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Title: Structure of an N276-Dependent HIV-1 Neutralizing Antibody Targeting a Rare V5 Glycan Hole Adjacent to the CD4 Binding Site

Abstract

ABSTRACT All HIV-1-infected individuals develop strain-specific neutralizing antibodies to their infecting virus, which in some cases mature into broadly neutralizing antibodies. Defining the epitopes of strain-specific antibodies that overlap conserved sites of vulnerability might provide mechanistic insights into how broadly neutralizing antibodies arise. We previously described an HIV-1 clade C-infected donor, CAP257, who developed broadly neutralizing plasma antibodies targeting an N276 glycan-dependent epitope in the CD4 binding site. The initial CD4 binding site response potently neutralized the heterologous tier 2 clade B viral strain RHPA, which was used to design resurfaced gp120 antigens for single-B-cell sorting. Here we report the isolation and structural characterization of CAP257-RH1, an N276 glycan-dependent CD4 binding site antibody representative of the early CD4 binding site plasma response in donor CAP257. The cocrystal structure of CAP257-RH1 bound to RHPA gp120 revealed critical interactions with the N276 glycan, loop D, and V5, but not with aspartic acid 368, similarly to HJ16 and 179NC75. The CAP257-RH1 monoclonal antibody was derived from the immunoglobulin-variable IGHV3-33 and IGLV3-10 genes and neutralized RHPA but not the transmitted/founder virus from donor CAP257. Its narrow neutralization breadth was attributed to a binding angle that was incompatible with glycosylated V5 loops present in almostmore » all HIV-1 strains, including the CAP257 transmitted/founder virus. Deep sequencing of autologous CAP257 viruses, however, revealed minority variants early in infection that lacked V5 glycans. These glycan-free V5 loops are unusual holes in the glycan shield that may have been necessary for initiating this N276 glycan-dependent CD4 binding site B-cell lineage. IMPORTANCEThe conserved CD4 binding site on gp120 is a major target for HIV-1 vaccine design, but key events in the elicitation and maturation of different antibody lineages to this site remain elusive. Studies have shown that strain-specific antibodies can evolve into broadly neutralizing antibodies or in some cases act as helper lineages. Therefore, characterizing the epitopes of strain-specific antibodies may help to inform the design of HIV-1 immunogens to elicit broadly neutralizing antibodies. In this study, we isolate a narrowly neutralizing N276 glycan-dependent antibody and use X-ray crystallography and viral deep sequencing to describe how gp120 lacking glycans in V5 might have elicited these early glycan-dependent CD4 binding site antibodies. These data highlight how glycan holes can play a role in the elicitation of B-cell lineages targeting the CD4 binding site.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
FOREIGN
OSTI Identifier:
1333961
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Virology; Journal Volume: 90; Journal Issue: 22
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Wibmer, Constantinos Kurt, Gorman, Jason, Anthony, Colin S., Mkhize, Nonhlanhla N., Druz, Aliaksandr, York, Talita, Schmidt, Stephen D., Labuschagne, Phillip, Louder, Mark K., Bailer, Robert T., Abdool Karim, Salim S., Mascola, John R., Williamson, Carolyn, Moore, Penny L., Kwong, Peter D., Morris, Lynn, and Kirchhoff, F. Structure of an N276-Dependent HIV-1 Neutralizing Antibody Targeting a Rare V5 Glycan Hole Adjacent to the CD4 Binding Site. United States: N. p., 2016. Web. doi:10.1128/JVI.01357-16.
Wibmer, Constantinos Kurt, Gorman, Jason, Anthony, Colin S., Mkhize, Nonhlanhla N., Druz, Aliaksandr, York, Talita, Schmidt, Stephen D., Labuschagne, Phillip, Louder, Mark K., Bailer, Robert T., Abdool Karim, Salim S., Mascola, John R., Williamson, Carolyn, Moore, Penny L., Kwong, Peter D., Morris, Lynn, & Kirchhoff, F. Structure of an N276-Dependent HIV-1 Neutralizing Antibody Targeting a Rare V5 Glycan Hole Adjacent to the CD4 Binding Site. United States. doi:10.1128/JVI.01357-16.
