). 447D recognized SF162gp140 and ΔV2gp140 equally and failed to recognize ΔV2ΔV3gp140 and ΔV3gp140. Derby2006 (antibody binding site)
447-52D: 447-52D was not found to inhibit binding of gp120 to DC-SIGN. This Ab bound to Fc-gp120 construct but not to the chimeras missing the V3 loop. Binley2006 (binding affinity)
447-52D: 29 subtype B V3 peptides were designed and used for immunization of guinea pigs. Peptides that induced Abs that neutralized more than 3 HIV isolates were shown to bind to this Ab better than peptides unable to induce neutralization of any of the HIV-1 primary isolates. Haynes2006 (neutralization, binding affinity)
447-52D: 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 447-52D. Cham2006 (neutralization, variant cross-reactivity, subtype comparisons)
447-52D: Guinea-pigs were immunized with 447-52D epitope inserted at three different surface V3 loop locations in the small Escherichia coli Trx protein in order to generate a competent immunogen. Only one complex was shown to successfully generate anti-V3 Abs capable of out-competing 447-52D binding to gp120 and recognizing the same epitope as this Ab. However, these 447-52D-like Abs were not able to affect neutralization of JRFL and BAL. Chakraborty2006 (neutralization, vaccine antigen design, variant cross-reactivity, binding affinity)
447-52D: The ability of this Ab to inhibit viral growth was increased when macrophages and immature dendritic cells (iDCs) were used as target cells instead of PHA-stimulated PBMCs. It is suggested that inhibition of HIV replication by this Ab for macrophages and iDCs can occur by two distinct mechanisms, neutralization of infectivity involving only the Fab part of the IgG, and, an IgG-FcγR-dependent interaction leading to endocytosis and degradation of HIV particles. Holl2006 (dendritic cells)
447-52D: Inhibition of R5 HIV replication by monoclonal and polyclonal IgGs and IgAs in iMDDCs was evaluated. The neutralizing activity of 447-52D was observed to be higher in iMDDCs than in PBLs and PHA-stimulated PBMCs. A 90% reduction of HIV infection was observed without induction of MDDC maturation by this MAb. It was also demonstrated that binding of this MAb to HIV-1 was necessary for inhibition of iMDDC infection. Increased expression of FcγRI on iMDDCs increased inhibition of HIV by 447-52D, suggesting the involvement of this receptor in the HIV-inhibitory activity of this MAb. Holl2006a (neutralization, dendritic cells)
447-52D: The neutralization potency of this Ab against 7 HIV-1 primary isolates was compared to the neutralization potency of the anti-V3 MAb KD-247. Same Ab concentrations were needed for neutralization of the MN, N-NIID, and 92TH022 isolates, while higher concentrations of 447-52D were needed for the neutralization of the rest of the HIV-1 isolates suggesting KD-247 is more potent. Eda2006a
447-52D: In this study the neutralization breadth of F425 B4e8 was assessed using a panel of 40 primary HIV-1 isolates, and 447-52D was found to have a similar profile, and was used as a control to gauge the effects of the amino acid substitutions in the V3 region. As expected, replacing Arg 315 with Ala or Gln and Pro 313 with Ala reduced binding affinity of this 447-52D substantially. Ala substitutions of residues in positions 304-309 and 319-320 also unexpectedly resulted in diminished binding affinity of the Ab. Pantophlet2007 (antibody binding site, subtype comparisons)
447-52D: Z13e1, a high affinity variant of Fab Z13, was identified through targeted mutagenesis and affinity selection against gp41 and an MPER peptide. Z13e1 showed 100-fold improvement in binding affinity for MPER antigens over Z13. 447-52D was used as a control in this study. 447-52D was shown to clearly bind to monomers of gp120-gp41 while trimer binding was negligible, in accordance with its modest neutralization potency against HIV-1 JR-FL. Nelson2007 (vaccine antigen design)
447-52D: G1 and G2 recombinant gp120 proteins, consisting of 2F5 and 4E10, and 4E10 epitopes, respectively, engrafted into the V1/V2 region of gp120, were tested as an immunogen to see if they could elicit MPER antibody responses. Deletion of V1/V2 from gp120, or its replacement with G1 and G2 grafts, did not greatly affect binding of 447-52D to gp120. Shortening of the N and C termini of the V3 loop enhanced the binding of 447-52D. Law2007 (vaccine antigen design)
447-52D: This review describes the effectiveness of the current HIV-1 immunogens in eliciting neutralizing antibody responses to different clades of HIV-1. It also summarizes different evasion and antibody escape mechanisms, as well as the most potent neutralizing MAbs and their properties. MAbs reviewed in this article are: 2G12, IgG1b12, 2F5, 4E10, A32, 447-52D and, briefly, D50. Novel immunogen design strategies are also discussed. Haynes2006a (neutralization)
447-52D: Viruses from early and late infection of a macaque with SHIV SF162P4 were resistant to contemporaneous serum that had broadly reactive NAbs. SF162 was highly susceptible to neutralization by anti-V3 MAbs 447D and P3E1, as well as anti-V1 MAb P3C8, while envelopes cloned from this animal at 304 days and at 643 days (time of death) post infection had developed resistance to all three of these antibodies. Kraft2007 (neutralization, escape)
447-52D: This Ab was used to help define the antigenic profile of envelopes used in serum depletion experiments to attempt to define the neutralizing specificities of the broadly cross-reactive neutralizing serum. Peptides containing epitopes for 447-52D did not inhibit neutralization by broadly neutralizing sera from two clade B and one clade A infected asymptomatic individuals, indicating that the V3 epitope for this MAb did not account for the broad neutralizing activity observed. 447-52D bound to JR-FL and JR-CSF gp120 monomers but not to core JR-CSF gp120 monomer. Dhillon2007 (antibody binding site, neutralization)
447-52D: 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. V3 MAbs (447-52D, 19b, F245-B4e8 and 39F) bound to the GDMR antigen, but either did not bind or had diminished binding to mCHO. Selvarajah2005 (vaccine-induced immune responses, Th2)
447-52D: This study is about the V2 MAb C108g, which is type-specific and neutralizes BaL and HXB2. JR-FL is a neutralization resistant strain; modification of JRFL at V2 positions 167 and 168 (GK->DE) created a C108g epitope, and C108g could potently neutralize the modified JR-FL. The modification in V2 also increased neutralization sensitivity to V3 MAbs 4117c, 2219, 2191, and 447-52D (447-52D was the only one of the 4 V3 MAbs that could neutralize the unmodified JRFL); but only had minor effects on neutralization by CD4BS MAb 5145A, and broadly neutralizing MAbs IgG1b12, 2G12, and 2F5. Pinter2005 (antibody binding site)
447-52D: The HIV-1 Bori-15 variant was adapted from the Bori isolate for replication in 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 microglial-adapted HIV-1 Bori-15 was assessed in ELISA binding assays using CD4BS MAbs F105 and IgG1b12, glycan-specific 2G12, and V3-specific 447-52D, and were unchanged. Association rates of sCD4 and 17b were not changed, but dissociation rates were 3-fold slower for sCD4 and 14-fold slower for 17b. Martin-Garcia2005 (antibody binding site)
447-52D: 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. It had an overlapping binding region with MAbs 447-52D, B4e8, and 268-D, but different reactivity patterns and fine specificity. While B4e8 and 447-52D could bind to the R5 virus BaL in the absence of sCD4, treatment with sCD4 did increase the binding of both B4e8 and 447-52D, but did not impact their ability to neutralize BaL. Lusso2005 (antibody binding site)
447-52D: Sera from subtype A infected individuals from Cameroon have antibodies that react strongly with subtype A and subtype B V3 loops in fusion proteins, and neutralize SF162 pseudotypes, while sera from 47 subtype B infected individuals reacted only with subtype B. Sera from Cameroon did not neutralize primary A or B isolates, due to indirect masking by the V1/V2 domain rather than due to loss of the target epitope. Neutralization by anti-V3 B clade specific MAbs 447-52D and 4117C was fully blocked by a clade V3 loop fusion protein, but not an A clade fusion protein, while Cameroonian sera neutralization was fully blocked by both A and B clade fusion proteins. Krachmarov2005 (antibody binding site, variant cross-reactivity, subtype comparisons)
447-52D: 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. 447-52D has no indication of polyspecific autoreactivity. Haynes2005 (antibody binding site)
447-52d: 2909 is a human anti-Env NAb that was selected by a neutralization assay and binds to the quaternary structure on the intact virion. ELISA-based competition assays and subsequent mutational analysis determined that the CD4BS and V2 and V3 loops contribute to the 2909 epitope: 2909 binding was inhibited by MAbs 447-52d (anti-V3), 830A (anti-V2), and IgG1b12 (anti-CD4BS) and sCD4. 2909 was not inhibited by MAbs 670, 1418, nor 2G12. Gorny2005
447-52D: 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 447-52D. Pantophlet2004 (vaccine antigen design)
447-52D: 93 viruses from different clades were tested for their neutralization cross-reactivity using a panel of HIV antibodies. Neutralization outside of the B clade was very rare, and seemed to depend on the presence of a GPGR V3 tip, which is rare outside of the B clade. Binley2004 (variant cross-reactivity, subtype comparisons)
447-52D: Analysis of the conformation of 447-52D in complex with the V3MN18 peptide (gp12 aa 310-329, KRKRIHIGPGRAFYTTKN) was undertaken using solid state NMR. The bound peptide had a well-defined constrained structure that was in good agreement with solution NMR and crystallographic studies. Sharpe2004 (structure)
447-52D: A primary isolate, CC1/85, was passaged 19 times in PBMC and gradually acquired increased sensitivity to FAb b12 and sCD4 that was attributed to changes in the V1V2 loop region, in particular the loss of a potential glycosylation site. The affinity for sCD4 was unchanged in the monomer, suggesting that the structural impact of the change was manifested at the level of the trimer. The passaged virus, CCcon19, retained an R5 phenotype and its neutralization susceptibility to other Abs was essentially the same as CC1/85. 447-52D did not neutralize the primary or passaged variant. Pugach2004 (variant cross-reactivity, viral fitness and reversion)
447-52D: 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. 5/6 anti-V3 MAbs, including 447-52D, had similar binding affinity to soluble SF162 and JR-FL rgp120s, although the V3 loop differs at three positions (HigpgrafyTtgE for JR-FL and TigpgrafyAtgD for SF162). Pinter2004 (variant cross-reactivity)
447-52D: 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 any of three glycans within or adjacent to the V3 loop (GM299 V3), C2 (GM292 C2), C3 (GM329 C3) increased neutralization susceptibility to 447-52D, but C4 (GM438 C4) or V5 (GM454 V5) removal did not make SF162 more sensitive. 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)
447-52D: 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 the V3 MAbs 694-98D and 447-52D, that both bind near the tip of the loop, was decreased by both thrombin and trypsin. Ling2004 (antibody binding site)
447-52D: V3 MAb neutralization is influenced by retaining the epitope, exposure on the intact virion, mobility during CD4-induced conformational change, and affinity. Anti-V3 MAbs selected using V3 peptides neutralize less effectively than V3 MAbs selected using fusion proteins or gp120, suggesting antigenic conformation is important. This MAb was selected using V3 peptides, but was an exception in that it is cross-neutralizing. 447-52D neutralized 12/13 clade B viruses. Gorny2004 (antibody binding site)
447-52D: This review provides summaries of Abs that bind to HIV-1 Env. There are many V3 MAbs, many neutralize some TCLA strains, and a subset can also neutralize some primary isolates. The set that can cross-neutralize primary isolates (2182, 2191, 2219, 2412, 2442, 2456) bind V3 but are conformationally sensitive, suggesting some structural conservation despite sequence variation. These MAbs have distinct epitopes relative to 447-52D, a MAb directed at the tip of the V3 loop that also can neutralize many primary isolates. Although 447-52D was selected using a peptide, it has conformational characteristics. Inter-clade cross-neutralization by anti-V3 conformation-dependent MAbs is reduced. Gorny2003 (antibody binding site, review)
447-52D: This paper attempts to engineer a gp120 molecule that would focus the immune response onto the IgG1b12 epitope. Adding a glycosylation sequon (P313N) to the V3 loop knocked out binding to anti-V3 MAbs loop 2, 19b and 447-52-D. Pantophlet2003b (vaccine antigen design)
447-52D: scFv 4KG5 reacts with a conformational epitope that is formed by the V1V2 and V3 loops and the bridging sheet (C4) region of gp120 and is influenced by carbohydrates. Of a panel of MAbs tested, only NAb b12 enhanced 4KG5 binding to gp120 JRFL. MAbs to the following regions diminished 4KG5 binding: V2 loop, V3 loop, V3-C4 region, CD4BS. MAbs directed against C1, CD4i, C5 regions didn't impact 4KG5 binding. These results suggest that the orientation or dynamics of the V1/V2 and V3 loops restricts CD4BS access on the envelope spike, and IgG1b12 can uniquely remain unaffected by these loops. This was one of the V3 MAbs used. Zwick2003a (antibody interactions)
447-52D: The Fv fragment (composed of just the light and heavy variable regions, and the smallest intact binding unit of an Ab) of 447-52 D was expressed and purified. Preliminary NMR with the peptide epitope indicates that an NMR structure determination is feasible. Kessler2003 (antibody sequence, structure)
447-52D: 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. 447-52D was able to neutralize the SOS protein better than the wildtype, but did not neutralize SOS well when added post-attachment, as the V3 loop is involved in co-receptor engagement. Binley2003 (vaccine antigen design)
447-52D: Virion capture assays are not a good predictor of neutralization, and the presentation of epitopes using this assay seems to be different from that of functional Envelope spikes on primary isolates -- F105 and b6 could efficiently block the b12-mediated capture of infectious virions in a virus capture, but did not inhibit b12 neutralization -- Ab 447-52D was able to potently neutralize 89.6 and to neutralize JR-CSF at a high concentration but poorly neutralized ADA -- b12 was potent at neutralizing the three primary virions JR-CSF, ADA, and 89.6, but anti-V3 Abs 447-52D and 19b, which did not neutralize JR-CSF and ADA, captured amounts of p24 equal to or higher than the amounts captured by the neutralizing Ab b12. Poignard2003 (antibody binding site, assay or method development, variant cross-reactivity)
447-52D: Review of NAbs. Ferrantelli2002
447-52D: Transgenic mice carrying human genes allowing production of fully human MAbs were used to rapidly create a panel of anti-HIV gp120 MAb producing hybridomas by immunization with HIV SF162 gp120 -- the previously described human MAbs 5145A(CD4BS) , 4117C (plus others, V3) and 697D (and SC258, V2) were used as controls. He2002
447-52D: Conformation-dependent anti-V3 loop Abs may be more cross-reactive, so six new V3 MAbs were generated -- the six new MAbs all bind to the tip of the V3 loop and cross-compete with the MAb 447-52D and are conformationally sensitive -- MAbs showed cross-clade binding to native, intact virions of clades A(N=2), B(N=4), and F(N=2), limited binding to C(N=3) and D(N=3), and did not bind to CRF01(subtype E, N=2) -- the strength binding was highly correlated with percent neutralization using the ghost cell or PHA blast assay -- five well-characterized MAbs were used as controls: anti-V3 447-52D (anti-V3 MAb for competition and neutralization studies), 654 (anti-CD4BS used as a conformation-sensitive MAb control), 1331A (anti-C5 used as a linear binding site MAb control), MAb 246 (anti-gp41 MAb that bound to primary isolates of all clades) -- 447-52D bound to primary isolates from all clades except CRF01 (E), was conformationally sensitive and showed the some of the most potent neutralizing activity. Gorny2002 (variant cross-reactivity)
447-52D: The feasibility of determining the NMR structure of the V3(MN) peptide bound to the 447-52D Fab fragment was tested and a general strategy for obtaining NMR structures of V3 peptide-Fab fragments developed -- preliminary NMR spectra for 447-52D complexed to a 23 amino acid V3 peptide was obtained. Sharon2002 (structure)
447-52D: 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---447-D recognized the gp120 monomer much more readily than o-gp140, suggesting the V3 loop is less exposed on o-gp140 and on intact virions. Srivastava2002 (antibody binding site, vaccine antigen design)
447-52D: A panel of 12 MAbs was used to identify those that could neutralize the dual-tropic primary isolate HIV-1 89.6 -- six gave significant neutralization at 2 to 10 ug/ml: 2F5, 50-69, IgG1b12, 447-52D, 2G12, and 670-D six did not have neutralizing activity: 654-D, 4.8D, 450-D, 246-D, 98-6, and 1281 -- no synergy, only additive effects were seen for pairwise combinations of MAbs, and antagonism was noted between gp41 MAbs 50-69 and 98-6, as well as 98-6 and 2F5. Verrier2001 (antibody interactions, variant cross-reactivity)
447-52D: 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 -- the dissociation constant, Kd of 447-52D for the cell associated primary and TCLA Envs was equal, 3nM. York2001 (antibody binding site, variant cross-reactivity, binding affinity)
447-52D: 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)
447-52D: A panel of 47 human MAbs was tested against 26 HIV-1 group M primary isolates from clades A through H -- 19 V3 MAbs were tested, and of 494 combinations, 44% displayed some viral binding -- V3 MAbs tended to have the most cross-reactive binding to clade A, B, C, and D isolates, less to E, F, G, and H -- 447-52D showed the highest cross-reactivity, bound to 24/26 viruses tested, but achieved 90% neutralization only against MN, 50% against CA5, and no neutralization was observed for 3 other isolates tested. Nyambi2000 (subtype comparisons)
447-52D: Called 447D -- 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 (447D 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 (antibody binding site)
447-52D: Ab responses, because of their capacity to alter antigen uptake and processing, can influence helper T cell responses -- CD4BS MAbs or serum Ig from HIV+ individuals inhibited proliferative responses of gp120 specific T cells -- V3 MAbs 447-52-D and 268-10-D did not affect proliferation. Hioe2000
447-52D: 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)
447-52D: Binding of panel of 21 MAbs to soluble oligomeric gp140 versus gp41 or gp120 monomers was compared -- no MAb was oligomer specific, though anti-V3 and CD4BS MAbs reacted better with the oligomer and V2 and C5 tended to favor the monomer -- V3 MAbs 447-52D, 838-D, and 1334 bound with a 7-10 fold preference for the oligomer. Gorny2000b (antibody binding site)
447-52D: rgp120 derived from a R5X4 subtype B virus, HIV-1 W61D, was used to vaccinate healthy volunteers and the resulting sera were compared with sera from HIV-1 positive subjects and neutralizing MAbs -- TCLA strains showed enhanced 447-52D neutralization sensitivity relative to PBMC-adapted lines (32X increase between HIV-1(M2424/PBMC(p0)) and HIV-1(M2424/H9(p9)) and a >128X increase between HIV-1(W61D/PBMC) and HIV-1(W61D/SupT1) isolates) Beddows1999 (variant cross-reactivity)
447-52D: The presence of leukocyte function-associated molecule 1 (LFA-1) promotes virus infectivity and hinders neutralization, and anti-LFA-1 MAbs can enhance the neutralizing effect of anti-HIV V3 MAb 447-52D and anti-HIV CD4BS MAb IgG1b12 -- non-neutralizing anti-HIV CD4BS MAb 654-D did not become neutralizing in the presence of anti-LFA-1 MAbs. Hioe1999
447-52D: MAb peptide-reactivity pattern clustered with the immunological related MAbs: 1334, 419, 504, 447, 453 and 537 -- the core amino acids GP tended to be critical for reactivity in this group -- 447 reacted with peptides containing GPGR, but also with many lacking this sequence (GPGQ, for example), and it failed to react with 2/14 peptides containing GPGR, illustrating the importance of context. Zolla-Pazner1999a (antibody binding site, variant cross-reactivity)
447-52D: Review of clade specificity and anti-V3 HIV-1-Abs. Zolla-Pazner1999b (review, subtype comparisons)
447-52D: Using a whole virion-ELISA method, 18 human MAbs were tested for their ability to bind to a panel of 9 viruses from clades A, B, D, F, G, and H -- 447-52D was the most potent and cross-reactive of 18 human MAbs tested and was the only MAb which bound to virions from isolates CA20 (subtype F), CA13 (subtype H), and VI526 (subtype G) Nyambi1998 (subtype comparisons)
447-52D: Kinetic parameters were measured, and the association rates were similar, but dissociation rate constants were quite variable for V3 MAbs, 1324E was comparable to 447-52D. Gorny1998 (kinetics)
447-52D: Ab from gp120 vaccinated individuals prior to infection, who subsequently became HIV infected, could not achieve 90% neutralization of the primary virus by which the individuals were ultimately infected -- these viruses were not particularly refractive to neutralization, as determined by their susceptibility to neutralization by MAbs 2G12, IgG1b12, 2F5 and 447-52D. Connor1998
447-52D: The MAb and Fab binding to the oligomeric form of gp120 and neutralization were highly correlated -- authors suggest that neutralization is determined by the fraction of Ab sites occupied on a virion irrespective of the epitope. Parren1998 (antibody binding site)
447-52D: Called 447-52-D -- The tip of the MN V3 loop was inserted into cold causing human rhinovirus 14 (HRV14) -- chimeras were immunoselected, and chimeric viruses were neutralized by anti-V3 loop antibodies, and 447-52D was among the Abs used -- chimeric viruses elicited potent NAbs in guinea pigs against ALA-1 and MN. Smith1998 (vaccine antigen design)
447-52D: Inhibits binding of Hx10 to both CD4 positive and negative HeLa cells. Mondor1998 (variant cross-reactivity)
447-52D: Called 447-D -- 447-D resistance took longer to acquire in virus with the M184V substituted RT, and had the form (AAC N to TAC Y) at position 5 of the V3 loop, rather than the GPGR to GPGR resistance found with wildtype RT. Inouye1998
447-52D: Used as a control for comparison to five V3 RF selected antibodies -- 447-52D was reactive with A, B, and C clade peptides, but not E. Gorny1997 (subtype comparisons)
447-52D: Abs that recognize discontinuous epitopes can identify mimotopes from a phage peptide display library -- 447-52D has an epitope involving the tip of the V3 loop, that was previously studied with this method Keller1993 -- in Keller et al., with no competition, LxGPxR was the most common six-mer, 38% of the peptides -- after competition with a gp120 IIIB ligand (QRGPGR)i, RGPxR was the most common and one peptide had the sequence QRGPGR, showing type specific mimotopes can be enriched by strain specific ligand competition protocols Boots1997. Boots1997,Keller1993 (antibody binding site, mimotopes)
447-52D: Called 447 -- gp120 can inhibit MIP-1alpha from binding to CCR5, but this inhibitory effect is blocked by pre-incubation of gp120 with three anti-V3 MAbs: 447, 257, 1027 -- MAb 670 which binds in the C5 region had no effect. Hill1997 (co-receptor)
447-52D: Neutralizes TCLA strains but not primary isolates. Parren1997 (variant cross-reactivity)
447-52D: Viral binding inhibition by 447-D was correlated with neutralization (all other neutralizing MAbs tested showed some correlation except 2F5) Ugolini1997 (antibody binding site)
447-52D: Four primary isolates showed distinct patterns of sensitivity to neutralization by polyclonal sera or plasma and MAbs -- BZ167 was the only isolate inhibited by all polyclonal sera and plasma tested, and was also neutralized by 8/17 MAbs, in particular anti-V3 loop (419-D, 447-52D, 782-D, and 838-D), anti-CD4bd (559/64-D, 654-D and 830-D and a cluster II of gp41 directed MAb (98-6) -- isolates 92HT593 and 91US056 were neutralized by V3 loop (419-D, and 447-52D)and cluster II gp41 (98-6) MAbs at higher concentrations -- US4 was neutralized by some of the polyclonal sera/plasma tested and not at all by MAbs individually or by a cocktail of ten MAbs consisting of 419-D, 447-52D, 782-D, 838-D, 559/64-D, 654-D, 450-D, 670-D, 1281-D and 98-6. Hioe1997b (variant cross-reactivity)
447-52D: Tested using a resting cell neutralization assay. Hioe1997 (assay or method development)
447-52D: Study shows neutralization is not predicted by MAb binding to JRFL monomeric gp120, but is associated with oligomeric Env binding -- 447-52D bound monomer, oligomer, and neutralized JRFL. Fouts1997 (antibody binding site)
447-52D: In a multilaboratory blinded study, failed to consistently neutralize any of nine B clade primary isolates -- many of these isolates had the GPGR motif at the apex of the V3 loop. DSouza1997 (assay or method development, variant cross-reactivity)
447-52D: Review: called 447-52-D -- only four epitopes have been described which can stimulate a useful neutralizing response to a broad spectrum of primary isolates, represented by the binding sites of MAbs: 447-52-D, 2G12, Fab b12, and 2F5. Sattentau1996 (variant cross-reactivity, review)
447-52D: Neutralizes JR-FL -- strongly inhibits gp120 interaction with CCR-5 in a MIP-1beta-CCR-5 competition study. Trkola1996b (co-receptor, variant cross-reactivity)
447-52D: Called 447-52-D -- The sulfated polysaccharide curdlan sulfate (CRDS) binds to the Envelope of T-tropic viruses and neutralizes virus -- CRDS inhibits 447-52D binding. Jagodzinski1996 (antibody binding site)
447-52D: Neutralizing, no viral enhancing activity. Epitope provided as GPGR, but no details are given. Forthal1995 (complement, enhancing activity)
447-52D: Review: the V3 loop motif GPGR is not common outside subtype B isolates, MAb 19b is more cross-reactive than 447-52D. Moore1995c (variant cross-reactivity)
447-52D: Binding affected by identity of amino acids flanking GPGR core -- poor breadth of primary virus neutralization. Moore1995b (variant cross-reactivity)
447-52D: Neutralization of primary and prototype laboratory HIV-1 isolates using a resting cell assay enhances sensitivity. Zolla-Pazner1995a (assay or method development, variant cross-reactivity)
447-52D: Serotyping study using flow-cytometry -- bound only to GPGR V3 loop tips. Zolla-Pazner1995 (antibody binding site)
447-52D: Ab-mediated activation of complement on HIV+ cells is higher than Ab independent activation---what has been termed ''Ab independent'' in fact results in part from IgM in normal human serum that is HIV-cross-reactive. Saarloos1995 (complement)
447-52D: Called 447 -- The tip of the V3 loop was presented in a mucin backbone -- higher valency correlates with stronger affinity constant. Fontenot1995 (vaccine antigen design)
447-52D: Called 447d -- Formalin inactivation of virus at 0.1% formalin for 10 hours at 4 degrees was optimal for inactivation of virus while maintaining epitope integrity. Sattentau1995 (vaccine antigen design)
447-52D: Competition studies with human sera from seroconverting individuals showed that anti-CD4 BS antibodies can arise very early in infection, comparable or prior to anti-V3 antibodies. Moore1994d (acute/early infection)
447-52D: Mild oxidation of carbohydrate moieties does not alter binding. Gorny1994 (antibody binding site)
447-52D: GPGQ in MAL resulted in enhanced dissociation -- GPGQ in CM234 or K14T did not bind -- binding affected by identity of amino acids flanking GPGR core. VanCott1994 (antibody binding site)
447-52D: Neutralization synergy in combination with CD4 binding domain MAbs. Laal1994 (antibody interactions)
447-52D: Requires GPxR at the tip of the V3 loop, common in B clade -- neutralized primary isolates. Conley1994 (antibody binding site, variant cross-reactivity)
447-52D: Complement mediated virolysis of IIIB, but not in the presence of sCD4. Spear1993 (complement)
447-52D: Additive neutralization of MN and SF2 when combined with CD4 binding site MAb F105 -- supra-additive neutralization of RF. Cavacini1993 (antibody interactions)
447-52D: Peptide phage library showed that any of the residues ADGLMNQRS in the X position tolerated in peptides that react well with the antibody. Keller1993 (antibody binding site, variant cross-reactivity)
447-52D: Neutralizes MN and IIIB: GPGR, and binds SF2: GPGR. Gorny1993 (variant cross-reactivity)
447-52D: Reacts with MN, NY5, CDC4, SF2, RF, WM52, and HXB2. Karwowska1992a (variant cross-reactivity)
447-52D: Describes production of mAb 447-D by EBV transformation of PBMC from an HIV-infected individual, followed by fusion with a heteromyeloma. 60-fold increase in neutralization potency when combined 1:1 with human MAb 588-D. Buchbinder1992 (antibody generation, antibody interactions)
447-52D: Requires GPXR at the tip of the V3 loop -- neutralizes a broad array of B clade lab isolates. Gorny1992 (antibody binding site, antibody generation, variant cross-reactivity)

