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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

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 allmore » 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.« less

Authors:
 [1];  [2];  [3];  [4];  [2];  [3];  [2];  [5];  [2];  [2];  [6];  [2];  [7];  [8];  [2];  [8];  [9]
  1. National Inst. for Communicable Diseases, Johannesburg (South Africa); Univ. of Witwatersrand, Johannesburg (South Africa); National Inst. of Health (NIH), Bethesda, MD (United States)
  2. National Inst. of Health (NIH), Bethesda, MD (United States)
  3. Univ. of Cape Town and National Health Lab. Service, Cape Town (South Africa)
  4. National Inst. for Communicable Diseases, Johannesburg (South Africa); Univ. of Witwatersrand, Johannesburg (South Africa)
  5. Univ. of the Western Cape, Cape Town (South Africa)
  6. Univ. of KwaZulu-Natal, Durban (South Africa); Columbia Univ., New York, NY (United States)
  7. Univ. of Cape Town and National Health Lab. Service, Cape Town (South Africa); Univ. of KwaZulu-Natal, Durban (South Africa)
  8. National Inst. for Communicable Diseases, Johannesburg (South Africa); Univ. of Witwatersrand, Johannesburg (South Africa); Univ. of KwaZulu-Natal, Durban (South Africa)
  9. Ulm Univ. Medical Center (Germany)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1333961
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Virology
Additional Journal Information:
Journal Volume: 90; Journal Issue: 22; Journal ID: ISSN 0022-538X
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

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. https://doi.org/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. 2016. "Structure of an N276-Dependent HIV-1 Neutralizing Antibody Targeting a Rare V5 Glycan Hole Adjacent to the CD4 Binding Site". United States. https://doi.org/10.1128/JVI.01357-16. https://www.osti.gov/servlets/purl/1333961.
@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 = {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.},
doi = {10.1128/JVI.01357-16},
url = {https://www.osti.gov/biblio/1333961}, journal = {Journal of Virology},
issn = {0022-538X},
number = 22,
volume = 90,
place = {United States},
year = {Fri Oct 28 00:00:00 EDT 2016},
month = {Fri Oct 28 00:00:00 EDT 2016}
}

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Cited by: 24 works
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  • Tandile, Hermanus,; Abdool, Karim, Quarraisha; E., Lambson, Bronwen
  • The University of North Carolina at Chapel Hill University Libraries
  • https://doi.org/10.17615/e8bk-6082

Works referencing / citing this record:

Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers
journal, September 2018


Diverse pathways of escape from all well-characterized VRC01-class broadly neutralizing HIV-1 antibodies
journal, August 2018