Wibmer, Constantinos Kurt, Gorman, Jason, Anthony, Colin S., Mkhize, Nonhlanhla N., Druz, Aliaksandr, York, Talita, Schmidt, Stephen D., Labuschagne, Phillip, Louder, Mark K., Bailer, Robert T., Abdool Karim, Salim S., Mascola, John R., Williamson, Carolyn, Moore, Penny L., Kwong, Peter D., Morris, Lynn, and Kirchhoff, F. Wed . "Structure of an N276-Dependent HIV-1 Neutralizing Antibody Targeting a Rare V5 Glycan Hole Adjacent to the CD4 Binding Site". United States. doi:10.1128/JVI.01357-16.
@article{osti_1333961,
title = {Structure of an N276-Dependent HIV-1 Neutralizing Antibody Targeting a Rare V5 Glycan Hole Adjacent to the CD4 Binding Site},
author = {Wibmer, Constantinos Kurt and Gorman, Jason and Anthony, Colin S. and Mkhize, Nonhlanhla N. and Druz, Aliaksandr and York, Talita and Schmidt, Stephen D. and Labuschagne, Phillip and Louder, Mark K. and Bailer, Robert T. and Abdool Karim, Salim S. and Mascola, John R. and Williamson, Carolyn and Moore, Penny L. and Kwong, Peter D. and Morris, Lynn and Kirchhoff, F.},
abstractNote = {ABSTRACT All HIV-1-infected individuals develop strain-specific neutralizing antibodies to their infecting virus, which in some cases mature into broadly neutralizing antibodies. Defining the epitopes of strain-specific antibodies that overlap conserved sites of vulnerability might provide mechanistic insights into how broadly neutralizing antibodies arise. We previously described an HIV-1 clade C-infected donor, CAP257, who developed broadly neutralizing plasma antibodies targeting an N276 glycan-dependent epitope in the CD4 binding site. The initial CD4 binding site response potently neutralized the heterologous tier 2 clade B viral strain RHPA, which was used to design resurfaced gp120 antigens for single-B-cell sorting. Here we report the isolation and structural characterization of CAP257-RH1, an N276 glycan-dependent CD4 binding site antibody representative of the early CD4 binding site plasma response in donor CAP257. The cocrystal structure of CAP257-RH1 bound to RHPA gp120 revealed critical interactions with the N276 glycan, loop D, and V5, but not with aspartic acid 368, similarly to HJ16 and 179NC75. The CAP257-RH1 monoclonal antibody was derived from the immunoglobulin-variable IGHV3-33 and IGLV3-10 genes and neutralized RHPA but not the transmitted/founder virus from donor CAP257. Its narrow neutralization breadth was attributed to a binding angle that was incompatible with glycosylated V5 loops present in almost all HIV-1 strains, including the CAP257 transmitted/founder virus. Deep sequencing of autologous CAP257 viruses, however, revealed minority variants early in infection that lacked V5 glycans. These glycan-free V5 loops are unusual holes in the glycan shield that may have been necessary for initiating this N276 glycan-dependent CD4 binding site B-cell lineage. IMPORTANCEThe conserved CD4 binding site on gp120 is a major target for HIV-1 vaccine design, but key events in the elicitation and maturation of different antibody lineages to this site remain elusive. Studies have shown that strain-specific antibodies can evolve into broadly neutralizing antibodies or in some cases act as helper lineages. Therefore, characterizing the epitopes of strain-specific antibodies may help to inform the design of HIV-1 immunogens to elicit broadly neutralizing antibodies. In this study, we isolate a narrowly neutralizing N276 glycan-dependent antibody and use X-ray crystallography and viral deep sequencing to describe how gp120 lacking glycans in V5 might have elicited these early glycan-dependent CD4 binding site antibodies. These data highlight how glycan holes can play a role in the elicitation of B-cell lineages targeting the CD4 binding site.},
doi = {10.1128/JVI.01357-16},
journal = {Journal of Virology},
number = 22,
volume = 90,
place = {United States},
year = {Wed Aug 31 00:00:00 EDT 2016},
month = {Wed Aug 31 00:00:00 EDT 2016}
}