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Derby2007 Nina R. Derby, Sean Gray, Elizabeth Wayner, Dwayne Campogan, Giorgos Vlahogiannis, Zane Kraft, Susan W. Barnett, Indresh K. Srivastava, and Leonidas Stamatatos. Isolation and Characterization of Monoclonal Antibodies Elicited by Trimeric HIV-1 Env gp140 Protein Immunogens. Virology, 366(2):433-445, 30 Sep 2007. PubMed ID: 17560621. Show all entries for this paper.

Dervillez2010 Xavier Dervillez, Volker Klaukien, Ralf Dürr, Joachim Koch, Alexandra Kreutz, Thomas Haarmann, Michaela Stoll, Donghan Lee, Teresa Carlomagno, Barbara Schnierle, Kalle Möbius, Christoph Königs, Christian Griesinger, and Ursula Dietrich. Peptide Ligands Selected with CD4-Induced Epitopes on Native Dualtropic HIV-1 Envelope Proteins Mimic Extracellular Coreceptor Domains and Bind to HIV-1 gp120 Independently of Coreceptor Usage. J. Virol., 84(19):10131-10138, Oct 2010. PubMed ID: 20660187. Show all entries for this paper.

Dey2008 Antu K. Dey, Kathryn B. David, Neelanjana Ray, Thomas J. Ketas, Per J. Klasse, Robert W. Doms, and John P. Moore. N-Terminal Substitutions in HIV-1 gp41 Reduce the Expression of Non-Trimeric Envelope Glycoproteins on the Virus. Virology, 372(1):187-200, 1 Mar 2008. PubMed ID: 18031785. Show all entries for this paper.

Dhillon2007 Amandeep K. Dhillon, Helen Donners, Ralph Pantophlet, Welkin E. Johnson, Julie M. Decker, George M. Shaw, Fang-Hua Lee, Douglas D. Richman, Robert W. Doms, Guido Vanham, and Dennis R. Burton. Dissecting the Neutralizing Antibody Specificities of Broadly Neutralizing Sera from Human Immunodeficiency Virus Type 1-Infected Donors. J. Virol., 81(12):6548-6562, Jun 2007. PubMed ID: 17409160. Show all entries for this paper.

Dhillon2008 Amandeep K. Dhillon, Robyn L. Stanfield, Miroslaw K. Gorny, Constance Williams, Susan Zolla-Pazner, and Ian A. Wilson. Structure Determination of an Anti-HIV-1 Fab 447-52D-Peptide Complex from an Epitaxially Twinned Data Set. Acta. Crystallogr. D Biol. Crystallogr., D64(7):792-802, Jul 2008. PubMed ID: 18566514. Show all entries for this paper.

Doria-Rose2010 Nicole A. Doria-Rose, Rachel M. Klein, Marcus G. Daniels, Sijy O'Dell, Martha Nason, Alan Lapedes, Tanmoy Bhattacharya, Stephen A. Migueles, Richard T. Wyatt, Bette T. Korber, John R. Mascola, and Mark Connors. Breadth of Human Immunodeficiency Virus-Specific Neutralizing Activity in Sera: Clustering Analysis and Association with Clinical Variables. J. Virol., 84(3):1631-1636, Feb 2010. PubMed ID: 19923174. Show all entries for this paper.

Douagi2010 Iyadh Douagi, Mattias N. E. Forsell, Christopher Sundling, Sijy O'Dell, Yu Feng, Pia Dosenovic, Yuxing Li, Robert Seder, Karin Loré, John R. Mascola, Richard T. Wyatt, and Gunilla B. Karlsson Hedestam. Influence of Novel CD4 Binding-Defective HIV-1 Envelope Glycoprotein Immunogens on Neutralizing Antibody and T-Cell Responses in Nonhuman Primates. J. Virol., 84(4):1683-1695, Feb 2010. PubMed ID: 19955308. Show all entries for this paper.

Eda2006 Yasuyuki Eda, Toshio Murakami, Yasushi Ami, Tadashi Nakasone, Mari Takizawa, Kenji Someya, Masahiko Kaizu, Yasuyuki Izumi, Naoto Yoshino, Shuzo Matsushita, Hirofumi Higuchi, Hajime Matsui, Katsuaki Shinohara, Hiroaki Takeuchi, Yoshio Koyanagi, Naoki Yamamoto, and Mitsuo Honda. Anti-V3 Humanized Antibody KD-247 Effectively Suppresses Ex Vivo Generation of Human Immunodeficiency Virus Type 1 and Affords Sterile Protection of Monkeys against a Heterologous Simian/Human Immunodeficiency Virus Infection. J. Virol., 80(11):5563-5570, Jun 2006. PubMed ID: 16699037. Show all entries for this paper.

Eda2006a Yasuyuki Eda, Mari Takizawa, Toshio Murakami, Hiroaki Maeda, Kazuhiko Kimachi, Hiroshi Yonemura, Satoshi Koyanagi, Kouichi Shiosaki, Hirofumi Higuchi, Keiichi Makizumi, Toshihiro Nakashima, Kiyoshi Osatomi, Sachio Tokiyoshi, Shuzo Matsushita, Naoki Yamamoto, and Mitsuo Honda. Sequential Immunization with V3 Peptides from Primary Human Immunodeficiency Virus Type 1 Produces Cross-Neutralizing Antibodies against Primary Isolates with a Matching Narrow-Neutralization Sequence Motif. J. Virol., 80(11):5552-5562, Jun 2006. PubMed ID: 16699036. Show all entries for this paper.

Fenyo2009 Eva Maria Fenyö, Alan Heath, Stefania Dispinseri, Harvey Holmes, Paolo Lusso, Susan Zolla-Pazner, Helen Donners, Leo Heyndrickx, Jose Alcami, Vera Bongertz, Christian Jassoy, Mauro Malnati, David Montefiori, Christiane Moog, Lynn Morris, Saladin Osmanov, Victoria Polonis, Quentin Sattentau, Hanneke Schuitemaker, Ruengpung Sutthent, Terri Wrin, and Gabriella Scarlatti. International Network for Comparison of HIV Neutralization Assays: The NeutNet Report. PLoS One, 4(2):e4505, 2009. PubMed ID: 19229336. Show all entries for this paper.

Ferrantelli2002 Flavia Ferrantelli and Ruth M. Ruprecht. Neutralizing Antibodies Against HIV --- Back in the Major Leagues? Curr. Opin. Immunol., 14(4):495-502, Aug 2002. PubMed ID: 12088685. Show all entries for this paper.

Fontenot1995 J. D. Fontenot, T. C. VanCott, B. S. Parekh, C. P. Pau, J. R. George, D. L. Birx, S. Zolla-Pazner, M. K. Gorny, and J. M. Gatewood. Presentation of HIV V3 Loop Epitopes for Enhanced Antigenicity, Immunogenicity and Diagnostic Potential. AIDS, 9:1121-1129, 1995. PubMed ID: 8519447. Show all entries for this paper.

Forsell2008 Mattias N. E. Forsell, Barna Dey, Andreas Mörner, Krisha Svehla, Sijy O'dell, Carl-Magnus Högerkorp, Gerald Voss, Rigmor Thorstensson, George M. Shaw, John R. Mascola, Gunilla B. Karlsson Hedestam, and Richard T. Wyatt. B Cell Recognition of the Conserved HIV-1 Co-Receptor Binding Site Is Altered by Endogenous Primate CD4. PLoS Pathog., 4(10):e1000171, 2008. PubMed ID: 18833294. Show all entries for this paper.

Forsman2008 Anna Forsman, Els Beirnaert, Marlén M. I. Aasa-Chapman, Bart Hoorelbeke, Karolin Hijazi, Willie Koh, Vanessa Tack, Agnieszka Szynol, Charles Kelly, Áine McKnight, Theo Verrips, Hans de Haard, and Robin A Weiss. Llama Antibody Fragments with Cross-Subtype Human Immunodeficiency Virus Type 1 (HIV-1)-Neutralizing Properties and High Affinity for HIV-1 gp120. J. Virol., 82(24):12069-12081, Dec 2008. PubMed ID: 18842738. Show all entries for this paper.

Forthal1995 D. N. Forthal, G. Landucci, M. K. Gorny, S. Zolla-Pazner, and W. E. Robinson, Jr. Functional Activities of 20 Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Human Monoclonal Antibodies. AIDS Res. Hum. Retroviruses, 11:1095-1099, 1995. A series of tests were performed on 20 human monoclonal antibodies to assess their potential therapeutic utility. Antibodies were tested for potentially harmful complement-mediated antibody enhancing activity (C-ADE), and for potentially beneficial neutralizing activity and antibody dependent cellular cytotoxicity ADCC. PubMed ID: 8554906. Show all entries for this paper.

Forthal2009 Donald N. Forthal and Christiane Moog. Fc Receptor-Mediated Antiviral Antibodies. Curr. Opin. HIV AIDS, 4(5):388-393, Sep 2009. PubMed ID: 20048702. Show all entries for this paper.

Gao2005a Feng Gao, Eric A. Weaver, Zhongjing Lu, Yingying Li, Hua-Xin Liao, Benjiang Ma, S Munir Alam, Richard M. Scearce, Laura L. Sutherland, Jae-Sung Yu, Julie M. Decker, George M. Shaw, David C. Montefiori, Bette T. Korber, Beatrice H. Hahn, and Barton F. Haynes. Antigenicity and Immunogenicity of a Synthetic Human Immunodeficiency Virus Type 1 Group M Consensus Envelope Glycoprotein. J. Virol., 79(2):1154-1163, Jan 2005. PubMed ID: 15613343. Show all entries for this paper.

Gazarian2013 Karlen G. Gazarian, Yadira Palacios-Rodríguez, Tatiana G. Gazarian, and Leonor Huerta. HIV-1 V3 Loop Crown Epitope-Focused Mimotope Selection by Patient Serum from Random Phage Display Libraries: Implications for the Epitope Structural Features. Mol. Immunol., 54(2):148-156, Jun 2013. PubMed ID: 23270686. Show all entries for this paper.

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.

Gorny1992 M. K. Gorny, A. J. Conley, S. Karwowska, A. Buchbinder, J.-Y. Xu, E. A. Emini, S. Koenig, and S. Zolla-Pazner. Neutralization of Diverse Human Immunodeficiency Virus Type 1 Variants by an Anti-V3 Human Monoclonal Antibody. J. Virol., 66:7538-7542, 1992. PubMed ID: 1433529. Show all entries for this paper.

Gorny1993 M. K. Gorny, J.-Y. Xu, S. Karwowska, A. Buchbinder, and S. Zolla-Pazner. Repertoire of Neutralizing Human Monoclonal Antibodies Specific for The V3 Domain of HIV-1 gp120. J. Immunol., 150:635-643, 1993. Characterizaton of 12 human MAbs that bind and neutralize the MN isolate with 50\% neutralization. Two of these antibodies also bound and neutralized IIIB: 447-52-D and 694/98-D; all others could not bind HXB2 peptides. All but two, 418-D and 412-D could bind to SF2 peptides. PubMed ID: 7678279. Show all entries for this paper.

Gorny1994 M. K. Gorny, J. P. Moore, A. J. Conley, S. Karwowska, J. Sodroski, C. Williams, S. Burda, L. J. Boots, and S. Zolla-Pazner. Human Anti-V2 Monoclonal Antibody That Neutralizes Primary but Not Laboratory Isolates of Human Immunodeficiency Virus Type 1. J. Virol., 68:8312-8320, 1994. Detailed characterization of the MAb 697-D. PubMed ID: 7525987. Show all entries for this paper.

Gorny1997 Miroslaw K. Gorny, Thomas C. VanCott, Catarina Hioe, Zimra R. Israel, Nelson L. Michael, Anthony J. Conley, Constance Williams, Joseph A. Kessler II, Padmasree Chigurupati, Sherri Burda, and Susan Zolla-Pazner. Human Monoclonal Antibodies to the V3 Loop of HIV-1 With Intra- and Interclade Cross-Reactivity. J. Immunol., 159:5114-5122, 1997. PubMed ID: 9366441. Show all entries for this paper.

Gorny1998 M. K. Gorny, J. R. Mascola, Z. R. Israel, T. C. VanCott, C. Williams, P. Balfe, C. Hioe, S. Brodine, S. Burda, and S. Zolla-Pazner. A Human Monoclonal Antibody Specific for the V3 Loop of HIV Type 1 Clade E Cross-Reacts with Other HIV Type 1 Clades. AIDS Res. Hum. Retroviruses, 14:213-221, 1998. PubMed ID: 9491911. Show all entries for this paper.

Gorny2000b M. K. Gorny, T. C. VanCott, C. Williams, K. Revesz, and S. Zolla-Pazner. Effects of oligomerization on the epitopes of the human immunodeficiency virus type 1 envelope glycoproteins. Virology, 267:220-8, 2000. PubMed ID: 10662617. Show all entries for this paper.

Gorny2002 Miroslaw K. Gorny, Constance Williams, Barbara Volsky, Kathy Revesz, Sandra Cohen, Victoria R. Polonis, William J. Honnen, Samuel C. Kayman, Chavdar Krachmarov, Abraham Pinter, and Susan Zolla-Pazner. Human Monoclonal Antibodies Specific for Conformation-Sensitive Epitopes of V3 Neutralize Human Immunodeficiency Virus Type 1 Primary Isolates from Various Clades. J. Virol., 76(18):9035-9045, Sep 2002. PubMed ID: 12186887. Show all entries for this paper.

Gorny2004 Miroslaw K. Gorny, Kathy Revesz, Constance Williams, Barbara Volsky, Mark K. Louder, Christopher A. Anyangwe, Chavdar Krachmarov, Samuel C. Kayman, Abraham Pinter, Arthur Nadas, Phillipe N. Nyambi, John R. Mascola, and Susan Zolla-Pazner. The V3 Loop is Accessible on the Surface of Most Human Immunodeficiency Virus Type 1 Primary Isolates and Serves as a Neutralization Epitope. J. Virol., 78(5):2394-2404, Mar 2004. PubMed ID: 14963135. Show all entries for this paper.

Gorny2005 Miroslaw K. Gorny, Leonidas Stamatatos, Barbara Volsky, Kathy Revesz, Constance Williams, Xiao-Hong Wang, Sandra Cohen, Robert Staudinger, and Susan Zolla-Pazner. Identification of a New Quaternary Neutralizing Epitope on Human Immunodeficiency Virus Type 1 Virus Particles. J. Virol., 79(8):5232-5237, Apr 2005. PubMed ID: 15795308. Show all entries for this paper.

Gorny2006 Miroslaw K. Gorny, Constance Williams, Barbara Volsky, Kathy Revesz, Xiao-Hong Wang, Sherri Burda, Tetsuya Kimura, Frank A. J. Konings, Arthur Nádas, Christopher A. Anyangwe, Phillipe Nyambi, Chavdar Krachmarov, Abraham Pinter, and Susan Zolla-Pazner. Cross-Clade Neutralizing Activity of Human Anti-V3 Monoclonal Antibodies Derived from the Cells of Individuals Infected with Non-B Clades of Human Immunodeficiency Virus Type 1. J. Virol., 80(14):6865-6872, Jul 2006. PubMed ID: 16809292. Show all entries for this paper.

Gorny2009 Miroslaw K. Gorny, Xiao-Hong Wang, Constance Williams, Barbara Volsky, Kathy Revesz, Bradley Witover, Sherri Burda, Mateusz Urbanski, Phillipe Nyambi, Chavdar Krachmarov, Abraham Pinter, Susan Zolla-Pazner, and Arthur Nadas. Preferential Use of the VH5-51 Gene Segment by the Human Immune Response to Code for Antibodies against the V3 Domain of HIV-1. Mol. Immunol., 46(5):917-926, Feb 2009. PubMed ID: 18952295. Show all entries for this paper.

Grovit-Ferbas2000 K. Grovit-Ferbas, J. F. Hsu, J. Ferbas, V. Gudeman, and I. S. Chen. Enhanced binding of antibodies to neutralization epitopes following thermal and chemical inactivation of human immunodeficiency virus type 1. J. Virol., 74(13):5802-9, Jul 2000. URL: http://jvi.asm.org/cgi/content/full/74/13/5802. PubMed ID: 10846059. Show all entries for this paper.

Grundner2005 Christoph Grundner, Yuxing Li, Mark Louder, John Mascola, Xinzhen Yang, Joseph Sodroski, and Richard Wyatt. Analysis of the Neutralizing Antibody Response Elicited in Rabbits by Repeated Inoculation with Trimeric HIV-1 Envelope Glycoproteins. Virology, 331(1):33-46, 5 Jan 2005. PubMed ID: 15582651. 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.

