skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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. 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. Fri . "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. 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},
journal = {Journal of Virology},
issn = {0022-538X},
number = 22,
volume = 90,
place = {United States},
year = {2016},
month = {10}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 14 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo
journal, October 2012

  • Moldt, B.; Rakasz, E. G.; Schultz, N.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 46
  • DOI: 10.1073/pnas.1214785109

Limited Neutralizing Antibody Specificities Drive Neutralization Escape in Early HIV-1 Subtype C Infection
journal, September 2009


Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice
journal, June 2015


Broad and potent neutralization of HIV-1 by a gp41-specific human antibody
journal, September 2012


Antibody 8ANC195 Reveals a Site of Broad Vulnerability on the HIV-1 Envelope Spike
journal, May 2014


Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning
journal, January 2008

  • Tiller, Thomas; Meffre, Eric; Yurasov, Sergey
  • Journal of Immunological Methods, Vol. 329, Issue 1-2
  • DOI: 10.1016/j.jim.2007.09.017

Restricting HIV-1 pathways for escape using rationally designed anti–HIV-1 antibodies
journal, May 2013

  • Diskin, Ron; Klein, Florian; Horwitz, Joshua A.
  • The Journal of Experimental Medicine, Vol. 210, Issue 6
  • DOI: 10.1084/jem.20130221

Analysis of Neutralization Specificities in Polyclonal Sera Derived from Human Immunodeficiency Virus Type 1-Infected Individuals
journal, November 2008


Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape
journal, October 2012

  • Moore, Penny L.; Gray, Elin S.; Wibmer, C. Kurt
  • Nature Medicine, Vol. 18, Issue 11
  • DOI: 10.1038/nm.2985

Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding
journal, July 2011


Neutralizing Antibody Responses in Acute Human Immunodeficiency Virus Type 1 Subtype C Infection
journal, April 2007

  • Gray, E. S.; Moore, P. L.; Choge, I. A.
  • Journal of Virology, Vol. 81, Issue 12
  • DOI: 10.1128/JVI.00239-07

Trimmomatic: a flexible trimmer for Illumina sequence data
journal, April 2014


Two Distinct Broadly Neutralizing Antibody Specificities of Different Clonal Lineages in a Single HIV-1-Infected Donor: Implications for Vaccine Design
journal, February 2012

  • Bonsignori, Mattia; Montefiori, David C.; Wu, Xueling
  • Journal of Virology, Vol. 86, Issue 8
  • DOI: 10.1128/JVI.07163-11

Rational HIV Immunogen Design to Target Specific Germline B Cell Receptors
journal, March 2013


A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo
journal, October 2015


Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1
journal, July 2010


Primer ID Validates Template Sampling Depth and Greatly Reduces the Error Rate of Next-Generation Sequencing of HIV-1 Genomic RNA Populations
journal, June 2015

  • Zhou, Shuntai; Jones, Corbin; Mieczkowski, Piotr
  • Journal of Virology, Vol. 89, Issue 16
  • DOI: 10.1128/JVI.00522-15

HIV broadly neutralizing antibody targets
journal, January 2015

  • Wibmer, Constantinos Kurt; Moore, Penny L.; Morris, Lynn
  • Current Opinion in HIV and AIDS, Vol. 10, Issue 3
  • DOI: 10.1097/COH.0000000000000153

Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor
journal, July 2014


HIV-1 Fitness Cost Associated with Escape from the VRC01 Class of CD4 Binding Site Neutralizing Antibodies
journal, January 2015

  • Lynch, Rebecca M.; Wong, Patrick; Tran, Lillian
  • Journal of Virology, Vol. 89, Issue 8
  • DOI: 10.1128/JVI.03608-14

Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus
journal, April 2013

  • Liao, Hua-Xin; Lynch, Rebecca; Zhou, Tongqing
  • Nature, Vol. 496, Issue 7446
  • DOI: 10.1038/nature12053

Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies
journal, October 2015

  • Bhiman, Jinal N.; Anthony, Colin; Doria-Rose, Nicole A.
  • Nature Medicine, Vol. 21, Issue 11
  • DOI: 10.1038/nm.3963

Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody
journal, April 2016


MAFFT Multiple Sequence Alignment Software Version 7: Improvements in Performance and Usability
journal, January 2013

  • Katoh, K.; Standley, D. M.
  • Molecular Biology and Evolution, Vol. 30, Issue 4
  • DOI: 10.1093/molbev/mst010

Accurate sampling and deep sequencing of the HIV-1 protease gene using a Primer ID
journal, November 2011

  • Jabara, C. B.; Jones, C. D.; Roach, J.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 50
  • DOI: 10.1073/pnas.1110064108

Antibody potency relates to the ability to recognize the closed, pre-fusion form of HIV Env
journal, February 2015

  • Guttman, Miklos; Cupo, Albert; Julien, Jean-Philippe
  • Nature Communications, Vol. 6, Issue 1
  • DOI: 10.1038/ncomms7144

Computational analysis of anti-HIV-1 antibody neutralization panel data to identify potential functional epitope residues
journal, June 2013

  • West, A. P.; Scharf, L.; Horwitz, J.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 26
  • DOI: 10.1073/pnas.1309215110

HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen
journal, March 2016


Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01
journal, July 2010


Holes in the Glycan Shield of the Native HIV Envelope Are a Target of Trimer-Elicited Neutralizing Antibodies
journal, August 2016


Selection Pressure on HIV-1 Envelope by Broadly Neutralizing Antibodies to the Conserved CD4-Binding Site
journal, March 2012


Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G
journal, May 2016


Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies
journal, July 2014


Multiple Pathways of Escape from HIV Broadly Cross-Neutralizing V2-Dependent Antibodies
journal, February 2013

  • Moore, P. L.; Sheward, D.; Nonyane, M.
  • Journal of Virology, Vol. 87, Issue 9
  • DOI: 10.1128/JVI.03424-12

Composition and Antigenic Effects of Individual Glycan Sites of a Trimeric HIV-1 Envelope Glycoprotein
journal, March 2016


Incomplete Neutralization and Deviation from Sigmoidal Neutralization Curves for HIV Broadly Neutralizing Monoclonal Antibodies
journal, August 2015


Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target
journal, September 2009


Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site
journal, January 2016


Analysis of Memory B Cell Responses and Isolation of Novel Monoclonal Antibodies with Neutralizing Breadth from HIV-1-Infected Individuals
journal, January 2010


Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies
journal, March 2013

  • McGuire, Andrew T.; Hoot, Sam; Dreyer, Anita M.
  • The Journal of Experimental Medicine, Vol. 210, Issue 4
  • DOI: 10.1084/jem.20122824

Characterization of Host-Cell Line Specific Glycosylation Profiles of Early Transmitted/Founder HIV-1 gp120 Envelope Proteins
journal, February 2013

  • Go, Eden P.; Liao, Hua-Xin; Alam, S. Munir
  • Journal of Proteome Research, Vol. 12, Issue 3
  • DOI: 10.1021/pr300870t

Rapid evolution of the neutralizing antibody response to HIV type 1 infection
journal, March 2003

  • Richman, D. D.; Wrin, T.; Little, S. J.
  • Proceedings of the National Academy of Sciences, Vol. 100, Issue 7
  • DOI: 10.1073/pnas.0630530100

Mechanism of Neutralization by the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01
journal, June 2011

  • Li, Y.; O'Dell, S.; Walker, L. M.
  • Journal of Virology, Vol. 85, Issue 17
  • DOI: 10.1128/JVI.00754-11

The C3-V4 Region Is a Major Target of Autologous Neutralizing Antibodies in Human Immunodeficiency Virus Type 1 Subtype C Infection
journal, December 2007

  • Moore, Penny L.; Gray, Elin S.; Choge, Isaac A.
  • Journal of Virology, Vol. 82, Issue 4
  • DOI: 10.1128/JVI.02187-07

Human anti–HIV-neutralizing antibodies frequently target a conserved epitope essential for viral fitness
journal, August 2010

  • Pietzsch, John; Scheid, Johannes F.; Mouquet, Hugo
  • The Journal of Experimental Medicine, Vol. 207, Issue 9
  • DOI: 10.1084/jem.20101176

PEAR: a fast and accurate Illumina Paired-End reAd mergeR
journal, October 2013


Antibody neutralization and escape by HIV-1
journal, March 2003

  • Wei, Xiping; Decker, Julie M.; Wang, Shuyi
  • Nature, Vol. 422, Issue 6929
  • DOI: 10.1038/nature01470

Cross‐Reactive Neutralizing Humoral Immunity Does Not Protect from HIV Type 1 Disease Progression
journal, April 2010

  • Euler, Zelda; van Gils, Marit J.; Bunnik, Evelien M.
  • The Journal of Infectious Diseases, Vol. 201, Issue 7
  • DOI: 10.1086/651144

Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection
journal, November 2008

  • Sather, D. N.; Armann, J.; Ching, L. K.
  • Journal of Virology, Vol. 83, Issue 2
  • DOI: 10.1128/JVI.02036-08

Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors
journal, June 2015


Mass Spectrometric Characterization of the Glycosylation Pattern of HIV-gp120 Expressed in CHO Cells
journal, September 2000

  • Zhu, Xuegong; Borchers, Christoph; Bienstock, Rachelle J.
  • Biochemistry, Vol. 39, Issue 37
  • DOI: 10.1021/bi000432m

Immunotypes of a Quaternary Site of HIV-1 Vulnerability and Their Recognition by Antibodies
journal, February 2011


Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120
journal, May 2013

  • Kong, Leopold; Lee, Jeong Hyun; Doores, Katie J.
  • Nature Structural & Molecular Biology, Vol. 20, Issue 7
  • DOI: 10.1038/nsmb.2594

Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies
journal, March 2014

  • Doria-Rose, Nicole A.; Schramm, Chaim A.; Gorman, Jason
  • Nature, Vol. 509, Issue 7498
  • DOI: 10.1038/nature13036

Identification of a New Quaternary Neutralizing Epitope on Human Immunodeficiency Virus Type 1 Virus Particles
journal, April 2005


Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen
journal, June 2015


The N276 Glycosylation Site Is Required for HIV-1 Neutralization by the CD4 Binding Site Specific HJ16 Monoclonal Antibody
journal, July 2013


Development of broadly neutralizing antibodies from autologous neutralizing antibody responses in HIV infection
journal, January 2014


Role of V1V2 and Other Human Immunodeficiency Virus Type 1 Envelope Domains in Resistance to Autologous Neutralization during Clade C Infection
journal, November 2006

  • Rong, Rong; Bibollet-Ruche, Frederic; Mulenga, Joseph
  • Journal of Virology, Vol. 81, Issue 3
  • DOI: 10.1128/JVI.01839-06

Structural Basis of Immune Evasion at the Site of CD4 Attachment on HIV-1 gp120
journal, November 2009


    Works referencing / citing this record:

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