Haldar2011 Bijayesh Haldar, Sherri Burda, Constance Williams, Leo Heyndrickx, Guido Vanham, Miroslaw K. Gorny, and Phillipe Nyambi. Longitudinal Study of Primary HIV-1 Isolates in Drug-Naïve Individuals Reveals the Emergence of Variants Sensitive to Anti-HIV-1 Monoclonal Antibodies. PLoS One, 6(2):e17253, 2011. PubMed ID: 21383841. Show all entries for this paper.

Haynes2005 Barton F. Haynes, Judith Fleming, E. William St. Clair, Herman Katinger, Gabriela Stiegler, Renate Kunert, James Robinson, Richard M. Scearce, Kelly Plonk, Herman F. Staats, Thomas L. Ortel, Hua-Xin Liao, and S. Munir Alam. Cardiolipin Polyspecific Autoreactivity in Two Broadly Neutralizing HIV-1 Antibodies. Science, 308(5730):1906-1908, 24 Jun 2005. Comment in Science 2005 Jun 24;308(5730):1878-9. PubMed ID: 15860590. Show all entries for this paper.

Haynes2006 Barton F. Haynes, Benjiang Ma, David C. Montefiori, Terri Wrin, Christos J. Petropoulos, Laura L. Sutherland, Richard M. Scearce, Cathrine. Denton, Shi-Mao Xia, Bette T. Korber, and Hua-Xin Liao. Analysis of HIV-1 Subtype B Third Variable Region Peptide Motifs for Induction of Neutralizing Antibodies against HIV-1 Primary Isolates. Virology, 345(1):44-55, 5 Feb 2006. PubMed ID: 16242749. Show all entries for this paper.

Haynes2006a Barton F. Haynes and David C. Montefiori. Aiming to Induce Broadly Reactive Neutralizing Antibody Responses with HIV-1 Vaccine Candidates. Expert Rev. Vaccines, 5(4):579-595, Aug 2006. PubMed ID: 16989638. Show all entries for this paper.

He2002 Yuxian He, William J. Honnen, Chavdar P. Krachmarov, Michael Burkhart, Samuel C. Kayman, Jose Corvalan, and Abraham Pinter. Efficient Isolation of Novel Human Monoclonal Antibodies with Neutralizing Activity Against HIV-1 from Transgenic Mice Expressing Human Ig Loci. J. Immunol., 169(1):595-605, 1 Jul 2002. PubMed ID: 12077293. Show all entries for this paper.

Hill1997 C. M. Hill, H. Deng, D. Unutmaz, V. N. Kewalramani, L. Bastiani, M. K. Gorny, S. Zolla-Pazner, and D. R. Littman. Envelope glycoproteins from human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus can use human CCR5 as a coreceptor for viral entry and make direct CD4-dependent interactions with this chemokine receptor. J. Virol., 71:6296-6304, 1997. PubMed ID: 9261346. Show all entries for this paper.

Hioe1997 C. Hioe, S. Burda, P. Chigurupati, S. Xu, and S. Zolla-Pazner. Resting Cell Neutralization Assay for HIV-1 Primary Isolates. Methods: A companion to Methods in Enzymology, 12:300-305, 1997. A technique is described for detecting the activity of neutralizing polyclonal or MAbs against HIV-1 primary isolates, using unstimulated PBMC as the target cell. PubMed ID: 9245610. Show all entries for this paper.

Hioe1997b C. E. Hioe, S. Xu, P. Chigurupati, S. Burda, C. Williams, M. K. Gorny, and S. Zolla-Pazner. Neutralization of HIV-1 Primary Isolates by Polyclonal and Monoclonal Human Antibodies. Int. Immunol., 9(9):1281-1290, Sep 1997. PubMed ID: 9310831. Show all entries for this paper.

Hioe1999 C. E. Hioe, J. E. Hildreth, and S. Zolla-Pazner. Enhanced HIV Type 1 Neutralization by Human Anti-Glycoprotein 120 Monoclonal Antibodies in the Presence of Monoclonal Antibodies to Lymphocyte Function-Associated Molecule 1. AIDS Res. Hum. Retroviruses, 15:523-531, 1999. PubMed ID: 10221529. Show all entries for this paper.

Hioe2000 C. E. Hioe, G. J. Jones, A. D. Rees, S. Ratto-Kim, D. Birx, C. Munz, M. K. Gorny, M. Tuen, and S. Zolla-Pazner. Anti-CD4-Binding Domain Antibodies Complexed with HIV Type 1 Glycoprotein 120 Inhibit CD4+ T Cell-Proliferative Responses to Glycoprotein 120. AIDS Res. Hum. Retroviruses, 16:893-905, 2000. PubMed ID: 10875615. Show all entries for this paper.

Hioe2009 Catarina E. Hioe, Maria Luisa Visciano, Rajnish Kumar, Jianping Liu, Ethan A. Mack, Rachel E. Simon, David N. Levy, and Michael Tuen. The Use of Immune Complex Vaccines to Enhance Antibody Responses against Neutralizing Epitopes on HIV-1 Envelope gp120. Vaccine, 28(2):352-360, 11 Dec 2009. PubMed ID: 19879224. Show all entries for this paper.

Hioe2010 Catarina E. Hioe, Terri Wrin, Michael S. Seaman, Xuesong Yu, Blake Wood, Steve Self, Constance Williams, Miroslaw K. Gorny, and Susan Zolla-Pazner. Anti-V3 Monoclonal Antibodies Display Broad Neutralizing Activities against Multiple HIV-1 Subtypes. PLoS One, 5(4):e10254, 2010. PubMed ID: 20421997. 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.

Holl2006 Vincent Holl, Maryse Peressin, Thomas Decoville, Sylvie Schmidt, Susan Zolla-Pazner, Anne-Marie Aubertin, and Christiane Moog. Nonneutralizing Antibodies Are Able To Inhibit Human Immunodeficiency Virus Type 1 Replication in Macrophages and Immature Dendritic Cells. J. Virol., 80(12):6177-6181, Jun 2006. PubMed ID: 16731957. Show all entries for this paper.

Holl2006a Vincent Holl, Maryse Peressin, Sylvie Schmidt, Thomas Decoville, Susan Zolla-Pazner, Anne-Marie Aubertin, and Christiane Moog. Efficient Inhibition of HIV-1 Replication in Human Immature Monocyte-Derived Dendritic Cells by Purified Anti-HIV-1 IgG without Induction of Maturation. Blood, 107(11):4466-4474, 1 Jun 2006. PubMed ID: 16469871. Show all entries for this paper.

Hoxie2010 James A. Hoxie. Toward an Antibody-Based HIV-1 Vaccine. Annu. Rev. Med., 61:135-52, 2010. PubMed ID: 19824826. Show all entries for this paper.

Hu2007 Qinxue Hu, Naheed Mahmood, and Robin J. Shattock. High-Mannose-Specific Deglycosylation of HIV-1 gp120 Induced by Resistance to Cyanovirin-N and the Impact on Antibody Neutralization. Virology, 368(1):145-154, 10 Nov 2007. PubMed ID: 17658575. Show all entries for this paper.

Huang2005 Chih-chin Huang, Min Tang, Mei-Yun Zhang, Shahzad Majeed, Elizabeth Montabana, Robyn L. Stanfield, Dimiter S. Dimitrov, Bette Korber, Joseph Sodroski, Ian A. Wilson, Richard Wyatt, and Peter D. Kwong. Structure of a V3-Containing HIV-1 gp120 Core. Science, 310(5750):1025-1028, 11 Nov 2005. PubMed ID: 16284180. Show all entries for this paper.

Huang2010 Kuan-Hsiang G. Huang, David Bonsall, Aris Katzourakis, Emma C. Thomson, Sarah J. Fidler, Janice Main, David Muir, Jonathan N. Weber, Alexander J. Frater, Rodney E. Phillips, Oliver G. Pybus, Philip J. R. Goulder, Myra O. McClure, Graham S. Cooke, and Paul Klenerman. B-Cell Depletion Reveals a Role for Antibodies in the Control of Chronic HIV-1 Infection. Nat. Commun., 1:102, 2010. PubMed ID: 20981030. Show all entries for this paper.

Huber2007 M. Huber and A. Trkola. Humoral Immunity to HIV-1: Neutralization and Beyond. J. Intern. Med., 262(1):5-25, Jul 2007. PubMed ID: 17598812. Show all entries for this paper.

Inouye1998 P. Inouye, E. Cherry, M. Hsu, S. Zolla-Pazner, and M. A. Wainberg. Neutralizing Antibodies Directed against the V3 Loop Select for Different Escape Variants in a Virus with Mutated Reverse Transcriptase (M184V) Than in Wild-Type Human Immunodeficiency Virus Type 1. AIDS Res. Hum. Retroviruses, 14:735-740, 1998. The M184V substitution in RT yields high level resistance to 3TC and low level resistance to ddI and ddC, and alters the properties of RT. Virus containing the wt form of RT grown in the presence of the MAb 447-D develops 447-D resistance in 36 days, with the GPGR to GPGK substitutions (AGA(R) to AAA(K)). 447-D resistance took longer to acquire in virus with the M184V substituted RT, and had the form CTRPN to CTRPY (AAC(N) to TAC(Y)) at position 5 of the V3 loop. PubMed ID: 9643373. Show all entries for this paper.

Jagodzinski1996 P. P. Jagodzinski, J. Wustner, D. Kmieciak, T. J. Wasik, A. Fertala, A. L. Sieron, M. Takahashi, T. Tsuji, T. Mimura, M. S. Fung, M. K. Gorny, M. Kloczewiak, Y. Kaneko, and D. Kozbor. Role of the V2, V3, and CD4-Binding Domains of GP120 in Curdlan Sulfate Neutralization Sensitivity of HIV-1 during Infection of T Lymphocytes. Virology, 226:217-227, 1996. PubMed ID: 8955041. Show all entries for this paper.

Jiang2010 Xunqing Jiang, Valicia Burke, Maxim Totrov, Constance Williams, Timothy Cardozo, Miroslaw K. Gorny, Susan Zolla-Pazner, and Xiang-Peng Kong. Conserved Structural Elements in the V3 Crown of HIV-1 gp120. Nat. Struct. Mol. Biol., 17(8):955-961, Aug 2010. PubMed ID: 20622876. Show all entries for this paper.

Kang2005 Sang-Moo Kang, Fu Shi Quan, Chunzi Huang, Lizheng Guo, Ling Ye, Chinglai Yang, and Richard W. Compans. Modified HIV Envelope Proteins with Enhanced Binding to Neutralizing Monoclonal Antibodies. Virology, 331(1):20-32, 5 Jan 2005. PubMed ID: 15582650. Show all entries for this paper.

Karwowska1992a S. Karwowska, M. K. Gorny, A. Buchbinder, and S. Zolla-Pazner. Type-specific human monoclonal antibodies cross-react with the V3-loop of various HIV-1 isolates. Vaccines 92, :171-174, 1992. Editors: F. Brown, H. S. Ginsberg and R. Lerner, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. Show all entries for this paper.

Keele2008 Brandon F. Keele, Elena E. Giorgi, Jesus F. Salazar-Gonzalez, Julie M. Decker, Kimmy T. Pham, Maria G. Salazar, Chuanxi Sun, Truman Grayson, Shuyi Wang, Hui Li, Xiping Wei, Chunlai Jiang, Jennifer L. Kirchherr, Feng Gao, Jeffery A. Anderson, Li-Hua Ping, Ronald Swanstrom, Georgia D. Tomaras, William A. Blattner, Paul A. Goepfert, J. Michael Kilby, Michael S. Saag, Eric L. Delwart, Michael P. Busch, Myron S. Cohen, David C. Montefiori, Barton F. Haynes, Brian Gaschen, Gayathri S. Athreya, Ha Y. Lee, Natasha Wood, Cathal Seoighe, Alan S. Perelson, Tanmoy Bhattacharya, Bette T. Korber, Beatrice H. Hahn, and George M. Shaw. Identification and Characterization of Transmitted and Early Founder Virus Envelopes in Primary HIV-1 Infection. Proc. Natl. Acad. Sci. U.S.A., 105(21):7552-7557, 27 May 2008. PubMed ID: 18490657. Show all entries for this paper.

Keller1993 P. M. Keller, B. A. Arnold, A. R. Shaw, R. L. Tolman, F. Van Middlesworth, S. Bondy, V. K. Rusiecki, S. Koenig, S. Zolla-Pazner, P. Conard, E. A. Emini, and A. J. Conley. Identification of HIV Vaccine Candidate Peptides by Screening Random Phage Epitope Libraries. Virology, 193:709-716, 1993. A library of 15 mers was screened for reactivity with 447-52D. 100s of 15 mers reacted, of which 70 were sequenced. All but one contained the motif GPXR. PubMed ID: 7681612. Show all entries for this paper.

Kessler2003 Naama Kessler, Anat Zvi, Min Ji, Michal Sharon, Osnat Rosen, Rina Levy, Miroslaw Gorny, Suzan Zolla-Pazner, and Jacob Anglister. Expression, Purification, and Isotope Labeling of the Fv of the Human HIV-1 Neutralizing Antibody 447-52D for NMR Studies. Protein. Expr. Purif., 29(2):291-303, Jun 2003. PubMed ID: 12767822. Show all entries for this paper.

Kimura2009 Tetsuya Kimura, Xiao-Hong Wang, Constance Williams, Susan Zolla-Pazner, and Miroslaw K. Gorny. Human Monoclonal Antibody 2909 Binds to Pseudovirions Expressing Trimers but not Monomeric HIV-1 Envelope Proteins. Hum. Antibodies, 18(1-2):35-40, 2009. PubMed ID: 19478397. Show all entries for this paper.

Klein2013 Florian Klein, Ron Diskin, Johannes F. Scheid, Christian Gaebler, Hugo Mouquet, Ivelin S. Georgiev, Marie Pancera, Tongqing Zhou, Reha-Baris Incesu, Brooks Zhongzheng Fu, Priyanthi N. P. Gnanapragasam, Thiago Y. Oliveira, Michael S. Seaman, Peter D. Kwong, Pamela J. Bjorkman, and Michel C. Nussenzweig. Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization. Cell, 153(1):126-138, 28 Mar 2013. PubMed ID: 23540694. Show all entries for this paper.

Korber2009 Bette Korber and S. Gnanakaran. The Implications of Patterns in HIV Diversity for Neutralizing Antibody Induction and Susceptibility. Curr. Opin. HIV AIDS, 4(5):408-417, Sep 2009. PubMed ID: 20048705. Show all entries for this paper.

Krachmarov2005 Chavdar Krachmarov, Abraham Pinter, William J. Honnen, Miroslaw K. Gorny, Phillipe N. Nyambi, Susan Zolla-Pazner, and Samuel C. Kayman. Antibodies That Are Cross-Reactive for Human Immunodeficiency Virus Type 1 Clade A and Clade B V3 Domains Are Common in Patient Sera from Cameroon, but Their Neutralization Activity Is Usually Restricted by Epitope Masking. J. Virol., 79(2):780-790, Jan 2005. PubMed ID: 15613306. Show all entries for this paper.

Krachmarov2006 C. P. Krachmarov, W. J. Honnen, S. C. Kayman, M. K. Gorny, S. Zolla-Pazner, and Abraham Pinter. Factors Determining the Breadth and Potency of Neutralization by V3-Specific Human Monoclonal Antibodies Derived from Subjects Infected with Clade A or Clade B Strains of Human Immunodeficiency Virus Type 1. J. Virol., 80(14):7127-7135, Jul 2006. PubMed ID: 16809318. Show all entries for this paper.

Kraft2007 Zane Kraft, Nina R. Derby, Ruth A. McCaffrey, Rachel Niec, Wendy M. Blay, Nancy L. Haigwood, Eirini Moysi, Cheryl J. Saunders, Terri Wrin, Christos J. Petropoulos, M. Juliana McElrath, and Leonidas Stamatatos. Macaques Infected with a CCR5-Tropic Simian/Human Immunodeficiency Virus (SHIV) Develop Broadly Reactive Anti-HIV Neutralizing Antibodies. J. Virol., 81(12):6402-6411, Jun 2007. PubMed ID: 17392364. Show all entries for this paper.

Kwong2009a Peter D. Kwong and Ian A. Wilson. HIV-1 and Influenza Antibodies: Seeing Antigens in New Ways. Nat. Immunol., 10(6):573-578, Jun 2009. PubMed ID: 19448659. Show all entries for this paper.

Laal1994 Suman Laal, Sherri Burda, Miroslav K. Gorny, Sylwia Karwowska, Aby Buchbinder, and Susan Zolla-Pazner. Synergistic Neutralization of Human Immunodeficiency Virus Type 1 by Combinations of Human Monoclonal Antibodies. J. Virol., 68(6):4001-4008, Jun 1994. PubMed ID: 7514683. Show all entries for this paper.

Law2007 Mansun Law, Rosa M. F. Cardoso, Ian A. Wilson, and Dennis R. Burton. Antigenic and Immunogenic Study of Membrane-Proximal External Region-Grafted gp120 Antigens by a DNA Prime-Protein Boost Immunization Strategy. J. Virol., 81(8):4272-4285, Apr 2007. PubMed ID: 17267498. Show all entries for this paper.

Lewis1995 C. M. Lewis, G. F. Hollis, G. E. Mark, 3rd, J. S. Tung, and S. W. Ludmerer. Use of a Novel Mutagenesis Strategy, Optimized Residue Substitution, to Decrease the Off-Rate of an Anti-gp120 Antibody. Mol. Immunol., 32(14-15):1065-1072, Oct 1995. PubMed ID: 8544856. Show all entries for this paper.

Li2005a Ming Li, Feng Gao, John R. Mascola, Leonidas Stamatatos, Victoria R. Polonis, Marguerite Koutsoukos, Gerald Voss, Paul Goepfert, Peter Gilbert, Kelli M. Greene, Miroslawa Bilska, Denise L Kothe, Jesus F. Salazar-Gonzalez, Xiping Wei, Julie M. Decker, Beatrice H. Hahn, and David C. Montefiori. Human Immunodeficiency Virus Type 1 env Clones from Acute and Early Subtype B Infections for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies. J. Virol., 79(16):10108-10125, Aug 2005. PubMed ID: 16051804. Show all entries for this paper.

Li2007a Yuxing Li, Stephen A. Migueles, Brent Welcher, Krisha Svehla, Adhuna Phogat, Mark K. Louder, Xueling Wu, George M. Shaw, Mark Connors, Richard T. Wyatt, and John R. Mascola. Broad HIV-1 Neutralization Mediated by CD4-Binding Site Antibodies. Nat. Med., 13(9):1032-1034, Sep 2007. PubMed ID: 17721546. Show all entries for this paper.

Li2009c Yuxing Li, Krisha Svehla, Mark K. Louder, Diane Wycuff, Sanjay Phogat, Min Tang, Stephen A. Migueles, Xueling Wu, Adhuna Phogat, George M. Shaw, Mark Connors, James Hoxie, John R. Mascola, and Richard Wyatt. Analysis of Neutralization Specificities in Polyclonal Sera Derived from Human Immunodeficiency Virus Type 1-Infected Individuals. J Virol, 83(2):1045-1059, Jan 2009. PubMed ID: 19004942. Show all entries for this paper.

Lin2007 George Lin and Peter L. Nara. Designing Immunogens to Elicit Broadly Neutralizing Antibodies to the HIV-1 Envelope Glycoprotein. Curr. HIV Res., 5(6):514-541, Nov 2007. PubMed ID: 18045109. Show all entries for this paper.

Ling2004 Hong Ling, Peng Xiao, Osamu Usami, and Toshio Hattori. Thrombin Activates Envelope Glycoproteins of HIV Type 1 and Enhances Fusion. Microbes Infect., 6(5):414-420, Apr 2004. PubMed ID: 15109955. Show all entries for this paper.

Louder2005 Mark K. Louder, Anna Sambor, Elena Chertova, Tai Hunte, Sarah Barrett, Fallon Ojong, Eric Sanders-Buell, Susan Zolla-Pazner, Francine E. McCutchan, James D. Roser, Dana Gabuzda, Jeffrey D. Lifson, and John R. Mascola. HIV-1 Envelope Pseudotyped Viral Vectors and Infectious Molecular Clones Expressing the Same Envelope Glycoprotein Have a Similar Neutralization Phenotype, but Culture in Peripheral Blood Mononuclear Cells Is Associated with Decreased Neutralization Sensitivity. Virology, 339(2):226-238, 1 Sep 2005. PubMed ID: 16005039. Show all entries for this paper.

Lusso2005 Paolo Lusso, Patricia L. Earl, Francesca Sironi, Fabio Santoro, Chiara Ripamonti, Gabriella Scarlatti, Renato Longhi, Edward A. Berger, and Samuele E. Burastero. Cryptic Nature of a Conserved, CD4-Inducible V3 Loop Neutralization Epitope in the Native Envelope Glycoprotein Oligomer of CCR5-Restricted, but not CXCR4-Using, Primary Human Immunodeficiency Virus Type 1 Strains. J. Virol., 79(11):6957-6968, Jun 2005. PubMed ID: 15890935. Show all entries for this paper.

Ly2000 A. Ly and L. Stamatatos. V2 Loop Glycosylation of the Human Immunodeficiency Virus Type 1 SF162 Envelope Facilitates Interaction of this Protein with CD4 and CCR5 Receptors and Protects the Virus from Neutralization by Anti-V3 Loop and Anti-CD4 Binding Site Antibodies. J. Virol., 74:6769-6776, 2000. PubMed ID: 10888615. Show all entries for this paper.

Martin2008 Grégoire Martin, Yide Sun, Bernadette Heyd, Olivier Combes, Jeffrey B Ulmer, Anne Descours, Susan W Barnett, Indresh K Srivastava, and Loïc Martin. A Simple One-Step Method for the Preparation of HIV-1 Envelope Glycoprotein Immunogens Based on a CD4 Mimic Peptide. Virology, 381(2):241-250, 25 Nov 2008. PubMed ID: 18835005. Show all entries for this paper.

Martin2011 Grégoire Martin, Brian Burke, Robert Thaï, Antu K. Dey, Olivier Combes, Bernadette Heyd, Anthony R. Geonnotti, David C. Montefiori, Elaine Kan, Ying Lian, Yide Sun, Toufik Abache, Jeffrey B. Ulmer, Hocine Madaoui, Raphaël Guérois, Susan W. Barnett, Indresh K. Srivastava, Pascal Kessler, and Loïc Martin. Stabilization of HIV-1 Envelope in the CD4-Bound Conformation through Specific Cross-Linking of a CD4 Mimetic. J. Biol. Chem., 286(24):21706-21716, 17 Jun 2011. PubMed ID: 21487012. Show all entries for this paper.

Martin-Garcia2005 Julio Martín-García, Simon Cocklin, Irwin M. Chaiken, and Francisco González-Scarano. Interaction with CD4 and Antibodies to CD4-Induced Epitopes of the Envelope gp120 from a Microglial Cell-Adapted Human Immunodeficiency Virus Type 1 Isolate. J. Virol., 79(11):6703-6713, Jun 2005. PubMed ID: 15890908. Show all entries for this paper.

McCaffrey2004 Ruth A McCaffrey, Cheryl Saunders, Mike Hensel, and Leonidas Stamatatos. N-Linked Glycosylation of the V3 Loop and the Immunologically Silent Face of gp120 Protects Human Immunodeficiency Virus Type 1 SF162 from Neutralization by Anti-gp120 and Anti-gp41 Antibodies. J. Virol., 78(7):3279-3295, Apr 2004. PubMed ID: 15016849. 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.

McKnight2007 Aine McKnight and Marlen M. I. Aasa-Chapman. Clade Specific Neutralising Vaccines for HIV: An Appropriate Target? Curr. HIV Res., 5(6):554-560, Nov 2007. PubMed ID: 18045111. Show all entries for this paper.

Mester2009 Brenda Mester, Revital Manor, Amit Mor, Boris Arshava, Osnat Rosen, Fa-Xiang Ding, Fred Naider, and Jacob Anglister. HIV-1 Peptide Vaccine Candidates: Selecting Constrained V3 Peptides with Highest Affinity to Antibody 447-52D. Biochemistry, 48(33):7867-7877, 25 Aug 2009. PubMed ID: 19552398. Show all entries for this paper.

Moore2006 Penny L. Moore, Emma T. Crooks, Lauren Porter, Ping Zhu, Charmagne S. Cayanan, Henry Grise, Paul Corcoran, Michael B. Zwick, Michael Franti, Lynn Morris, Kenneth H. Roux, Dennis R. Burton, and James M. Binley. Nature of Nonfunctional Envelope Proteins on the Surface of Human Immunodeficiency Virus Type 1. J. Virol., 80(5):2515-2528, Mar 2006. PubMed ID: 16474158. Show all entries for this paper.

Mor2009 Amit Mor, Eugenia Segal, Brenda Mester, Boris Arshava, Osnat Rosen, Fa-Xiang Ding, Joseph Russo, Amnon Dafni, Fabian Schvartzman, Tali Scherf, Fred Naider, and Jacob Anglister. Mimicking the Structure of the V3 Epitope Bound to HIV-1 Neutralizing Antibodies. Biochemistry, 48(15):3288-3303, 21 Apr 2009. PubMed ID: 19281264. Show all entries for this paper.

Musich2011 Thomas Musich, Paul J. Peters, Maria José Duenas-Decamp, Maria Paz Gonzalez-Perez, James Robinson, Susan Zolla-Pazner, Jonathan K. Ball, Katherine Luzuriaga, and Paul R. Clapham. A Conserved Determinant in the V1 Loop of HIV-1 Modulates the V3 Loop to Prime Low CD4 Use and Macrophage Infection. J. Virol., 85(5):2397-2405, Mar 2011. PubMed ID: 21159865. Show all entries for this paper.

Nelson2007 Josh D. Nelson, Florence M. Brunel, Richard Jensen, Emma T. Crooks, Rosa M. F. Cardoso, Meng Wang, Ann Hessell, Ian A. Wilson, James M. Binley, Philip E. Dawson, Dennis R. Burton, and Michael B. Zwick. An Affinity-Enhanced Neutralizing Antibody against the Membrane-Proximal External Region of Human Immunodeficiency Virus Type 1 gp41 Recognizes an Epitope between Those of 2F5 and 4E10. J. Virol., 81(8):4033-4043, Apr 2007. PubMed ID: 17287272. Show all entries for this paper.

Nishiyama2009 Yasuhiro Nishiyama, Stephanie Planque, Yukie Mitsuda, Giovanni Nitti, Hiroaki Taguchi, Lei Jin, Jindrich Symersky, Stephane Boivin, Marcin Sienczyk, Maria Salas, Carl V. Hanson, and Sudhir Paul. Toward Effective HIV Vaccination: Induction of Binary Epitope Reactive Antibodies with Broad HIV Neutralizing Activity. J. Biol. Chem., 284(44):30627-30642, 30 Oct 2009. PubMed ID: 19726674. Show all entries for this paper.

Nyambi1998 P. N. Nyambi, M. K. Gorny, L. Bastiani, G. van der Groen, C. Williams, and S. Zolla-Pazner. Mapping of Epitopes Exposed on Intact Human Immunodeficiency Virus Type 1 (HIV-1) Virions: A New Strategy for Studying the Immunologic Relatedness of HIV-1. J. Virol., 72:9384-9391, 1998. 18 human MAbs binding to gp120 and gp41 were tested using a novel assay to test binding to intact HIV-1 virions. The new method involves using MAbs to the host proteins incorporated into virions to bind them to ELIZA plates. Antigenic conservation in epitopes of HIV-1 in clades A, B, D, F, G, and H was studied. MAbs were selected that were directed against V2, V3, CD4bd, C5 or gp41 regions. Antibodies against V2, the CD4BS, and sp41 showed weak and sporadic reactivities, while binding strongly to gp120, suggesting these epitopes are hidden when gp120 is in its native, quaternary structure. PubMed ID: 9765494. Show all entries for this paper.

Nyambi2000 P. N. Nyambi, H. A. Mbah, S. Burda, C. Williams, M. K. Gorny, A. Nadas, and S. Zolla-Pazner. Conserved and Exposed Epitopes on Intact, Native, Primary Human Immunodeficiency Virus Type 1 Virions of Group M. J. Virol., 74:7096-7107, 2000. PubMed ID: 10888650. Show all entries for this paper.

ORourke2010 Sara M. O'Rourke, Becky Schweighardt, Pham Phung, Dora P. A. J. Fonseca, Karianne Terry, Terri Wrin, Faruk Sinangil, and Phillip W. Berman. Mutation at a Single Position in the V2 Domain of the HIV-1 Envelope Protein Confers Neutralization Sensitivity to a Highly Neutralization-Resistant Virus. J. Virol., 84(21):11200-11209, Nov 2010. PubMed ID: 20702624. Show all entries for this paper.

Pantophlet2004 R. Pantophlet, I. A. Wilson, and D. R. Burton. Improved Design of an Antigen with Enhanced Specificity for the Broadly HIV-Neutralizing Antibody b12. Protein Eng. Des. Sel., 17(10):749-758, Oct 2004. PubMed ID: 15542540. Show all entries for this paper.

Pantophlet2006 Ralph Pantophlet and Dennis R. Burton. GP120: Target for Neutralizing HIV-1 Antibodies. Annu. Rev. Immunol., 24:739-769, 2006. PubMed ID: 16551265. Show all entries for this paper.

Pantophlet2007 Ralph Pantophlet, Rowena O. Aguilar-Sino, Terri Wrin, Lisa A. Cavacini, and Dennis R. Burton. Analysis of the Neutralization Breadth of the Anti-V3 Antibody F425-B4e8 and Re-assessment of its Epitope Fine Specificity by Scanning Mutagenesis. Virology, 364(2):441-453, 1 Aug 2007. PubMed ID: 17418361. Show all entries for this paper.

Pantophlet2010 Ralph Pantophlet. Antibody Epitope Exposure and Neutralization of HIV-1. Curr. Pharm. Des., 16(33):3729-3743, 2010. PubMed ID: 21128886. Show all entries for this paper.

Peressin2011 M. Peressin, V. Holl, S. Schmidt, T. Decoville, D. Mirisky, A. Lederle, M. Delaporte, K. Xu, A. M. Aubertin, and C. Moog. HIV-1 Replication in Langerhans and Interstitial Dendritic Cells Is Inhibited by Neutralizing and Fc-Mediated Inhibitory Antibodies. J. Virol., 85(2):1077-1085, Jan 2011. PubMed ID: 21084491. Show all entries for this paper.

Phogat2007 S. Phogat, R. T. Wyatt, and G. B. Karlsson Hedestam. Inhibition of HIV-1 Entry by Antibodies: Potential Viral and Cellular Targets. J. Intern. Med., 262(1):26-43, Jul 2007. PubMed ID: 17598813. Show all entries for this paper.

Pinter2004 Abraham Pinter, William J. Honnen, Yuxian He, Miroslaw K. Gorny, Susan Zolla-Pazner, and Samuel C. Kayman. The V1/V2 Domain of gp120 Is a Global Regulator of the Sensitivity of Primary Human Immunodeficiency Virus Type 1 Isolates to Neutralization by Antibodies Commonly Induced upon Infection. J. Virol., 78(10):5205-5215, May 2004. PubMed ID: 15113902. Show all entries for this paper.

Pinter2005 Abraham Pinter, William J. Honnen, Paul D'Agostino, Miroslaw K. Gorny, Susan Zolla-Pazner, and Samuel C. Kayman. The C108g Epitope in the V2 Domain of gp120 Functions as a Potent Neutralization Target When Introduced into Envelope Proteins Derived from Human Immunodeficiency Virus Type 1 Primary Isolates. J. Virol., 79(11):6909-6917, Jun 2005. PubMed ID: 15890930. Show all entries for this paper.

Pugach2004 Pavel Pugach, Shawn E. Kuhmann, Joann Taylor, Andre J. Marozsan, Amy Snyder, Thomas Ketas, Steven M. Wolinsky, Bette T. Korber, and John P. Moore. The Prolonged Culture of Human Immunodeficiency Virus Type 1 in Primary Lymphocytes Increases its Sensitivity to Neutralization by Soluble CD4. Virology, 321(1):8-22, 30 Mar 2004. PubMed ID: 15033560. Show all entries for this paper.

Pugach2008 Pavel Pugach, Thomas J. Ketas, Elizabeth Michael, and John P. Moore. Neutralizing Antibody and Anti-Retroviral Drug Sensitivities of HIV-1 Isolates Resistant to Small Molecule CCR5 Inhibitors. Virology, 377(2):401-407, 1 Aug 2008. PubMed ID: 18519143. Show all entries for this paper.

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.

Robinson2010 James E. Robinson, Kelly Franco, Debra Holton Elliott, Mary Jane Maher, Ashley Reyna, David C. Montefiori, Susan Zolla-Pazner, Miroslaw K. Gorny, Zane Kraft, and Leonidas Stamatatos. Quaternary Epitope Specificities of Anti-HIV-1 Neutralizing Antibodies Generated in Rhesus Macaques Infected by the Simian/Human Immunodeficiency Virus SHIVSF162P4. J. Virol., 84(7):3443-3453, Apr 2010. PubMed ID: 20106929. Show all entries for this paper.

Rosen2005 Osnat Rosen, Jordan Chill, Michal Sharon, Naama Kessler, Brenda Mester, Susan Zolla-Pazner, and Jacob Anglister. Induced Fit in HIV-Neutralizing Antibody Complexes: Evidence for Alternative Conformations of the gp120 V3 Loop and the Molecular Basis for Broad Neutralization. Biochemistry, 44(19):7250-7158, 17 May 2005. PubMed ID: 15882063. Show all entries for this paper.

Ruprecht2011 Claudia R. Ruprecht, Anders Krarup, Lucy Reynell, Axel M. Mann, Oliver F. Brandenberg, Livia Berlinger, Irene A. Abela, Roland R. Regoes, Huldrych F. Günthard, Peter Rusert, and Alexandra Trkola. MPER-Specific Antibodies Induce gp120 Shedding and Irreversibly Neutralize HIV-1. J. Exp. Med., 208(3):439-454, 14 Mar 2011. PubMed ID: 21357743. Show all entries for this paper.

Saarloos1995 M. N. Saarloos, T. F. Lint, and G. T. Spear. Efficacy of HIV-Specific and `Antibody-Independent' Mechanisms for Complement Activation by HIV-Infected Cells. Clin. Exp. Immunol., 99:189-195, 1995. PubMed ID: 7851010. Show all entries for this paper.

Sabin2010 Charles Sabin, Davide Corti, Victor Buzon, Mike S. Seaman, David Lutje Hulsik, Andreas Hinz, Fabrizia Vanzetta, Gloria Agatic, Chiara Silacci, Lara Mainetti, Gabriella Scarlatti, Federica Sallusto, Robin Weiss, Antonio Lanzavecchia, and Winfried Weissenhorn. Crystal Structure and Size-Dependent Neutralization Properties of HK20, a Human Monoclonal Antibody Binding to the Highly Conserved Heptad Repeat 1 of gp41. PLoS Pathog., 6(11):e1001195, 2010. PubMed ID: 21124990. Show all entries for this paper.

Sattentau1995b Q. J. Sattentau. Conservation of HIV-1 gp120 Neutralizing Epitopes after Formalin Inactivation. AIDS, 9:1383-1385, 1995. PubMed ID: 8605064. Show all entries for this paper.

Sattentau1996 Q. J. Sattentau. Neutralization of HIV-1 by Antibody. Curr. Opin. Immunol., 8:540-545, 1996. Review. PubMed ID: 8794008. Show all entries for this paper.

Scheid2009 Johannes F. Scheid, Hugo Mouquet, Niklas Feldhahn, Michael S. Seaman, Klara Velinzon, John Pietzsch, Rene G. Ott, Robert M. Anthony, Henry Zebroski, Arlene Hurley, Adhuna Phogat, Bimal Chakrabarti, Yuxing Li, Mark Connors, Florencia Pereyra, Bruce D. Walker, Hedda Wardemann, David Ho, Richard T. Wyatt, John R. Mascola, Jeffrey V. Ravetch, and Michel C. Nussenzweig. Broad Diversity of Neutralizing Antibodies Isolated from Memory B Cells in HIV-Infected Individuals. Nature, 458(7238):636-640, 2 Apr 2009. PubMed ID: 19287373. Show all entries for this paper.

Seaman2010 Michael S. Seaman, Holly Janes, Natalie Hawkins, Lauren E. Grandpre, Colleen Devoy, Ayush Giri, Rory T. Coffey, Linda Harris, Blake Wood, Marcus G. Daniels, Tanmoy Bhattacharya, Alan Lapedes, Victoria R Polonis, Francine E. McCutchan, Peter B. Gilbert, Steve G. Self, Bette T. Korber, David C. Montefiori, and John R. Mascola. Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Assessment of Neutralizing Antibodies. J Virol, 84(3):1439-1452, Feb 2010. PubMed ID: 19939925. Show all entries for this paper.

Sharon2002 Michal Sharon, Matthias Görlach, Rina Levy, Yehezkiel Hayek, and Jacob Anglister. Expression, Purification, and Isotope Labeling of a gp120 V3 Peptide and Production of a Fab from a HIV-1 Neutralizing Antibody for NMR Studies. Protein Expr. Purif., 24(3):374-383, Apr 2002. PubMed ID: 11922753. Show all entries for this paper.

Sharpe2004 Simon Sharpe, Naama Kessler, Jacob A. Anglister, Wai-Ming Yau, and Robert Tycko. Solid-State NMR Yields Structural Constraints on the V3 Loop from HIV-1 Gp120 Bound to the 447-52D Antibody Fv Fragment. J. Am. Chem. Soc., 126(15):4979-4990, 21 Apr 2004. PubMed ID: 15080704. Show all entries for this paper.

Shen2010 Xiaoying Shen, S. Moses Dennison, Pinghuang Liu, Feng Gao, Frederick Jaeger, David C. Montefiori, Laurent Verkoczy, Barton F. Haynes, S. Munir Alam, and Georgia D. Tomaras. Prolonged Exposure of the HIV-1 gp41 Membrane Proximal Region with L669S Substitution. Proc. Natl. Acad. Sci. U.S.A., 107(13):5972-5977, 30 Mar 2010. PubMed ID: 20231447. Show all entries for this paper.

Shibata2007 Junji Shibata, Kazuhisa Yoshimura, Akiko Honda, Atsushi Koito, Toshio Murakami, and Shuzo Matsushita. Impact of V2 Mutations on Escape from a Potent Neutralizing Anti-V3 Monoclonal Antibody during In Vitro Selection of a Primary Human Immunodeficiency Virus Type 1 Isolate. J. Virol., 81(8):3757-3768, Apr 2007. PubMed ID: 17251298. Show all entries for this paper.

Shmelkov2011 Evgeny Shmelkov, Arthur Nadas, James Swetnam, Susan Zolla-Pazner, and Timothy Cardozo. Indirect Detection of an Epitope-Specific Response to HIV-1 gp120 Immunization in Human Subjects. PLoS One, 6(11):e27279, 2011. PubMed ID: 22076145. Show all entries for this paper.

Shmelkov2014 Evgeny Shmelkov, Chavdar Krachmarov, Arsen V. Grigoryan, Abraham Pinter, Alexander Statnikov, and Timothy Cardozo. Computational Prediction of Neutralization Epitopes Targeted by Human Anti-V3 HIV Monoclonal Antibodies. PLoS One, 9(2):e89987, 2014. PubMed ID: 24587168. Show all entries for this paper.

Sirois2007 Suzanne Sirois, Mohamed Touaibia, Kuo-Chen Chou, and Rene Roy. Glycosylation of HIV-1 gp120 V3 Loop: Towards the Rational Design of a Synthetic Carbohydrate Vaccine. Curr. Med. Chem., 14(30):3232-3242, 2007. PubMed ID: 18220757. Show all entries for this paper.

Smalls-Mantey2012 Adjoa Smalls-Mantey, Nicole Doria-Rose, Rachel Klein, Andy Patamawenu, Stephen A. Migueles, Sung-Youl Ko, Claire W. Hallahan, Hing Wong, Bai Liu, Lijing You, Johannes Scheid, John C. Kappes, Christina Ochsenbauer, Gary J. Nabel, John R. Mascola, and Mark Connors. Antibody-Dependent Cellular Cytotoxicity against Primary HIV-Infected CD4+ T Cells Is Directly Associated with the Magnitude of Surface IgG Binding. J. Virol., 86(16):8672-8680, Aug 2012. PubMed ID: 22674985. Show all entries for this paper.

Smith1998 A. D. Smith, S. C. Geisler, A. A. Chen, D. A. Resnick, B. M. Roy, P. J. Lewi, E. Arnold, and G. F. Arnold. Human Rhinovirus Type 14: Human Immunodeficiency Virus Type 1 (HIV-1) V3 Loop Chimeras from a Combinatorial Library Induce Potent Neutralizing Antibody Responses against HIV-1. J. Virol., 72:651-659, 1998. The tip of the MN V3 loop, IGPGRAFYTTKN, was inserted into cold-causing human rhinovirus 14 (HRV14) and chimeras were immunoselected using MAbs 447-52-D, 694/98-D, NM-01, and 59.1, for good presentation of the V3 antigenic region. The selected chimeric viruses were neutralized by anti-V3 loop MAbs. The chimeric viruses elicited potent NAbs against ALA-1 and MN in guinea pigs. PubMed ID: 9420270. Show all entries for this paper.

Spear1993 G. T. Spear, D. M. Takefman, B. L. Sullivan, A. L. Landay, and S. Zolla-Pazner. Complement activation by human monoclonal antibodies to human immunodeficiency virus. J. Virol., 67:53-59, 1993. This study looked at the ability of 16 human MAbs to activate complement. MAbs directed against the V3 region could induce C3 deposition on infected cells and virolysis of free virus, but antibodies to the CD4BS and C-terminal region and two regions in gp41 could induce no complement mediated effects. Pre-treatment with sCD4 could increase complement-mediated effects of anti-gp41 MAbs, but decreased the complement-mediated effects of V3 MAbs. Anti-gp41 MAbs were able to affect IIIB but not MN virolysis, suggesting spontaneous shedding of gp120 on IIIB virions exposes gp41 epitopes. IgG isotype did not appear to have an effect on virolysis or C3 deposition. PubMed ID: 7677959. Show all entries for this paper.

Sreepian2009 Apichai Sreepian, Jongruk Permmongkol, Wannee Kantakamalakul, Sontana Siritantikorn, Nattaya Tanlieng, and Ruengpung Sutthent. HIV-1 Neutralization by Monoclonal Antibody against Conserved Region 2 and Patterns of Epitope Exposure on the Surface of Native Viruses. J. Immune Based Ther. Vaccines, 7:5, 2009. PubMed ID: 19821992. Show all entries for this paper.

Srivastava2002 Indresh K. Srivastava, Leonidas Stamatatos, Harold Legg, Elaine Kan, Anne Fong, Stephen R. Coates, Louisa Leung, Mark Wininger, John J. Donnelly, Jeffrey B. Ulmer, and Susan W. Barnett. Purification and Characterization of Oligomeric Envelope Glycoprotein from a Primary R5 Subtype B Human Immunodeficiency Virus. J. Virol., 76(6):2835-2847, Mar 2002. URL: http://jvi.asm.org/cgi/content/full/76/6/2835. PubMed ID: 11861851. Show all entries for this paper.

Srivastava2008 Indresh K. Srivastava, Elaine Kan, Yide Sun, Victoria A. Sharma, Jimna Cisto, Brian Burke, Ying Lian, Susan Hilt, Zohar Biron, Karin Hartog, Leonidas Stamatatos, Ruben Diaz-Avalos, R Holland Cheng, Jeffrey B. Ulmer, and Susan W. Barnett. Comparative Evaluation of Trimeric Envelope Glycoproteins Derived from Subtype C and B HIV-1 R5 Isolates. Virology, 372(2):273-290, 15 Mar 2008. PubMed ID: 18061231. Show all entries for this paper.

Stanfield2005 Robyn L. Stanfield and Ian A. Wilson. Structural Studies of Human HIV-1 V3 Antibodies. Hum Antibodies, 14(3-4):73-80, 2005. PubMed ID: 16720977. Show all entries for this paper.

Stanfield2006 Robyn L. Stanfield, Miroslaw K. Gorny, Susan Zolla-Pazner, and Ian A. Wilson. Crystal Structures of Human Immunodeficiency Virus Type 1 (HIV-1) Neutralizing Antibody 2219 in Complex with Three Different V3 Peptides Reveal a New Binding Mode for HIV-1 Cross-Reactivity. J. Virol., 80(12):6093-6105, Jun 2006. PubMed ID: 16731948. Show all entries for this paper.

Swetnam2010 James Swetnam, Evgeny Shmelkov, Susan Zolla-Pazner, and Timothy Cardozo. Comparative Magnitude of Cross-Strain Conservation of HIV Variable Loop Neutralization Epitopes. PLoS One, 5(12):e15994, 2010. PubMed ID: 21209919. Show all entries for this paper.

Tasca2008 Silvana Tasca, Siu-Hong Ho, and Cecilia Cheng-Mayer. R5X4 Viruses Are Evolutionary, Functional, and Antigenic Intermediates in the Pathway of a Simian-Human Immunodeficiency Virus Coreceptor Switch. J. Virol., 82(14):7089-7099, Jul 2008. PubMed ID: 18480460. Show all entries for this paper.

Teeraputon2005 Sirilak Teeraputon, Suda Louisirirojchanakul, and Prasert Auewarakul. N-Linked Glycosylation in C2 Region of HIV-1 Envelope Reduces Sensitivity to Neutralizing Antibodies. Viral Immunol., 18(2):343-353, Summer 2005. PubMed ID: 16035946. Show all entries for this paper.

Tomaras2011 Georgia D. Tomaras, James M. Binley, Elin S. Gray, Emma T. Crooks, Keiko Osawa, Penny L. Moore, Nancy Tumba, Tommy Tong, Xiaoying Shen, Nicole L. Yates, Julie Decker, Constantinos Kurt Wibmer, Feng Gao, S. Munir Alam, Philippa Easterbrook, Salim Abdool Karim, Gift Kamanga, John A. Crump, Myron Cohen, George M. Shaw, John R. Mascola, Barton F. Haynes, David C. Montefiori, and Lynn Morris. Polyclonal B Cell Responses to Conserved Neutralization Epitopes in a Subset of HIV-1-Infected Individuals. J. Virol., 85(21):11502-11519, Nov 2011. PubMed ID: 21849452. Show all entries for this paper.

Totrov2010 Maxim Totrov, Xunqing Jiang, Xiang-Peng Kong, Sandra Cohen, Chavdar Krachmarov, Aidy Salomon, Constance Williams, Michael S. Seaman, Ruben Abagyan, Timothy Cardozo, Miroslaw K. Gorny, Shixia Wang, Shan Lu, Abraham Pinter, and Susan Zolla-Pazner. Structure-Guided Design and Immunological Characterization of Immunogens Presenting the HIV-1 gp120 V3 Loop on a CTB Scaffold. Virology, 405(2):513-523, 30 Sep 2010. PubMed ID: 20663531. 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.

Vaine2010 Michael Vaine, Shixia Wang, Qin Liu, James Arthos, David Montefiori, Paul Goepfert, M. Juliana McElrath, and Shan Lu. Profiles of Human Serum Antibody Responses Elicited by Three Leading HIV Vaccines Focusing on the Induction of Env-Specific Antibodies. PLoS One, 5(11):e13916, 2010. PubMed ID: 21085486. Show all entries for this paper.

VanCott1994 T. C. VanCott, F. R. Bethke, V. R. Polonis, M. K. Gorny, S. Zolla-Pazner, R. R. Redfield, and D. L. Birx. Dissociation Rate of Antibody-gp120 Binding Interactions Is Predictive of V3-Mediated Neutralization of HIV-1. J. Immunol., 153:449-459, 1994. Using surface plasmon resonance it was found that the rate of the dissociation of the MAb-gp120 complex, but not the association rate, correlated with MAbs ability to neutralize homologous virus (measured by 50\% inhibition of p24 production). Association constants were similar for all MAbs tested, varying less than 4-fold. Dissociation rate constants were quite variable, with 100-fold differences observed. PubMed ID: 7515931. Show all entries for this paper.

vanGils2011 Marit J. van Gils, Evelien M. Bunnik, Brigitte D. Boeser-Nunnink, Judith A. Burger, Marijke Terlouw-Klein, Naomi Verwer, and Hanneke Schuitemaker. Longer V1V2 Region with Increased Number of Potential N-Linked Glycosylation Sites in the HIV-1 Envelope Glycoprotein Protects against HIV-Specific Neutralizing Antibodies. J. Virol., 85(14):6986-6995, Jul 2011. PubMed ID: 21593147. Show all entries for this paper.

Varadarajan2005 Raghavan Varadarajan, Deepak Sharma, Kausik Chakraborty, Mayuri Patel, Michael Citron, Prem Sinha, Ramkishor Yadav, Umar Rashid, Sarah Kennedy, Debra Eckert, Romas Geleziunas, David Bramhill, William Schleif, Xiaoping Liang, and John Shiver. Characterization of gp120 and Its Single-Chain Derivatives, gp120-CD4D12 and gp120-M9: Implications for Targeting the CD4i Epitope in Human Immunodeficiency Virus Vaccine Design. J. Virol., 79(3):1713-1723, Feb 2005. PubMed ID: 15650196. Show all entries for this paper.

Vermeire2009 Kurt Vermeire, Kristel Van Laethem, Wouter Janssens, Thomas W. Bell, and Dominique Schols. Human Immunodeficiency Virus Type 1 Escape from Cyclotriazadisulfonamide-Induced CD4-Targeted Entry Inhibition Is Associated with Increased Neutralizing Antibody Susceptibility. J. Virol., 83(18):9577-9583, Sep 2009. PubMed ID: 19570853. Show all entries for this paper.

Verrier2001 F. Verrier, A. Nadas, M. K. Gorny, and S. Zolla-Pazner. Additive effects characterize the interaction of antibodies involved in neutralization of the primary dualtropic human immunodeficiency virus type 1 isolate 89.6. J. Virol., 75(19):9177--86, Oct 2001. URL: http://jvi.asm.org/cgi/content/full/75/19/9177. PubMed ID: 11533181. Show all entries for this paper.

Visciano2008 Maria Luisa Visciano, Michael Tuen, Miroslaw K. Gorny, and Catarina E. Hioe. In Vivo Alteration of Humoral Responses to HIV-1 Envelope Glycoprotein gp120 by Antibodies to the CD4-Binding Site of gp120. Virology, 372(2):409-420, 15 Mar 2008. PubMed ID: 18054978. Show all entries for this paper.

Wang2007a Bao-Zhong Wang, Weimin Liu, Sang-Moo Kang, Munir Alam, Chunzi Huang, Ling Ye, Yuliang Sun, Yingying Li, Denise L. Kothe, Peter Pushko, Terje Dokland, Barton F. Haynes, Gale Smith, Beatrice H. Hahn, and Richard W. Compans. Incorporation of High Levels of Chimeric Human Immunodeficiency Virus Envelope Glycoproteins into Virus-Like Particles. J. Virol., 81(20):10869-10878, Oct 2007. PubMed ID: 17670815. Show all entries for this paper.

Wu2008 Xueling Wu, Anna Sambor, Martha C. Nason, Zhi-Yong Yang, Lan Wu, Susan Zolla-Pazner, Gary J. Nabel, and John R. Mascola. Soluble CD4 Broadens Neutralization of V3-Directed Monoclonal Antibodies and Guinea Pig Vaccine Sera against HIV-1 Subtype B and C Reference Viruses. Virology, 380(2):285-295, 25 Oct 2008. PubMed ID: 18804254. Show all entries for this paper.

Wu2010 Xueling Wu, Zhi-Yong Yang, Yuxing Li, Carl-Magnus Hogerkorp, William R. Schief, Michael S. Seaman, Tongqing Zhou, Stephen D. Schmidt, Lan Wu, Ling Xu, Nancy S. Longo, Krisha McKee, Sijy O'Dell, Mark K. Louder, Diane L. Wycuff, Yu Feng, Martha Nason, Nicole Doria-Rose, Mark Connors, Peter D. Kwong, Mario Roederer, Richard T. Wyatt, Gary J. Nabel, and John R. Mascola. Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1. Science, 329(5993):856-861, 13 Aug 2010. PubMed ID: 20616233. Show all entries for this paper.

Xu2010 Hengyu Xu, Likai Song, Mikyung Kim, Margaret A. Holmes, Zane Kraft, George Sellhorn, Ellis L. Reinherz, Leonidas Stamatatos, and Roland K. Strong. Interactions between Lipids and Human Anti-HIV Antibody 4E10 Can Be Reduced without Ablating Neutralizing Activity. J. Virol., 84(2):1076-1088, Jan 2010. PubMed ID: 19906921. Show all entries for this paper.

Yamamoto2008 Hiroyuki Yamamoto and Tetsuro Matano. Anti-HIV Adaptive Immunity: Determinants for Viral Persistence. Rev. Med. Virol., 18(5):293-303, Sep-Oct 2008. PubMed ID: 18416450. Show all entries for this paper.

Yang2010a Qiang Yang, Cishan Li, Yadong Wei, Wei Huang, and Lai-Xi Wang. Expression, Glycoform Characterization, and Antibody-Binding of HIV-1 V3 Glycopeptide Domain Fused with Human IgG1-Fc. Bioconjug. Chem., 21(5):875-883, 19 May 2010. PubMed ID: 20369886. 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.

York2001 J. York, K. E. Follis, M. Trahey, P. N. Nyambi, S. Zolla-Pazner, and J. H. Nunberg. Antibody binding and neutralization of primary and T-cell line-adapted isolates of human immunodeficiency virus type 1. J. Virol., 75(6):2741--52, Mar 2001. URL: http://jvi.asm.org/cgi/content/full/75/6/2741. PubMed ID: 11222697. Show all entries for this paper.

Yoshimura2006 Kazuhisa Yoshimura, Junji Shibata, Tetsuya Kimura, Akiko Honda, Yosuke Maeda, Atsushi Koito, Toshio Murakami, Hiroaki Mitsuya, and Shuzo Matsushita. Resistance Profile of a Neutralizing Anti-HIV Monoclonal Antibody, KD-247, that Shows Favourable Synergism with Anti-CCR5 Inhibitors. AIDS, 20(16):2065-2073, 24 Oct 2006. PubMed ID: 17053352. Show all entries for this paper.

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Yu2018 Wen-Han Yu, Peng Zhao, Monia Draghi, Claudia Arevalo, Christina B. Karsten, Todd J. Suscovich, Bronwyn Gunn, Hendrik Streeck, Abraham L. Brass, Michael Tiemeyer, Michael Seaman, John R. Mascola, Lance Wells, Douglas A. Lauffenburger, and Galit Alter. Exploiting Glycan Topography for Computational Design of Env Glycoprotein Antigenicity. PLoS Comput. Biol., 14(4):e1006093, Apr 2018. PubMed ID: 29677181. Show all entries for this paper.

Yuste2006 Eloisa Yuste, Hannah B. Sanford, Jill Carmody, Jacqueline Bixby, Susan Little, Michael B. Zwick, Tom Greenough, Dennis R. Burton, Douglas D. Richman, Ronald C. Desrosiers, and Welkin E. Johnson. Simian Immunodeficiency Virus Engrafted with Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Epitopes: Replication, Neutralization, and Survey of HIV-1-Positive Plasma. J. Virol., 80(6):3030-3041, Mar 2006. PubMed ID: 16501112. Show all entries for this paper.

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Zolla-Pazner1999b S. Zolla-Pazner, M. K. Gorny, and P. N. Nyambi. The implications of antigenic diversity for vaccine development. Immunol. Lett., 66:159-64, 1999. PubMed ID: 10203049. Show all entries for this paper.

Displaying record number 777

Download this epitope record as JSON.

MAb ID	F240
HXB2 Location	gp160(592-606) DNA(7998..8042)	gp160 Epitope Map
Author Location	gp41(592-606 BH10)
Research Contact	L. Cavacina or M. Posner, Dept. of Med. Harvard Med. School, Boston MA, USA
Epitope	`LLGIWGCSGKLICTT`	Epitope Alignment
Ab Type	gp41 cluster I
Neutralizing	no
Species (Isotype)	human(IgG1κ)
Patient
Immunogen	HIV-1 infection
Keywords	ADCC, antibody binding site, antibody generation, antibody interactions, antibody sequence, assay or method development, binding affinity, co-receptor, dendritic cells, enhancing activity, genital and mucosal immunity, glycosylation, immunoprophylaxis, isotype switch, neutralization, NK cells, review, structure, vaccine antigen design, variant cross-reactivity, viral fitness and reversion

Notes

Showing 36 of 36 notes.

F240: Structural studies reveal details of the F240-gp41 interface and describe a structure of the disulfide loop region that is distinct from known conformations of this region studied in the context of either CD4-unliganded Env trimer or the gp41 peptide in the unbound state. These data, coupled with binding and functional analyses, indicate that F240 recognizes non-trimeric Env forms which are significantly overexpressed on intact virions but poorly represented at surfaces of cells infected with infectious molecular clones and endogenously-infected CD4 T cells. Although ADCC activities of F240 were detected against cells with intact virions, the data suggest that these activities result from F240 recognition of gp41 stumps or misfolded Env variants present on virions rather than its ability to recognize functional gp41 transition structures emerging on trimeric Env post CD4 receptor engagement. Gohain2016 (ADCC, antibody binding site)
F240: The study identified a primary HIV-1 Env variant from patient 653116 that consistently supports >300% increased viral infectivity in the presence of autologous or heterologous HIV-positive plasma. In the absence of HIV-positive plasma, viruses with this Env exhibited reduced infectivity that was not due to decreased CD4 binding. This phenotype was mapped to a change Q563R, in the gp41 heptad repeat 1 (HR1) region. The authors provide evidence that Q563R reduces viral infection by disrupting formation of the gp41 six-helix bundle required for virus-cell membrane fusion. Anti-cluster I monoclonal antibodies (240-D, 246-D, F240, T32) targeting HR1 and the C-C loop of gp41 restored infectivity defects observed with Q563R. Viruses with the Q563R mutation were shown to have increased sensitivity to MPER mAbs (10E8, 7H6, 2F5, Z13e1, 4E10). Joshi2020 (viral fitness and reversion)
F240: 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 F240 recognized L193A variants of CH58 and CH77 IMCs with a significant increase compared to the WT. Ab F240 had modest ADCC activity on cells infected with one of 3 strains tested. Prevost2018 (ADCC)
F240: 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 non-NAb F240, 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)
F240: 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)
F240: 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. F240, N5-U1, N5-U3, N10-U1, M785-U1, and 7B2 were selected Abs that recognize gp41. Ding2015 (ADCC)
F240: 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. Three non-nAb combinations were assayed: 7B2/CH58/CH90, 7B2/CH58/CH22, and F240/M785-U1/N10-U1. Cheeseman2017 (genital and mucosal immunity, immunoprophylaxis)
F240: 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)
F240: 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
F240: Two clade C recombinant Env glycoprotein trimers, DU422 and ZM197M, with native-like structural and antigenic properties involving epitopes against all known classes of bNAbs, were produced and characterized. These Clade C trimers (10-15% of which are in a partially open form) were more like B41 Clade B trimers which have 50-75% trimers in the partially open configuration than like B505 Clade B trimers, almost 100% in the closed, prefusion state. The Clade C trimers have no affinity for the gp41_ECTO non-NAb, F240. Julien2015 (assay or method development, structure)
F240: 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-gp41 non-NAb F240 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)
F240: This study described a natural interaction between Abs and mucin protein, especially, MUC16 that is enhanced in chronic HIV infection. Agalactosylated (G0) Abs demonstrated the highest binding to MUC16. Binding of Abs to epithelial cells was diminished following MUC16 knockdown, and the MUC16 N-linked glycans were critical for binding.These point to a novel opportunity to enrich Abs at mucosal sites by targeting Abs to MUC16 through changes in Fc glycosylation, potentially blocking viral movement. In F240 differential G0 content was linked to MUC16 binding supporting a role for G0 glycosylation in preferential MUC16 binding, independent of antigen specificity (Fig: S4). Gunn2016 (antibody interactions, glycosylation)
F240: 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). Non-nAb, F240, did not react to any of the immunogens. Yasmeen2014 (antibody binding site, assay or method development)
F240: This study developed a whole blood ADCC assay that measures NK cell activation in response to HIV peptide epitopes. An HIV-1 subtype B linear ADCC peptide in the HIV-1 Vpu protein (sequence EMGHHAPWDVDDL) was used. These ADCC responses are associated with escape from immune recognition and represent vaccine antigens. The mechanism by which these epitopes are expressed and their function is not understood. The peptide-associated granulocytes become a specific target for ADCC. F240 and an anti-IgA receptor (CD89) antibody were effective at directing neutrophils to destroy HIV. Madhavi2013 (ADCC, assay or method development, NK cells)
F240: 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.F240 showed ˜60% capacity. Liu2014 (binding affinity)
F240: The effect of low pH and HIV-1 Abs which increased the transcytosis of the virus by 20 fold, has been reported. This enhanced transcytosis was due to the Fc neonatal receptor (FcRn), which facilitates HIV-1's own transmission by usurping Ab responses directed against itself. Viruses transcytosed by poorly neutralizing F240 at pH 6.0 were more infectious than those by non-FcRn binding pathway. Gupta2013
F240: 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. F240 wwas used as an anti-gp41 mAb to compare its binding with other PGT151 family Abs. Blattner2014
F240:The capacity of F240 to block completely the activity of the anti-HIV peptide T20 was investigated. T20 inhibited the fusion or syncytia formation between co-cultured CHO-WT cells expressing HIV-1 HXB2 envelope glycoprotein on their surface and HeLaT4 cells. F240 was not able to block the anti-fusion effect of T20. Vincent2012 (antibody interactions)
F240: Human MAbs b12 and b6 against CD4bs on HIV-1 gp120 and F240 against an immundominant epitope on gp41 were assessed for prevention of vaginal transmission of simian SHIV-162P4 to macaques. Applied vaginally at a high dose, F240 provided sterilizing immunity in 2/5 animals. This was not significant, but there was a trend toward lowered viremia. The potential protective effect of F240 may relate to the relatively strong ability of this antibody to capture infectious virions. Burton2011 (immunoprophylaxis, neutralization, binding affinity)
F240: Unlike the MPER MAbs tested, F240 did not show any Env-independent virus capture in the conventional or in the modified version of the virus capture assay. Leaman2010
F240: F240 recognized trimeric, dimeric and monomeric forms of cross-linked sgp140(-) Env glycoprotein, indicating that the epitope of this MAb is accessible on different oligomeric forms of soluble envelope proteins. Yuan2009 (antibody binding site)
F240: Although a substantial increase in neutralization potency of MPER-specific Abs 4E10 and 2F5 was observed in cells expressing FcγR I and IIb, no such effect was observed for F240. Perez2009 (neutralization)
F240: The Ig usage for variable heavy chain of this Ab was as follows: IGHV:3-11*01, IGHD:3-22, D-RF:2, IGHJ:5. Non-V3 mAbs preferentially used the VH1-69 gene segment. In contrast to V3 mAbs, these non-V3 mAbs used several VH4 gene segments and the D3-9 gene segment. Similarly to the V3 mAbs, the non-V3 mAbs used the VH3 gene family in a reduced manner. Gorny2009 (antibody sequence)
F240: F240 neutralized infection of PBLs with various HIV-1 strains. However, F240 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 F240, 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)
F240: F240 reacted with maltose-binding protein MBP32, containing both HR1 and HR2 domains of gp41, and with MBP37, containing only the HR2 domain, but not with MBP-HR1, containing only the HR1 domain. Vincent2008 (antibody binding site)
F240: F240 Ab was produced in Chinese hamster ovary (CHO)-K1 cells as three different isotypes, F240-IgG1, F240-IgG3, and F240-IgG4. The produced Abs were shown to be equivalently immunoreactive with recombinant gp140 and primary isolate viruses as the parental F240. In contrast to parental F240, F240-IgG1 from CHO cells was able to neutralize the majority of tier 1 and 2 clade B isolates, and two clade C tier 2 isolates. Clade A tier 2 isolates were not neutralized by this Ab. F240-IgG3 isotype was most potent in neutralizing the virus, while F240-IgG4 was less able to neutralize infection. There were no differences found in the sequences of the L and H chain variable regions of all the F240 Abs, but there was an increase in glycans associated with the Abs generated in CHO cells. PNGase F treatment, which removes all types of N-linked glycosylation, did not affect binding properties of CHO-derived F240 Abs, but it significantly abolished the neutralizing activity of F240 with isolate 89.6. PNGase F-treatment had no effect on the neutralization of SF162 and 93MW960 isolates, while it was required to neutralize the 67970 isolate by F240-IgG1 Ab. Miranda2007 (isotype switch, neutralization, binding affinity, antibody sequence)
F240: 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. F240 showed a decrease in binding to the LLP-2 mutant compared to the wildtype virus, indicating that its epitope was altered by the mutation. Kalia2005 (antibody binding site, binding affinity)
F240: This Ab was shown to inhibit HIV-1 BaL replication in macrophages but not in PHA-stimulated PBMCs. It is suggested that inhibition of HIV replication by this Ab for macrophages and iDCs occurs by an IgG-FcγR-dependent interaction leading to endocytosis and degradation of HIV particles. It is also suggested that this Ab is directed against epitopes distinct from those recognized by NAbs and that it will not impair virus entry into PBMCs but that it could participate in the protection of mucosal HIV transmission by preventing the infection of macrophages and iDCs. Holl2006 (neutralization, dendritic cells)
F240: Transduction of human CD4+ H9 T cells with both the intracellularly expressed and secreted forms of the single-chain F240 Ab inhibited MN virus production. The secreted form was more potent. Viral replication of HIV-1 primary isolates was not reduced. Liu2005
F240: One of 24 MAbs and Fabs in this database that bind to the highly immunogenic gp41 cluster I region (aa 579 - 604). Only one of these has any neutralizing potential, clone 3. Gorny2003 (review)
F240: Anti-gp41 MAbs were tested in a cell-cell fusion system to investigate the antigenic changes in gp41 during binding and fusion. Cluster I MAbs 50-69, F240, 240-D,3D6, and 246-D recognize a nonhelical hydrophobic region, positions 598-604, that forms a disulfide loop in the six-helix bundle. Cluster II MAbs 98-6 and 126-6 recognized residues 644-663 of gp41, a portion of the second heptad repeat. These MAbs were found to behave similarly, so 50-69 and 98-6 were used as representatives. Exposure of cluster I and cluster II epitopes required CD4 expression on HIV HXB2 Env expressing HeLa target cells, but not the CXCR4 co-receptor. Binding to CD4 exposed hidden cluster I and II epitopes. The MAbs were found to bind to gp120/gp41 complexes, not to gp41 after shedding of gp120, and were localized to at fusing-cell interfaces. Kinetic and binding results indicate that these MAbs are exposed in transitional structures during the fusion process, possibly the prehairpin intermediate prior to co-receptor binding, although other intermediate structures may be involved. They do not bind once syncytia begin to show extensive cytoplasmic mixing. These MAbs failed to inhibit fusion. The NAb 2F5 has a very different behavior in this study. Finnegan2002 (antibody binding site)
F240: Alanine mutations were introduced into the N- and C-terminal alpha-helices of gp41 to destabilize interhelical packing interactions in order to study their inhibitory effect on viral infectivity. These mutations were shown to inhibit viral replication though affecting the conformational transition to the fusion-active form of gp41, and allow increased inhibition by gp41 peptides. 2F5 sensitivity is increased in the mutated viruses, presumably because 2F5s neutralization activity is focused on the transition to the fusion active state. No other gp41 MAb against tested, including NC-1, 50-69D, 1281, 98-6D, 246-D and F240, neutralized the parental or the fusion-deficient mutated viruses. Follis2002 (antibody binding site)
F240: The MAb B4e8 binds to the base of the V3 loop, neutralizes multiple primary isolates and was studied for interaction with other MAbs. Anti-gp41 MAb F240 could inhibit B4e8 neutralization. Cavacini2003 (antibody interactions)
F240: 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, with the exception of F240 which bound both equally well, which captured more virus than any other human MAb tested, and didn't neutralize either isolate.F240 enhanced the binding of CD4BS MAbs IgG1b12 and F105 and the gp41 MAb 2F5 for both R5X4 and R5 isolates. F240 binding to gp41 was not affected by the binding of the V3 loop MAb B4a1, but preincubation with F240 could enhance B4a1 binding of the R5 isolate. Synergistic neutralization between F240 and CD4i MAbs 17b and 48d was noted for the R5X4 but not the R5 isolate, and F240 also enhanced neutralization of the R5X4 isolate by 2F5, but had no effect on R5 virus. In contrast, F240 combined with 2G12 demonstrated enhanced neutralization of R5 virus at low Ab concentrations. Cavacini2002 (antibody interactions, co-receptor)
F240: Abs against the V3 loop (50.1, 58.2, 59.1, 257-D, 268-D, 447-52D), CD4BS (IgG1b12, 559-64D, F105), CD4i (17b), and to gp41 (2F5, F240) each showed similar binding efficiency to Env derived from related pairs of primary and TCLA lines (primary: 168P and 320SI, and TCLA: 168C and 320SI-C3.3), but the TCLA lines were much more susceptible to neutralization suggesting that the change in TCLA lines that make them more susceptible to NAbs alters some step after binding. York2001 (variant cross-reactivity)
F240: Distinct from MAb 240-D, an antibody with a similar epitope in the immunodominant region of gp41. Isolated from spleen cells from a patient undergoing splenectomy. Dose-dependent reactivity with HIV isolates RF, SF2, IIIB, and MN was observed. F240 had no neutralizing activity and enhances infection in the presence of complement. Reactivity of F240 is enhanced by preincubation of cells with sCD4 or anti-CD4BS MAb F105. Heavy and light chain variable domains were sequenced, and a strong homology to hu MAb 3D6 was observed, as 3D6 binds to the same epitope, these MAbs may define a human Ab clonotype. Cavacini1998a (antibody generation, enhancing activity, variant cross-reactivity, antibody sequence)

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Displaying record number 2655

Download this epitope record as JSON.

MAb ID	CH01
HXB2 Location	gp160	gp160 Epitope Map
Author Location	gp160(126-196)
Epitope
Subtype	A
Ab Type	gp120 V2 // V2 glycan(V2g) // V2 apex, quaternary structure
Neutralizing	P View neutralization details
Contacts and Features	View contacts and features
Species (Isotype)	human(IgG1)
Patient	CH0219
Immunogen	HIV-1 infection
Keywords	antibody binding site, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, assay or method development, autoantibody or autoimmunity, binding affinity, broad neutralizer, computational epitope prediction, escape, glycosylation, junction or fusion peptide, memory cells, neutralization, review, structure, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity

Notes

Showing 37 of 37 notes.

CH01: 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)
CH01: Extensive structural and biochemical analyses demonstrated that PGT145 achieves recognition and neutralization by targeting quaternary structure of the cationic trimer apex with long and unusually stabilized anionic β-hairpin HCDR3 loops. In BG505.Env.C2 alanine-scanning neutralization assays, CH01 had similar results as PG9, consistent with both CH01 and PG9 being members of hammerhead-class, and very dissimilar results to PGT145-like antibodies. Lee2017 (antibody binding site, neutralization)
CH01: 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)
CH01: 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)
CH01: 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. CH01 was used for analyzing clade sensitivity, structural mapping and analyses of Ab signatures. Bricault2019 (antibody binding site, vaccine antigen design, computational epitope prediction, broad neutralizer)
CH01: 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)
CH01: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. Recombinant native-like HIV Env trimers have enabled the identification of CH01, a potent ‘PG9-class’ bNAb. Antigenic region V2 apex (Table:1). Walker2018 (antibody binding site, review, broad neutralizer)
CH01: 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)
CH01: 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)
CH01: 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)
CH01: 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 CH01 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)
CH01: Assays of poly- and autoreactivity demonstrated that broadly neutralizing NAbs are significantly more poly- and autoreactive than non-neutralizing NAbs. CH01 is neither autoreactive nor polyreactive. Liu2015a (autoantibody or autoimmunity, antibody polyreactivity)
CH01: 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)
CH01: This review classified and mapped the binding regions of 32 bNAbs isolated 2010-2016. Wu2016 (review)
CH01: 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 CH01 to trimers was minimally affected by trimer cross-linking. Schiffner2016 (assay or method development, binding affinity, structure)
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 CH01, 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)
CH01: 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. CH01, a V2-glycan bnAb belonged to a group with slopes <1. Webb2015 (neutralization)
CH01: 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 germline 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-CH01 precursor bound to 2/3 trimers, BG505 and B41. Sliepen2015 (binding affinity, antibody lineage)
CH01: 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. CH01 neutralized 50% of the 199 viruses tested. Hraber2014 (neutralization)
CH01: 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. Andrabi2015 (antibody binding site, neutralization, vaccine antigen design, antibody lineage)
CH01: 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. CH01 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)
CH01: 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)
CH01: The V2 region where CH01, an anti-V1V2 bNAb binds exists as a beta-strand. Haynes2013 (review)
CH01: 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. CH01 showed IVCI of 2.4 and captured 3 out of the 4 strains tested. Liu2014 (binding affinity)
CH01: Binding properties of a synthesized V1V2 glycopeptide immunogen that selectively targets bnAbs' naive B cells is reported. The unmutated common ancestor (UCA) of CH01 showed nanomolar affinity to V1V2 bearing Man₅GlcNAc₂ glycan units. Binding of CH01 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 CH01 binding to V1V2. Alam2013 (glycosylation)
CH01: 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)
CH01: 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
CH01: 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. CH01 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. Liao2013b (antibody binding site)
CH01: "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)
CH01: 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, CH01 family. Kwong2012 (review, structure, broad neutralizer)
CH01: 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)
CH01: 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)
CH01: 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. CH01 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)
CH01: The use of computationally derived B cell clonal lineages as templates for HIV-1 immunogen design is discussed. CH01 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)
CH01: Antigenic properties of undigested VLPs and endo H-digested WT trimer VLPs were compared. Binding to E168K+ N189A WT VLPs was merely a trend of better antibody binding compared to the parent WT VLPs, uncleaved VLPs. There was no significant correlation between E168K+N189A WT VLP binding and CH01 neutralization. Tong2012 (neutralization, binding affinity)
CH01: This is the first isolation of two clonal lineages of bnAbs with distinct specificities from memory B-cells of a single individual CH0219, whose plasma displays broad and potent neutralization. bnAbs CH01 and VRC-CH31 largely recapitulate the breadth of the donor’s serum neutralization and together achieve near pan-HIV-1 neutralization (95% of 91 strains neutralized by this donor's serum). This suggests that a vaccine capable of inducing bnAbs against both the CD4bs and the V1V2 conformational epitope could achieve broader HIV-1 neutralization than a vaccine inducing only one of the two specificities, and provides proof-of-concept supporting the design of polyvalent vaccines. Bonsignori2012 (neutralization)
CH01: Clonal lineage of four V2/V3 conformational epitope broadly neutralizing antibodies (CH01 to CH04) from an African HIV-1-infected broad neutralizer was identified. Common reverted unmutated ancestor (RUA) antibodies were inferred. CH01 neutralized 46% of 91 isolates from major clades, while the RUAs neutralized only 16% of HIV-1 isolates. The RUAa however retained the ability to bind to the E.A244 gp120 HIV-1 envelope with an affinity predicted to trigger B cell development. MAbs CH01 to CH04 recognized a PG9/PG16-like conformational epitope. Despite notable similarities, differences in breadths of neutralization and sensitivities to amino acids at positions 127, 159, 171, and 181 indicated either that MAbs CH01 to CH04 bind to a discretely different epitope or that they approach the same epitopes of PG9 and PG16 but in a different orientation. MAb CH03 was autoreactive for ribonucleoprotein, centromere B, and histone antigens, and MAbsCH01 to CH03 were polyreactive with the hepatitis C virus E2 protein and gut flora antigens, raising the possibility that MAbs CH01 to CH04 may be subjected to tolerance mechanisms. Bonsignori2011 (antibody binding site, antibody generation, neutralization, antibody polyreactivity, broad neutralizer)

References

Showing 37 of 37 references.

Isolation 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.

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.

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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.

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.

Displaying record number 2165

Download this epitope record as JSON.

MAb ID	VRC03 (VRC03_d45)
HXB2 Location	gp160	gp160 Epitope Map
Author Location	gp120
Epitope
Subtype	B
Ab Type	gp120 CD4BS
Neutralizing	P View neutralization details
Contacts and Features	View contacts and features
Species (Isotype)	human(IgG1)
Patient	NIH45
Immunogen	HIV-1 infection
Keywords	ADCC, adjuvant comparison, antibody binding site, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autoantibody or autoimmunity, binding affinity, broad neutralizer, computational epitope prediction, escape, germline, glycosylation, immunotherapy, kinetics, memory cells, neutralization, polyclonal antibodies, review, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity

Notes

Showing 44 of 44 notes.

VRC03: This study demonstrated that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens eliciting Ab responses with greater neutralization breadth. Data from four large virus panels were used to comprehensively map viral signatures associated with bNAb sensitivity, hypervariable region characteristics, and clade effects. The bNAb signatures defined for the V2 epitope region were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine which resulted in increased breadth of NAb responses compared with Env 459C alone. VRC03 was used for analyzing clade sensitivity. Bricault2019 (antibody binding site, vaccine antigen design, computational epitope prediction, broad neutralizer)
VRC03: The influence of a V2 State 2/3-stabilizing Env mutation, L193A, on ADCC responses mediated by sera from HIV-1-infected individuals was evaluated. Conformations spontaneously sampled by the Env trimer at the surface of infected cells had a significant impact on ADCC. State 1-preferring ligand VRC03 recognized L193A variants of CH58 and CH77 IMCs with less efficiently compared to the WT. Prevost2018 (ADCC)
VRC03: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. VRC03 was isolated from human B cell clones and is functionally similar to VRC01. Antigenic region CD4 binding site (Table:1) Walker2018 (antibody binding site, review, broad neutralizer)
VRC03: A panel of bnAbs were studied to assess ongoing adaptation of the HIV-1 species to the humoral immunity of the human population. Resistance to neutralization is increasing over time, but concerns only the external glycoprotein gp120, not the MPER, suggesting a high selective pressure on gp120. Almost all the identified major neutralization epitopes of gp120 are affected by this antigenic drift, suggesting that gp120 as a whole has progressively evolved in less than 3 decades. Bouvin-Pley2014 (neutralization)
VRC03: Assays of poly- and autoreactivity demonstrated that broadly neutralizing NAbs are significantly more poly- and autoreactive than non-neutralizing NAbs. VRC03 is neither autoreactive nor polyreactive. Liu2015a (autoantibody or autoimmunity, antibody polyreactivity)
VRC03: This study describes a computational method to calculate the binding affinities of antibodies and antigens. The method called free-energy perturbation (FEP) was developed using HIV-1 Env gp120 and 3 VRC01-class mAbs, VRC01, VRC03, and VRC-PG04. Clark2017 (binding affinity, structure)
VRC03: This study performed cyclical permutation of the V1 loop of JRFL in order to develop better gp120 trimers to elicit neutralizing antibodies. Some mutated trimers showed improved binding to several mAbs, including VRC01, VRC03, VRC-PG04, PGT128, PGT145, PGDM1400, b6, and F105. Guinea pigs immunized with prospective trimers showed improved neutralization of a panel of HIV-1 pseudoviruses. Kesavardhana2017 (vaccine antigen design, vaccine-induced immune responses)
VRC03: This study investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit NAbs. Rabbits were immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). N197 glycan- and residue 230- removal conferred sensitivity to Trimer VLP sera and DNA trimer sera respectively, showing for the first time that strain-specific holes in the "glycan fence" can allow the development of tier 2 NAbs to native spikes. All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. All the neutralizing rabbit sera showed significant competition with CD4bs mAbs VRC03, VRC07, b12 and 1F7. Crooks2015 (glycosylation, neutralization)
VRC03: Env residue N197 on the BG505-SOSIP trimer was mutated to test the effect of its glycosylation on the binding kinetics of CD4BS and other mAbs. Removal of the glycan had little effect on the overall structure of the molecule. Its removal resulted in increased binding of CD4 and CD4BS antibodies (VRC01, VRC03, V3-3074), but little effect on bNAbs targeting other epitopes (PG9, PG16, PGT145, 17b, A32, 2G12, PGT121, PGT126). Two CD4BS-binding antibodies tested (b12, F105) had insufficient breadth to bind the BG505-SOSIP trimer. Removal of the N197 glycan may allow for the development of better SOSIP immunogens, particularly to elicit CD4BS-specific Abs. Liang2016 (glycosylation, vaccine antigen design)
VRC03: Somatic hypermutation and affinity maturation improve an antibody's complementarity with its target epitope. Mass spectroscopy and X-ray structures were used to examine two classes of mAbs, CD4 binding Abs (VRC03, VRC-PG04) and V2 binding Abs (VRC26.01, VRC26.03, VRC26.10, PG16, CH03), to determine how specific mutations that occurred during maturation affected the binding of the mAbs to their target epitope. Davenport2016 (structure, antibody lineage)
VRC03: Env trimer BG505 SOSIP.664 as well as the clade B trimer B41 SOSIP.664 were stabilized using a bifunctional aldehyde (glutaraldehye, GLA) or a heterobifunctional cross-linker, EDC/NHS with modest effects on antigenicity and barely any on biochemistry or structural morphology. ELISA, DSC and SPR were used to test recognition of the trimers by bNAbs, which was preserved and by weakly NAbs or non-NAbs, which was reduced. Cross-linking partially preserves quaternary morphology so that affinity chromatography by positive selection using quaternary epitope-specific bNAabs, and negative selection using non-NAbs, enriched antigenic characteristics of the trimers. Binding of the anti-CD4bs bNAb VRC03 to trimers was minimally affected by trimer cross-linking. Schiffner2016 (assay or method development, binding affinity, structure)
VRC03: A new trimeric immunogen, BG505 SOSIP.664 gp140, was developed that bound and activated most known neutralizing antibodies but generally did not bind antibodies lacking neuralizing activity. This highly stable immunogen mimics the Env spike of subtype A transmitted/founder (T/F) HIV-1 strain, BG505. Anti-CD4bs bNAb VRC03 neutralized BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, and was shown to recognize and bind the immunogen too. Sanders2013 (assay or method development, neutralization, binding affinity)
VRC03: This study described a natural interaction between Abs and mucin protein, especially, MUC16 that is enhanced in chronic HIV infection. Agalactosylated (G0) Abs demonstrated the highest binding to MUC16. Binding of Abs to epithelial cells was diminished following MUC16 knockdown, and the MUC16 N-linked glycans were critical for binding.These point to a novel opportunity to enrich Abs at mucosal sites by targeting Abs to MUC16 through changes in Fc glycosylation, potentially blocking viral movement. VRC03 produced in either wild-type or FUT8kd 293T cells to produce fucosylated or afucosylated Abs, respectively, was assayed for MUC16 binding by ELISA. Gunn2016
VRC03: This study examined the neutralization of group N, O, and P primary isolates of HIV-1 by diverse antibodies. Cross-group neutralization was observed only with the bNAbs targeting the N160 glycan-V1/V2 site. Four group O isolates, 1 group N isolate, and the group P isolates were neutralized by PG9 and/or PG16 or PGT145 at low concentrations. None of the non-M primary isolates were neutralized by bNAbs targeting other regions, except 10E8, which weakly neutralized 2 group N isolates, and 35O22 which neutralized 1 group O isolate. Bispecific bNAbs (PG9-iMab and PG16-iMab) very efficiently neutralized all non-M isolates with IC₅₀ below 1 ug/mL, except for 2 group O strains. Anti-CD4bs bNAb VRC03 was unable to neutralize any of the 16 tested non-M primary isolates at an IC₅₀< 10µg/ml. Morgand2015 (neutralization, subtype comparisons)
VRC03: The rate of maturation and extent of diversity for the VRC01 lineage were characterized through longitudinal sampling of peripheral B cell transcripts from donor 45 over 15 years and co-crystal structures. VRC01-lineage clades underwent continuous evolution, with rates of ˜2 substitutions per 100 nucleotides per year, comparable with HIV-1 evolution. 39 VRC01-lineage Abs segregated into three major clades, and all Abs from donor 45 contained a cysteine at position 98 (99 in some sequences due to a 1-aa insertion) which was used as a signature to assess membership in the VRC01 lineage. Of 1,041 curated NGS sequences assigned to the VRC01 lineage, six did not contain the cysteine while 1,035 did (99.4%). For this Ab CDR H3 length is 14 and VH changes 30%, Vk nucleotide change is 20%. Wu2015 (antibody lineage)
VRC03: The human Ab gene repertoires of uninfected and HIV-1-infected individuals were studied at genomic DNA (gDNA) and cDNA levels to determine the frequencies of putative germline Ab genes of known HIV-1 bnAbs. All libraries were deep sequenced and analysed using IMGT/HighV-QUEST software (http://imgt.org/HighV-QUEST/index. The human gDNA Ab libraries were more diverse in heavy and light chain V-gene lineage usage than the cDNA libraries. This implied that the human gDNA Ab gene repertoires may have more potential than the cDNA repertoires to develop HIV-1 bnmAbs. Relatively high frequencies of the VH and VKs and VLs that used the same V-genes and had the same CDR3 lengths as known HIV-1 bnmAbs regardless of (D)J-gene usage. The putative germline genes were determined for a set of mAbs (b12, VRC01, VRC03, NIH45-46, 3BNC60, PG9, PGT127, and X5). Zhang2013 (antibody lineage, germline)
VRC03: The effect of PNGS on viral infectivity and antibody neutralization (2F5, 4E10, b12, VRC01, VRC03, PG9, PG16, 3869) was evaluated through systemic mutations of each PNGS on CRF07_BC strain. Mutations at N197 (C2), N301 (V3), N442 (C4), and N625 (gp41) rendered the virus more susceptible to neutralization by MAbs that recognize the CD4 binding site or gp41. Generally, mutations on V4/V5 loops, C2/C3/C4 regions, and gp41 reduced the neutralization sensitivity to PG16. However, mutation of N289 (C2) made the virus more sensitive to both PG9 and PG16. Mutations at N142 (V1), N355 (C3) and N463 (V5) conferred resistance to neutralization by anti-gp41 MAbs. Available structural information of HIV Env and homology modeling was used to provide a structural basis for the observed biological effects of these mutations. Wang2013 (neutralization, structure)
VRC03: The ability of bNAbs to inhibit the HIV cell entry was tested for b12, VRC01,VRC03, PG9, PG16, PGT121, 2F5, 10E8, 2G12. Among them, PGT121, VRC01, and VRC03 potently inhibited HIV entry into CD4+ T cells of infected individuals whose viremia was suppressed by ART. Chun2014 (immunotherapy)
VRC03: Cross-group neutralization of HIV-1 isolates from groups M, N, O, and P was tested with diverse patient sera and bNAbs PG9, PG16, 4E10, b12, 2F5, 2G12, VRC01, VRC03, and HJ16. The primary isolates displayed a wide spectrum of sensitivity to neutralization by the human sera, with some cross-group neutralization clearly observed. Among the bNAbs, only PG9 and PG16 showed any cross-group neutralization. The group N prototype strain YBF30 was highly sensitive to neutralization by PG9, and the interaction between their key residues was confirmed by molecular modeling. The conservation of the PG9/PG16 epitope within groups M and N suggests its relevance as a vaccine immunogen. Braibant2013 (neutralization, variant cross-reactivity)
VRC03: VCRC03 was one of 10 MAbs used to study chronic vs. consensus vs. transmitted/founder (T/F) gp41 Envs for immunogenicity. Consensus Envs were the most potent eliciters of response but could only neutralize tier 1 and some tier 2 viruses. T/F Envs elicited the greatest breadth of NAb response; and chronic Envs elicited the lowest level and narrowest response. This CD4BS binding Nab bound well at <10 nM to 1/5 chronic Envs, 0/6 Consensus Envs and 3/7 T/F Envs. It was the only antibody unable to bind Consensus-S gp140 Env. Liao2013c (antibody interactions, binding affinity)
VRC03: A highly conserved mechanism of exposure of ADCC epitopes on Env is reported, showing that binding of Env and CD4 within the same HIV-1 infected cell effectively exposes these epitopes. The mechanism might explain the evolutionary advantage of downregulation of cell surface CD4v by the Vpu and Nef proteins. VRC03 was used in CD4 coexpression and competitive binding assay. Veillette2014 (ADCC)
VRC03_d45: The ontogeny of VRC01 class Abs was determined by enumerating VRC01-class characteristics in many donors by next-gen sequencing and X-ray crystallography. Analysis included VRC01 (donor NIH 45), VRC-PG04 (donor IAVI 74), VRC-CH31 (donor 0219), 3BNC117 (donor RU3), 12A21 (donor IAVI 57), and somatically related VRC-PG19,19b, 20, 20b MAbs from donor IAVI 23. Despite the sequence differences of VRC01-class Abs, exceeding 50%, Ab-gp120 cocrystal structures showed VRC01-class recognition to be remarkably similar. Zhou2013a (antibody sequence, structure, antibody lineage)
VRC03: Next generation sequencing was applied to a new donor C38 (different from donor NIH45) to identify VRC01 class bNAbs. VRC01 class heavy chains were selected through a cross-donor phylogenetic analysis. VRC01 class light chains were identified through a five-amino-acid sequence motif. (CDR L3 length of 5 amino acids and Q or E at position 96 (Kabat numbering) or position 4 within the CDR L3 sequence.) VRC03 was used to compare the heavy & light chain sequences as a template of VRC01 class Ab. Zhu2013a (antibody sequence)
VRC03: N276D was determined as the critical binding site of MAb HJ16 by resistance induction in a sensitive primary CRF02_AG strain. N-linked glycosylation site removing N276D mutation was responsible for resistance to HJ16 by site-directed mutagenesis in envs of the homologous CRF02_AG, as well as of a subtype A and a subtype C primary isolate. Sensitivity to the CD4bs VRC01 and VRC03 mAbs was increased in the N276D mutated viruses. Balla-Jhagjhoorsingh2013 (glycosylation)
VRC03: A computational method to predict Ab epitopes at the residue level, based on structure and neutralization panels of diverse viral strains has been described. This method was evaluated using 19 Env-Abs, including VRC03, against 181 diverse HIV-1 strains with available Ab-Ag complex structures. Chuang2013 (computational epitope prediction)
VRC03: "Neutralization fingerprints" for 30 neutralizing antibodies were determined using a panel of 34 diverse HIV-1 strains. 10 antibody clusters were defined: VRC01-like, PG9-like, PGT128-like, 2F5-like, 10E8-like and separate clusters for b12, CD4, 2G12, HJ16, 8ANC195. This mAb belongs to VRC01-like cluster. Georgiev2013 (neutralization)
VRC03: Cryoelectron tomography was used to determine structures of A12, m36, or m36/CD4 complexed to trimeric Env displayed on intact HIV-1 BaL virus. The steric interactions at the distal ends of the bound Ab moieties are likely to play a role in determining the rotation of gp120 as in A12 and b12 or without any quaternary structure change as in VRC03. Meyerson2013 (antibody binding site, structure)
VRC03: Isolation of VRC06 and VRC06b MAbs from a slow progressor donor 45 is reported. This is the same donor from whom bnMAbs VRC01, VRC03 and NIH 45-46 were isolated and the new MAbs are clonal variants of VRC03. VRC03 was used as a control to compare neutralizing specificity of VRC06. Li2012
VRC03: This is a comment on Tan2012. It is noted that Tran and colleagues used high-resolution 3D cryoelectron tomography to define the conformation of Env when bound to soluble CD4 and to a series of monoclonal antibodies. It was demonstrated that antibodies binding to the CD4 binding site or coreceptor binding site of Env may lead to significantly different conformations of the trimeric Env complex. VRC01 locks the complex in a closed conformation, while binding to soluble CD4 or the monoclonal antibody 17b fixed the trimer in an open conformation. Wright2012 (review, structure)
VRC03: Previous cryo-electron tomographic studies were extended. A more complete picture of the HIV entry process was presented by showing that HIV-1 Env binding to either soluble CD4 (sCD4) or the co-receptor mimic 17b leads to the same structural opening, or activation, of the Env spike. Atudy also demonstrated structurally that the broadly neutralizing antibodies VRC01, VRC02, VRC03 are able to block this activation, locking Env in a state that resembles closed, native Env. The cryo-electron microscopic structure of soluble trimeric Env in the 17b-bound state is presented at ˜9 Å resolution, revealing it as a novel, activated intermediate conformation of trimeric Env that could serve as a new template for immunogen design. Tran2012 (structure)
VRC03: A computational tool (Antibody Database) identifying Env residues affecting antibody activity was developed. As input, the tool incorporates antibody neutralization data from large published pseudovirus panels, corresponding viral sequence data and available structural information. The model consists of a set of rules that provide an estimated IC₅₀ based on Env sequence data, and important residues are found by minimizing the difference between logarithms of actual and estimated IC₅₀. The program was validated by analysis of MAb 8ANC195, which had unknown specificity. Predicted critical N-glycosylation for 8ANC195 were confirmed in vitro and in humanized mice. The key associated residues for each MAb are summarized in the Table 1 of the paper and also in the Neutralizing Antibody Contexts & Features tool at Los Alamos Immunology Database. West2013 (glycosylation, computational epitope prediction)
VRC03: Somatic hypermutations are preferably found in CDR loops, which alter the Ab combining sites, but not the overall structure of the variable domain. FWR of CDR are usually resistant to and less tolerant of mutations. This study reports that most bnAbs require somatic mutations in the FWRs which provide flexibility, increasing Ab breadth and potency. To determine the consequence of FWR mutations the framework residues were reverted to the Ab's germline counterpart (FWR-GL) and binding and neutralizing properties were then evaluated. Fig S4C described the comparison of Ab framework amino acid replacement vs. interactive surface area on VRC03. Klein2013 (neutralization, structure, antibody lineage)
VRC03: Antigenic properties of 2 biochemically stable and homogeneous gp140 trimers (A clade 92UG037 and C clade CZA97012) were compared with the corresponding gp120 monomers derived from the same percursor sequences. The trimers had nearly all the antigenic properties expected for native viral spikes and were markedly different from monomeric gp120. VRC03 has been discussed as NAb against CD4BS. Kovacs2012 (antibody binding site, neutralization, binding affinity)
VRC03: Existing structural and sequence data was analyzed. A set of signature features for potent VRC01-like (PVL) and almost PVL abs was proposed and verified by mutagenesis. VRC03 has been referred as an almost PVL in discussing the breadth and potency of antiCD4 abs. West2012a (antibody lineage)
VRC03: The use of computationally derived B cell clonal lineages as templates for HIV-1 immunogen design is discussed. VRC03 has been discussed in terms of immunogenic and functional characteristics of representative HIV-1 BnAbs and their reactions to antigens. Haynes2012 (antibody interactions, memory cells, vaccine antigen design, review, antibody polyreactivity, broad neutralizer)
VRC03: Polyclonal B cell responses to conserved neutralization epitopes are reported. Cross-reactive plasma samples were identified and evaluated from 308 subjects tested. VRC03 was used as a control mAb in the comprehensive set of assays performed. Plasma sample C1-0219 showed binding and neutralizing activities against native Env trimers similar to VRC03 and b12. D368R mutant trimers completely knocked out VRC03 and b12 but partially reduced C1-0219 binding. C1-0219 was unaffected by the W479G mutant suggesting that its nAbs are more akin to b12 than to VRC03. Tomaras2011 (neutralization, polyclonal antibodies)
VRC03: The rational design of vaccines to elicit broadly neutralizing antibodies to HIV-1 is discussed in relation to understanding of vaccine recognition sites, the structural basis of interaction with HIV-1 env and vaccine developmental pathways. Role of VRC03 has been discussed relating to humoral immune response during HIV1 infection and sites of HIV-1 vulnerability to neutralizing antibodies. VRC03 appears to target the site very effectively resulting in neutralization of ˜90% of circulating isolates. Kwong2011 (antibody binding site, neutralization, vaccine antigen design, review)
VRC03: In order to increase recognition of CD4 by Env and to elicit stronger neutralizing antibodies against it, two Env probes were produced and tested - monomeric Env was stabilized by pocket filling mutations in the CD4bs (PF2) and trimeric Env was formed by appending trimerization motifs to soluble gp120/gp14. PF2-containing proteins were better recognized by bNMAb against CD4bs and more rapidly elicited neutralizing antibodies against the CD4bs. Trimeric Env, however, elicited a higher neutralization potency that mapped to the V3 region of gp120. Feng2012 (neutralization)
VRC03: The strategy of incorporating extra glycans onto gp120 was explored, with the goal to occlude the epitopes of non-neutralizing MAbs while maintaining exposure of the b12 site. The focus was on the head-to-head comparison of the ability of 2 adjuvants, monophosphoryl lipid A (MPL) and Quil A, to promote CD4-specific Ab responses in mice immunized with the engineered mutant Q105N compared to gp120wt. Neutralizing and non-neutralizing antibodies targeting three areas on gp120 – the CD4bs (F105, b6, b12, b13, VRC01, VRC03 and CD4- IgG2), the glycosylated ‘silent face’ (2G12) and the V3 loop (B4e8) – were assessed for binding. The antibodies b6, b12, b13, VRC01 and 2G12 bound best to mutant Q105N, albeit with lower affinities than to gp120wt. Retention of b6 and b13 binding was not expected, but can be explained by their very similar mode of interaction with the CD4bs compared to b12. Abs F105 and VRC03 did not bind Q105N at all. The V3-specific antibody B4e8 did not bind to Q105N. Ahmed2012 (adjuvant comparison, antibody binding site, glycosylation, neutralization, escape)
VRC03: VRC01 and VRC03 selection pressures were studied using viral quasispecies from 3 time points (2001, 2006, 2009) in donor 45, from whom VRC01 and VRC03 were initially isolated, and from several time points in 5 additional donors with broadly serum neutralizing Abs. 473 Envs were assessed in total. While most plasma derived autologous Env variants from donor 45 were highly resistant to VRC01, some 2001 Env clones (which are all resistant to VRC01) were sensitive to VRC03 and its clonal relatives VRC06 and VRC06b, suggesting that these mAbs might have evolved at a time point later than VRC01. Wu2012 (escape)
VRC03: Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies was studied by isolation of VRC01-like neutralizers with CD4bs probe; structural definition of gp120 recognition by RSC3-identified antibodies from different donors; functional complementation of heavy and light chains among VRC01-like antibodies; identification of VRC01 antibodies by 454 pyrosequencing; and cross-donor phylogenetic analysis of sequences derived from the same precursor germline gene. VRC03 bound to YU2 gp120 wild type and several mutated proteins, HXB2 gp120 and antigenically resurfaced protein RSC3, but not bound to gp120 YU2 D368R, D368R/I420R and M475S/R476A mutants. gp120-Fab VRC03 complex was crystallized. Heavy- and light-chain cross-pairing chimeras of VRC01, VRC03, VRC-PG04, VRC-CH31 could neutralize up to 90% of 20 clade A, B and C viruses. Thousands of heavy and light chain sequences were found by 454 pyrosequencing, of which 109 sequences, all of IGHV1-2*02 origin, had >90% sequence identity to VRC03, although sequence identity to VRC01 and VRC02 heavy chains was below 75%. Dozens chimeric antibodies obtained by pairing heavy-chain sequences with VRC03 and PG04 light chains and light-chain sequences with VRC01, VRC03,PG04 heavy chains displayed potent neutralization (up to 90%) of A, B and C clade viruses. Wu2011 (neutralization, antibody sequence, structure)
VRC03: Two SHIV-C mutants were designed: SHIV-1157ipEL-pΔ3N, a mutant of the early SHIV-1157ipEL-p which lacked the 3N residues in the V2 stem, and SHIV-1157ipd3N4+3N, a mutant of the late SHIV-1157ipd3N4 where 3N residues was added in the V2 stem. VRC03 neutralizes all four SHIV-Cs and avoids the conformational masking by the V2 loop in SHIV-Cs. Watkins2011 (neutralization)
VRC03: This review discusses current understanding of Env neutralization by antibodies in relation to epitope exposure and how this insight might benefit vaccine design strategies. This MAb is in the list of current MAbs with notable cross-neutralizing activity. Pantophlet2010 (neutralization, variant cross-reactivity, review)
VRC03: This broadly neutralizing Ab was derived from B-cells from a donor that were screened for CD4bs mAbs with resurfaced stabilized core 3 (RSC3) protein. The protein was designed to preserve the antigenic structure of the gp120 CD4bs neutralizing surface but eliminate other antigenic regions of HIV-1. VRC03 neutralized 57% of 190 virus strains of different HIV-1 clades. VRC03 bound strongly to RSC3 and was highly somatically mutated. Binding of VRC03 to gp120 was competed by b12 and F105. Unlike for VRC01 and VRC02, binding of 17b was not enhanced by the addition of VRC03. Wu2010 (antibody binding site, antibody generation, antibody interactions, neutralization, variant cross-reactivity, kinetics, binding affinity, antibody sequence)

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Davenport2016 Thaddeus M. Davenport, Jason Gorman, M. Gordon Joyce, Tongqing Zhou, Cinque Soto, Miklos Guttman, Stephanie Moquin, Yongping Yang, Baoshan Zhang, Nicole A. Doria-Rose, Shiu-Lok Hu, John R. Mascola, Peter D. Kwong, and Kelly K. Lee. Somatic Hypermutation-Induced Changes in the Structure and Dynamics of HIV-1 Broadly Neutralizing Antibodies. Structure, 20 Jul 2016. PubMed ID: 27477385. Show all entries for this paper.

Feng2012 Yu Feng, Krisha McKee, Karen Tran, Sijy O'Dell, Stephen D. Schmidt, Adhuna Phogat, Mattias N. Forsell, Gunilla B. Karlsson Hedestam, John R. Mascola, and Richard T. Wyatt. Biochemically Defined HIV-1 Envelope Glycoprotein Variant Immunogens Display Differential Binding and Neutralizing Specificities to the CD4-Binding Site. J. Biol. Chem., 287(8):5673-5686, 17 Feb 2012. PubMed ID: 22167180. 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.

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.

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.

Li2012 Yuxing Li, Sijy O'Dell, Richard Wilson, Xueling Wu, Stephen D. Schmidt, Carl-Magnus Hogerkorp, Mark K. Louder, Nancy S. Longo, Christian Poulsen, Javier Guenaga, Bimal K. Chakrabarti, Nicole Doria-Rose, Mario Roederer, Mark Connors, John R. Mascola, and Richard T. Wyatt. HIV-1 Neutralizing Antibodies Display Dual Recognition of the Primary and Coreceptor Binding Sites and Preferential Binding to Fully Cleaved Envelope Glycoproteins. J. Virol., 86(20):11231-11241, Oct 2012. PubMed ID: 22875963. 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.

Liao2013c Hua-Xin Liao, Chun-Yen Tsao, S. Munir Alam, Mark Muldoon, Nathan Vandergrift, Ben-Jiang Ma, Xiaozhi Lu, Laura L. Sutherland, Richard M. Scearce, Cindy Bowman, Robert Parks, Haiyan Chen, Julie H. Blinn, Alan Lapedes, Sydeaka Watson, Shi-Mao Xia, Andrew Foulger, Beatrice H. Hahn, George M. Shaw, Ron Swanstrom, David C. Montefiori, Feng Gao, Barton F. Haynes, and Bette Korber. Antigenicity and Immunogenicity of Transmitted/Founder, Consensus, and Chronic Envelope Glycoproteins of Human Immunodeficiency Virus Type 1. J. Virol., 87(8):4185-4201, Apr 2013. PubMed ID: 23365441. Show all entries for this paper.

Meyerson2013 Joel R. Meyerson, Erin E. H. Tran, Oleg Kuybeda, Weizao Chen, Dimiter S. Dimitrov, Andrea Gorlani, Theo Verrips, Jeffrey D. Lifson, and Sriram Subramaniam. Molecular Structures of Trimeric HIV-1 Env in Complex with Small Antibody Derivatives. Proc. Natl. Acad. Sci. U.S.A., 110(2):513-518, 8 Jan 2013. PubMed ID: 23267106. 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.

Pantophlet2010 Ralph Pantophlet. Antibody Epitope Exposure and Neutralization of HIV-1. Curr. Pharm. Des., 16(33):3729-3743, 2010. PubMed ID: 21128886. Show all entries for this paper.

Tran2012 Erin E. H. Tran, Mario J. Borgnia, Oleg Kuybeda, David M. Schauder, Alberto Bartesaghi, Gabriel A. Frank, Guillermo Sapiro, Jacqueline L. S. Milne, and Sriram Subramaniam. Structural Mechanism of Trimeric HIV-1 Envelope Glycoprotein Activation. PLoS Pathog., 8(7):e1002797, 2012. PubMed ID: 22807678. 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.

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.

Watkins2011 Jennifer D. Watkins, Juan Diaz-Rodriguez, Nagadenahalli B. Siddappa, Davide Corti, and Ruth M. Ruprecht. Efficiency of Neutralizing Antibodies Targeting the CD4-Binding Site: Influence of Conformational Masking by the V2 Loop in R5-Tropic Clade C Simian-Human Immunodeficiency Virus. J Virol, 85(23):12811-12814, Dec 2011. PubMed ID: 21957314. 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.

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.

Wright2012 Elizabeth R. Wright and Paul W. Spearman. Unraveling the Structural Basis of HIV-1 Neutralization. Future Microbiol., 7(11):1251-1254, Nov 2012. PubMed ID: 23075444. 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.

Wu2012 Xueling Wu, Charlene Wang, Sijy O'Dell, Yuxing Li, Brandon F. Keele, Zhongjia Yang, Hiromi Imamichi, Nicole Doria-Rose, James A. Hoxie, Mark Connors, George M. Shaw, Richard T. Wyatt, and John R. Mascola. Selection Pressure on HIV-1 Envelope by Broadly Neutralizing Antibodies to the Conserved CD4-Binding Site. J. Virol., 86(10):5844-5856, May 2012. PubMed ID: 22419808. 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.

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.

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.

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.

Displaying record number 2825

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MAb ID	3BC176
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 lineage, assay or method development, binding affinity, broad neutralizer, chimeric antibody, escape, genital and mucosal immunity, immunoprophylaxis, immunotherapy, neutralization, review, structure, vaccine antigen design

Notes

Showing 13 of 13 notes.

3BC176: 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 3BC176 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)
3BC176: This review classified and mapped the binding regions of 32 bNAbs isolated 2010-2016. Wu2016 (review)
3BC176: 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/CD4i (a conformational epitope) 3BC176 Fab and mouse Fc had improved or reduced in vivo activity depending on the Fc used. Bournazos2014 (neutralization, chimeric antibody)
3BC176: 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. MPER Ab 3BC176 did not bind cell surface whether gp160 was missing C-terminal or not, but did neutralize 92UG037.8 HIV-1 isolate weakly. Chen2015 (neutralization, binding affinity)
3BC176: 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 3BC176 to trimers was unaffected by trimer cross-linking. Schiffner2016 (assay or method development, binding affinity, structure)
3BC176: 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 3BC176, 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)
3BC176: 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)
3BC176: 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. 3BC176 was only partially effective in blocking cell to cell transmission of viruses. Malbec2013
3BC176: 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. Pretreatment with 3BC176 led to an ≈85% reduction of infection. Gruell2013 (genital and mucosal immunity)
3BC176: This is a review of a satellite symposium at the AIDS Vaccine 2012 conference, focusing on antibody gene transfer. Michel Nussenzweig presented studies exploring the possibility that antibodies might also be used to treat established infections. They found that combinations of five broadly neutralizing antibodies NIH45-46G54W, PG16, PGT128, 10-1074 and 3BC176 MAbs, controlled HIV-1 infection and suppressed the viral load to below the limit of detection during the entire therapy period of up to 60 days. Balazs2013 (immunoprophylaxis, immunotherapy)
3BC176: 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. 3BNC176 was used in the experiment to study the effect of a FWR insertion and a C beta strand Proline in clone RU01. Klein2013 (neutralization, structure, antibody lineage)
3BC176: HIV therapy by combinations of 5 bNAbs was tested in YU2-infected humanized mice. Penta-mix (PG16, 45-46W, 3BC176, PGT128 and 10-1074) was the most effective in controlling viraemia compared to tri-mix (PG16, 45-46, 3BC176) and monotherapy (Fig S9). 3BC176 recognizes a conformational, yet-to-be-defined epitope and neutralizes CD4bs antibodies-resistant HIV-1 strains. Klein2012a (escape, immunotherapy)
3BC176: 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 3BC176 and 3BC315 are found to be broadly neutralizing and bind to a novel conformational HIV-1 spike epitope. 3BC176 neutralized 10/36 viruses, mainly Clade C and D, complementing the spectrum of viruses neutralized by anti-CD4bs. 3BC176 recognized a conformational, yet-to-be-defined epitope in close proximity to the V3 loop and the CD4i site. The epitope differs from the epitopes that are recognized by traditional anti-V3 loop, anti-CD4bs, and anti-CD4i Abs. Klein2012 (antibody binding site, antibody generation, neutralization, broad neutralizer)

References

Showing 13 of 13 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.

Balazs2013 Alejandro B. Balazs and Anthony P. West, Jr. Antibody Gene Transfer for HIV Immunoprophylaxis. Nat. Immunol., 14(1):1-5, Jan 2013. PubMed ID: 23238748. 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.

Gruell2013 Henning Gruell, Stylianos Bournazos, Jeffrey V. Ravetch, Alexander Ploss, Michel C. Nussenzweig, and John Pietzsch. Antibody and Antiretroviral Preexposure Prophylaxis Prevent Cervicovaginal HIV-1 Infection in a Transgenic Mouse Model. J. Virol., 87(15):8535-8544, Aug 2013. PubMed ID: 23720722. Show all entries for this paper.

Klein2012a Florian Klein, Ariel Halper-Stromberg, Joshua A. Horwitz, Henning Gruell, Johannes F. Scheid, Stylianos Bournazos, Hugo Mouquet, Linda A. Spatz, Ron Diskin, Alexander Abadir, Trinity Zang, Marcus Dorner, Eva Billerbeck, Rachael N. Labitt, Christian Gaebler, Paola M. Marcovecchio, Reha-Baris Incesu, Thomas R. Eisenreich, Paul D. Bieniasz, Michael S. Seaman, Pamela J. Bjorkman, Jeffrey V. Ravetch, Alexander Ploss, and Michel C. Nussenzweig. HIV Therapy by a Combination of Broadly Neutralizing Antibodies in Humanized Mice. Nature, 492(7427):118-122, 6 Dec 2012. PubMed ID: 23103874. 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.

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.

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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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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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.

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.

Nkolola2014 Joseph P. Nkolola, Christine A. Bricault, Ann Cheung, Jennifer Shields, James Perry, James M. Kovacs, Elena Giorgi, Margot van Winsen, Adrian Apetri, Els C. M. Brinkman-van der Linden, Bing Chen, Bette Korber, Michael S. Seaman, and Dan H. Barouch. Characterization and Immunogenicity of a Novel Mosaic M HIV-1 gp140 Trimer. J. Virol., 88(17):9538-9552, 1 Sep 2014. PubMed ID: 24965452. Show all entries for this paper.

Patel2018 Shabnum Patel, Elizabeth Chorvinsky, Shuroug Albihani, Conrad Russell Cruz, R. Brad Jones, Elizabeth J. Shpall, David M. Margolis, Richard F. Ambinder, and Catherine M. Bollard. HIV-Specific T Cells Generated from Naive T Cells Suppress HIV In Vitro and Recognize Wide Epitope Breadths. Mol. Ther., 26(6):1435-1446, 6 Jun 2018. PubMed ID: 29724686. Show all entries for this paper.

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.

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.

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.

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.

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.

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.

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 2460

Download this epitope record as JSON.

MAb ID	HJ16 (HJ16_22)
HXB2 Location	gp160	gp160 Epitope Map
Author Location	gp120
Epitope
Subtype	C
Ab Type	gp120 CD4BS
Neutralizing	P View neutralization details
Contacts and Features	View contacts and features
Species (Isotype)	human(IgG1)
Patient	VI3208
Immunogen	HIV-1 infection
Keywords	adjuvant comparison, antibody binding site, antibody gene transfer, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, binding affinity, broad neutralizer, computational epitope prediction, escape, glycosylation, immunoprophylaxis, memory cells, neutralization, optimal epitope, polyclonal antibodies, review, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity

Notes

Showing 47 of 47 notes.

HJ16: 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. HJ16-Env formed a distinct group within the CD4bs category, Class HJ16. Crystal structure data on HJ16 complexed to HIV-1 gp120 was found in PDB ID: 4YE4. Chuang2019 (antibody binding site, antibody interactions, neutralization, binding affinity, antibody sequence, structure, antibody lineage, broad neutralizer)
HJ16: 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)
HJ16: 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. HJ16 was used for analyzing clade sensitivity and the CD4b signature summaries. Bricault2019 (antibody binding site, vaccine antigen design, computational epitope prediction, broad neutralizer)
HJ16: 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 HJ16 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)
HJ16: In the RV305 HIV-1 vaccine trial, two boosts of either ALVAC-HIV, AIDSVAX B/E gp120 or ALVAC-HIV + AIDSVAX B/E gp120 were given to HIV-1-uninfected RV144 vaccine-recipients. While no bNAb plasma activity was induced in this trial as well, an increased frequency of memory B cells that produce Env-specific anti-CD4bs antibodies with long HCDR3s was detected. HJ16 binding to the N276A mutant of CRF01_AE Env protein A244 was reduced to 1% as compared to wt. Easterhoff2017 (binding affinity)
HJ16: 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)
HJ16: 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)
HJ16: 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)
HJ16: 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. HJ16 was used as a reference Ab. Crooks2015 (glycosylation, neutralization)
HJ16: This review classified and mapped the binding regions of 32 bNAbs isolated 2010-2016. Wu2016 (review)
HJ16: 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)
HJ16: 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 HJ16 to trimers was minimally affected by trimer cross-linking. Schiffner2016 (assay or method development, binding affinity, structure)
HJ16: 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 HJ16 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)
HJ16: 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. HJ16, a CD4bs bnAb belonged to a group with slopes >1. Webb2015 (neutralization)
HJ16: Donor EB179 was a long-term non-progressor with high serum neutralization breadth and potency. 8 B-cell clones produced antibodies of which 179NC75 had the highest neutralization, especially to Clade B virus, neutralizing 70% of a clade-B pseudovirus panel and 6 out of 9 cross-clade Env pseudoviruses as opposed to bNAb HJ16's neutralizing 3/9 of the same psuedoviral panel. 179NC75 was also more potent than HJ16 against 15 viruses of a 22 Tier-2 clade B panel. Binding studies revealed that 179NC75 is a glycan-dependent antibody that binds to the CD4bs in a way that involves the Asn276 residue and depends on the presence of complex glycans, in contrast to most CD4bs bNAbs which belong to the VRC01 class. It belongs to the same sub-class of CDRH3-dominated CD4bs antibodies as HJ16. Freund2015 (neutralization)
HJ16: 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. HJ16 was one of the antibodies in the CDR H3-dominated class. Zhou2015 (neutralization, structure, antibody lineage, broad neutralizer)
HJ16: 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)
HJ16: CD4-binding site Abs are reviewed. New insights from donor-serum responses, atomic-level structures of antibody-Env complexes, and next-generation sequencing of B-cell transcripts are invigorating vaccine-design efforts to elicit effective CD4-binding site Abs. Analysis of the epitopes recognized by CD4-binding Abs reveals substantial similarity in the recognized region of gp120. HJ16 is canonical CDR3H3 utilizer and targets outer domain of gp120 Georgiev2013a (review)
HJ16: This study examined the development and co-evolution of autologous antibodies and viruses in two patients. Antibodies with limited heterologous breadth were able to potently neutralize autologous viruses, and such antibodies could select for neutralization-resistant autologous viruses implicated in transmission. Viruses from subject CH0457 were largely susceptible to neutralization by CD4bs-binding heterologous nAbs CH31 and CH106. The CD4bs CH27 lineage mAbs from subject CH0457 were similar to HJ16, which neutralizes multiple tier 2 but not tier 1 viruses. Glycan-dependent HJ16 potently neturalized 6.9% of an 84-psuedoviral panel amplified from CH0457. Moody2015 (neutralization)
HJ16: 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)
HJ16: 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)
HJ16: 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. HJ16 is a CD4bs Ab, with breadth 30%, IC₅₀ 0.77 μg per ml, and its unique feature is extensive affinity maturation. Kwong2013 (review)
HJ16: 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)
HJ16: N276D was determined as the critical binding site of MAb HJ16 by resistance induction in a sensitive primary CRF02_AG strain. N-linked glycosylation site removing N276D mutation was responsible for resistance to HJ16 by site-directed mutagenesis in envs of the homologous CRF02_AG, as well as of a subtype A and a subtype C primary isolate. The effect of N276D was very selective, as it failed to confer resistance to a range of other entry inhibitors. Sensitivity to the CD4bs VRC01 and VRC03 mAbs was increased in the N276D mutated viruses. These data indicate that binding of the CD4bs specific HJ16 mAb critically depends on the interaction with the N276-glycan, thus indicating that HJ16 is the first glycan dependent CD4bs-specific mAb. Balla-Jhagjhoorsingh2013 (antibody binding site, glycosylation)
HJ16: "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)
HJ16: 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. HJ16 was used as a CD4bs MAb to compare neutralizing specificity of VRC06. Li2012
HJ16: 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, type not yet determined, HJ16 class, HJ16 family. Kwong2012 (review, structure, broad neutralizer)
HJ16: This review discusses how analysis of infection and vaccine candidate-induced antibodies and their genes may guide vaccine design. This MAb is listed as cross-reactive neutralizing antibody, binding near CD4 binding site isolated after 2009 by neutralization screening of cultured, unselected IgG+ memory B cells. Bonsignori2012b (vaccine antigen design, vaccine-induced immune responses, review)
HJ16: 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. HJ16, which recognizes the core epitope, was among the 17 bnAbs which were used in studying the mutations in FWR. Klein2013 (neutralization, structure, antibody lineage)
HJ16: 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. HJ16 was referred to as anti-CD4BS bnAbs. McGuire2013 (neutralization, antibody lineage)
HJ16: 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. HJ16 has been discussed as NAb against CD4BS. Kovacs2012 (antibody binding site, neutralization, binding affinity)
HJ16: 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. HJ16 has been referred in discussing the breadth and potency of antiCD4 abs. West2012a (antibody lineage)
HJ16: The use of computationally derived B cell clonal lineages as templates for HIV-1 immunogen design is discussed. HJ16 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)
HJ16: Polyclonal B cell responses to conserved neutralization epitopes are reported. Cross-reactive plasma samples were identified and evaluated from 308 subjects tested. HJ16 was used as a control mAb in the comprehensive set of assays performed. Tomaras2011 (neutralization, polyclonal antibodies)
HJ16: 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. HJ16 has been referred as gp120 binding Ab isolated from Clade C infected patients. Mouquet2011 (neutralization)
hj16: The strategy of incorporating extra glycans onto gp120 was explored, with the goal to occlude the epitopes of non-neutralizing MAbs while maintaining exposure of the b12 site. The focus was on the head-to-head comparison of the ability of 2 adjuvants, monophosphoryl lipid A (MPL) and Quil A, to promote CD4-specific Ab responses in mice immunized with the engineered mutant Q105N compared to gp120wt. Neutralizing and non-neutralizing antibodies targeting three areas on gp120 – the CD4bs (F105, b6, b12, b13, VRC01, VRC03 and CD4- IgG2), the glycosylated ‘silent face’ (2G12) and the V3 loop (B4e8) – were assessed for binding. The antibodies b6, b12, b13, VRC01 and 2G12 bound best to mutant Q105N, albeit with lower affinities than to gp120wt. Retention of b6 and b13 binding was not expected, but can be explained by their very similar mode of interaction with the CD4bs compared to b12. Abs F105 and VRC03 did not bind Q105N at all. The V3-specific antibody B4e8 did not bind to Q105N. Ahmed2012 (adjuvant comparison, antibody binding site, glycosylation, neutralization, escape)
HJ16: 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)
HJ16: 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. HJ16 strongly bound to RSC3/G367R, weakly bound to gp120 core, gp120 core D368R, RSC3 and RSC3 Δ3711, and very weakly bound to RSC3 Δ3711/P363N. Lynch2012 (binding affinity)
HJ16: Characteristics of the patients' plasma and their respective mAbs in multiple neutralization assay formats was presented. HJ16 MAb neutralized the subtype C isolate VI829, the subtype D CI 13 and two of the three CRF02_AG isolates, VI 1090 and CA18 against a panel of 17 primary viruses belonging to 6 subtypes in the 24/1/14 extended incubation PBMC assay. In another experiment, out of the 12 isolates, HJ16 MAb neutralized four in 24/1/14 PBMC assays, three in 1/2/7 PBMC assays, one in 1/24/14 PBMC assays, two in TZMbl_IV assays, three in TZMbl_PV assays and four in GHOST_PV assays. When evaluating plasma vs. Ab in the TZMbl pseudovirus assay, HJ16 MAb was not able to neutralize the three tier 1 strains but neutralized seven out of eleven Tier 2 strains. Balla-Jhagjhoorsingh2011 (neutralization, subtype comparisons)
HJ16: Two SHIV-C mutants were designed: SHIV-1157ipEL-pΔ3N, a mutant of the early SHIV-1157ipEL-p which lacked the 3N residues in the V2 stem, and SHIV-1157ipd3N4+3N, a mutant of the late SHIV-1157ipd3N4 where 3N residues was added in the V2 stem. nMAb HJ16 neutralized neither early nor late SHIV-Cs indicating that the HJ16 epitope may not be present on the SHIV-C envelopes. Watkins2011 (neutralization)
HJ16: 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)
HJ16: 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 neutralizes a multi-clade panel of pseudoviruses with a breadth comparable to b12. Gonzalez2010 (neutralization, variant cross-reactivity, escape, review)
HJ16: This review discusses recent rational structure-based approaches in HIV vaccine design that helped in understanding the link between Env antigenicity and immunogenicity. This MAb was mentioned in the context of immunogens based on the epitopes recognized by bNAbs. HJ16 exhibited similar breadth and potency as b12 but showed a different pattern of neutralization sensitivity. Walker2010a (neutralization, review)
HJ16: 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)
HJ16: 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)
HJ16: This Ab was sensitive to mutations D474A, R476A and M475A/R476A but not to D368A, indicating that HJ16 targets the same epitope as anti-core Abs. It is suggested that HJ16 and anti-core Abs bind to a conformational epitope including the α5 helix at the outer-domain-inner-domain junction of gp120. This epitope was highly conserved across different HIV-1 isolates. Pietzsch2010a (antibody binding site, optimal epitope, binding affinity)
HJ16: This MAb was isolated from memory B cells of HIV-1 infected donor using an improved EBV immortalization method combined with a broad screening strategy. HJ16 bound to Env proteins from clades AE, AG, B and BC. The discontinuous epitope of this Ab was located in the proximity of the CD4bs b12 epitope but did not overlap with the b12 epitope. HJ16 showed broad neutralizing activity that was comparable to that of mAbs b12 and 2F5 and superior to that of mAbs 2G12 and 447-52D. HJ16 neutralized 1/10 Tier 1 and 32/82 Tier 2 viruses and did not discriminate between clades as much as mAbs b12, 2G12 and 2F5. HJ16 and b12 showed non-overlapping patterns of neutralizing activity. Corti2010 (antibody generation, neutralization, variant cross-reactivity, binding affinity, subtype comparisons)

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Displaying record number 2124

Download this epitope record as JSON.

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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Burton2010 Dennis R. Burton and Robin A. Weiss. A Boost for HIV Vaccine Design. Science, 329(5993):770-773, 13 Aug 2010. PubMed ID: 20705840. Show all entries for this paper.

Burton2012 Dennis R. Burton, Pascal Poignard, Robyn L. Stanfield, and Ian A. Wilson. Broadly Neutralizing Antibodies Present New Prospects to Counter Highly Antigenically Diverse Viruses. Science, 337(6091):183-186, 13 Jul 2012. PubMed ID: 22798606. Show all entries for this paper.

Chen2016 Danying Chen, Xiaozhou He, Jingrong Ye, Pengxiang Zhao, Yi Zeng, and Xia Feng. Genetic and Phenotypic Analysis of CRF01\_AE HIV-1 env Clones from Patients Residing in Beijing, China. AIDS Res. Hum. Retroviruses, 32(10-11):1113-1124, Nov 2016. PubMed ID: 27066910. Show all entries for this paper.

Chenine2018 Agnes-Laurence Chenine, Melanie Merbah, Lindsay Wieczorek, Sebastian Molnar, Brendan Mann, Jenica Lee, Anne-Marie O'Sullivan, Meera Bose, Eric Sanders-Buell, Gustavo H. Kijak, Carolina Herrera, Robert McLinden, Robert J. O'Connell, Nelson L. Michael, Merlin L. Robb, Jerome H. Kim, Victoria R. Polonis, and Sodsai Tovanabutra. Neutralization Sensitivity of a Novel HIV-1 CRF01\_AE Panel of Infectious Molecular Clones. J. Acquir. Immune Defic. Syndr., 78(3):348-355, 1 Jul 2018. PubMed ID: 29528942. 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.

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.

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Euler2011 Zelda Euler, Evelien M. Bunnik, Judith A. Burger, Brigitte D. M. Boeser-Nunnink, Marlous L. Grijsen, Jan M. Prins, and Hanneke Schuitemaker. Activity of Broadly Neutralizing Antibodies, Including PG9, PG16, and VRC01, against Recently Transmitted Subtype B HIV-1 Variants from Early and Late in the Epidemic. J. Virol., 85(14):7236-7245, Jul 2011. PubMed ID: 21561918. 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.

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.

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.

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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.

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.

Hoxie2010 James A. Hoxie. Toward an Antibody-Based HIV-1 Vaccine. Annu. Rev. Med., 61:135-52, 2010. PubMed ID: 19824826. 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.

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Hutchinson2019 Jennie M. Hutchinson, Kathryn A. Mesa, David L. Alexander, Bin Yu, Sara M. O'Rourke, Kay L. Limoli, Terri Wrin, Steven G. Deeks, and Phillip W. Berman. Unusual Cysteine Content in V1 Region of gp120 from an Elite Suppressor That Produces Broadly Neutralizing Antibodies. Front. Immunol., 10:1021, 2019. PubMed ID: 31156622. Show all entries for this paper.

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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.

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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.

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.

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.

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.

Miglietta2014 Riccardo Miglietta, Claudia Pastori, Assunta Venuti, Christina Ochsenbauer, and Lucia Lopalco. Synergy in Monoclonal Antibody Neutralization of HIV-1 Pseudoviruses and Infectious Molecular Clones. J. Transl. Med., 12:346, 2014. PubMed ID: 25496375. Show all entries for this paper.

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.

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.

Overbaugh2012 Julie Overbaugh and Lynn Morris. The Antibody Response against HIV-1. Cold Spring Harb. Perspect. Med., 2(1):a007039, Jan 2012. PubMed ID: 22315717. Show all entries for this paper.

Pancera2010 Marie Pancera, Jason S. McLellan, Xueling Wu, Jiang Zhu, Anita Changela, Stephen D. Schmidt, Yongping Yang, Tongqing Zhou, Sanjay Phogat, John R. Mascola, and Peter D. Kwong. Crystal Structure of PG16 and Chimeric Dissection with Somatically Related PG9: Structure-Function Analysis of Two Quaternary-Specific Antibodies That Effectively Neutralize HIV-1. J. Virol., 84(16):8098-8110, Aug 2010. PubMed ID: 20538861. Show all entries for this paper.

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.

Pantophlet2010 Ralph Pantophlet. Antibody Epitope Exposure and Neutralization of HIV-1. Curr. Pharm. Des., 16(33):3729-3743, 2010. PubMed ID: 21128886. 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.

Pejchal2011 Robert Pejchal, Katie J. Doores, Laura M. Walker, Reza Khayat, Po-Ssu Huang, Sheng-Kai Wang, Robyn L. Stanfield, Jean-Philippe Julien, Alejandra Ramos, Max Crispin, Rafael Depetris, Umesh Katpally, Andre Marozsan, Albert Cupo, Sebastien Maloveste, Yan Liu, Ryan McBride, Yukishige Ito, Rogier W. Sanders, Cassandra Ogohara, James C. Paulson, Ten Feizi, Christopher N. Scanlan, Chi-Huey Wong, John P. Moore, William C. Olson, Andrew B. Ward, Pascal Poignard, William R. Schief, Dennis R. Burton, and Ian A. Wilson. A Potent and Broad Neutralizing Antibody Recognizes and Penetrates the HIV Glycan Shield. Science, 334(6059):1097-1103, 25 Nov 2011. PubMed ID: 21998254. Show all entries for this paper.

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.

Provine2012 Nicholas M. Provine, Valerie Cortez, Vrasha Chohan, and Julie Overbaugh. The Neutralization Sensitivity of Viruses Representing Human Immunodeficiency Virus Type 1 Variants of Diverse Subtypes from Early in Infection Is Dependent on Producer Cell, as Well as Characteristics of the Specific Antibody and Envelope Variant. Virology, 427(1):25-33, 25 May 2012. PubMed ID: 22369748. Show all entries for this paper.

Qi2016 Yifei Qi, Sunhwan Jo, and Wonpil Im. Roles of Glycans in Interactions between gp120 and HIV Broadly Neutralizing Antibodies. Glycobiology, 26(3):251-260, Mar 2016. PubMed ID: 26537503. Show all entries for this paper.

Rademeyer2016 Cecilia Rademeyer, Bette Korber, Michael S. Seaman, Elena E. Giorgi, Ruwayhida Thebus, Alexander Robles, Daniel J. Sheward, Kshitij Wagh, Jetta Garrity, Brittany R. Carey, Hongmei Gao, Kelli M. Greene, Haili Tang, Gama P. Bandawe, Jinny C. Marais, Thabo E. Diphoko, Peter Hraber, Nancy Tumba, Penny L. Moore, Glenda E. Gray, James Kublin, M. Juliana McElrath, Marion Vermeulen, Keren Middelkoop, Linda-Gail Bekker, Michael Hoelscher, Leonard Maboko, Joseph Makhema, Merlin L. Robb, Salim Abdool Karim, Quarraisha Abdool Karim, Jerome H. Kim, Beatrice H. Hahn, Feng Gao, Ronald Swanstrom, Lynn Morris, David C. Montefiori, and Carolyn Williamson. Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization. PLoS Pathog., 12(7):e1005742, Jul 2016. PubMed ID: 27434311. 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.

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.

Sajadi2012 Mohammad M. Sajadi, George K. Lewis, Michael S. Seaman, Yongjun Guan, Robert R. Redfield, and Anthony L. DeVico. Signature Biochemical Properties of Broadly Cross-Reactive HIV-1 Neutralizing Antibodies in Human Plasma. J. Virol., 86(9):5014-5025, May 2012. PubMed ID: 22379105. Show all entries for this paper.

Sanchez-Merino2016 V. Sanchez-Merino, A. Fabra-Garcia, N. Gonzalez, D. Nicolas, A. Merino-Mansilla, C. Manzardo, J. Ambrosioni, A. Schultz, A. Meyerhans, J. R. Mascola, J. M. Gatell, J. Alcami, J. M. Miro, and E. Yuste. Detection of Broadly Neutralizing Activity within the First Months of HIV-1 Infection. J. Virol., 90(11):5231-5245, 1 Jun 2016. PubMed ID: 26984721. Show all entries for this paper.

Scott2015 Yanille M. Scott, Seo Young Park, and Charlene S. Dezzutti. Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo. Antimicrob. Agents Chemother., 60(2):904-912, Feb 2016. PubMed ID: 26596954. Show all entries for this paper.

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.

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.

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.

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.

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.

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.

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.

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.

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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.

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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.

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Displaying record number 3316

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MAb ID	14e (1.4e)
HXB2 Location	gp160	gp160 Epitope Map
Author Location	Env
Research Contact	James Robinson
Epitope
Ab Type	gp120 V3 // V3 glycan (V3g)
Neutralizing	no
Species (Isotype)	human
Patient
Immunogen	HIV-1 infection
Keywords	antibody binding site, assay or method development, binding affinity, neutralization, structure, vaccine antigen design

Notes

Showing 7 of 7 notes.

14E: 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 like 14e weakly or not at all. V3-specific non-NAbs showed 2.1–3.3-fold reduced binding. Three autologous rabbit monoclonal NAbs to the N241/N289 ‘glycan-hole’ surface, showed a median ˜1.5-fold reduction in binding. V3 non-NAb 4025 showed residual binding to the GLA-SOSIP trimer. By contrast, bNAbs broadly retained reactivity significantly better than non-NAbs, with exception of PGT145 (3.3-5.3 fold loss of binding in ELISA and SPR). Schiffner2018 (vaccine antigen design, binding affinity, structure)
14e: 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
14E: 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 bound to anti-V3 Ab 14E but their pseudotyped viruses were not neutralized by 14E. Julien2015 (assay or method development, structure)
14e: 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 non-NAb 14e did not neutralize BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, but did recognize and bind the immunogen itself. Sanders2013 (assay or method development, neutralization, binding affinity)
14e: 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). V3-specific 14e does not neutralize BG505.T332N pseudovirus, but binds strongly to monomer, substantially less to protomer, and negligibly to trimer. Yasmeen2014 (antibody binding site, assay or method development)
14e: 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)
1.4e is listed in the CHAVI reagents list as a human V3 monoclonal antibody. https://chavi-id-duke.org/about-us/chavi-history/chavi-reagents

References

Showing 6 of 6 references.

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