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

Title: Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL

Abstract

The V3 region of HIV-1 gp120 is important for virus-coreceptor interaction and highly immunogenic. Although most anti-V3 antibodies neutralize only the sensitive tier 1 viruses, anti-V3 antibodies effective against the more resistant viruses exist, and a better understanding of these antibodies and their epitopes would be beneficial for the development of novel vaccine immunogens against HIV. The HIV-1 isolate JRFL with its cryptic V3 is resistant to most V3-specific monoclonal antibodies (MAbs). However, the V3 MAb 2424 achieves 100% neutralization against JRFL. 2424 is encoded by IGHV3-53 and IGLV2-28 genes, a pairing rarely used by the other V3 MAbs. 2424 also has distinct binding and neutralization profiles. Studies of 2424-mediated neutralization of JRFL produced with a mannosidase inhibitor further revealed that its neutralizing activity is unaffected by the glycan composition of the virus envelope. To understand the distinct activity of 2424, we determined the crystal structure of 2424 Fab in complex with a JRFL V3 peptide and showed that the 2424 epitope is located at the tip of the V3 crown ( 307IHIGPGRAFYT 319), dominated by interactions with His P308, Pro P313, and Arg P315. The binding mode of 2424 is similar to that of the well-characterized MAb 447-52D, althoughmore » 2424 is more side chain dependent. The 2424 epitope is focused on the very apex of V3, away from nearby glycans, facilitating antibody access. Lastly, this feature distinguishes the 2424 epitope from the other V3 crown epitopes and indicates that the tip of V3 is a potential site to target and incorporate into HIV vaccine immunogens.« less

Authors:
 [1];  [2];  [1];  [3];  [1];  [1];  [1];  [2];  [4];  [1];  [1];  [2];  [1]
  1. Veterans Affairs New York Harbor Healthcare System, New York, NY (United States); NYU School of Medicine, New York, NY (United States)
  2. NYU School of Medicine, NY (United States)
  3. Veterans Affairs New York Harbor Healthcare System, New York, NY (United States); NYU School of Medicine, New York, NY (United States); Univ. de Strasbourg (France)
  4. Harvard Medical School, Boston, MA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH); National Cancer Inst.; National Inst. of General Medical Sciences
OSTI Identifier:
1213730
Grant/Contract Number:  
AC02-06CH11357; AI102740; AI100151; AI082274; Y1-CO-1020; Y1-GM-1104
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Virology
Additional Journal Information:
Journal Volume: 89; Journal Issue: 17; Journal ID: ISSN 0022-538X
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Kumar, Rajnish, Pan, Ruimin, Upadhyay, Chitra, Mayr, Luzia, Cohen, Sandra, Wang, Xiao-Hong, Balasubramanian, Preetha, Nádas, Arthur, Seaman, Michael S., Zolla-Pazner, Susan, Gorny, Miroslaw K., Kong, Xiang-Peng, and Hioe, Catarina E. Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL. United States: N. p., 2015. Web. doi:10.1128/JVI.01280-15.
Kumar, Rajnish, Pan, Ruimin, Upadhyay, Chitra, Mayr, Luzia, Cohen, Sandra, Wang, Xiao-Hong, Balasubramanian, Preetha, Nádas, Arthur, Seaman, Michael S., Zolla-Pazner, Susan, Gorny, Miroslaw K., Kong, Xiang-Peng, & Hioe, Catarina E. Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL. United States. doi:10.1128/JVI.01280-15.
Kumar, Rajnish, Pan, Ruimin, Upadhyay, Chitra, Mayr, Luzia, Cohen, Sandra, Wang, Xiao-Hong, Balasubramanian, Preetha, Nádas, Arthur, Seaman, Michael S., Zolla-Pazner, Susan, Gorny, Miroslaw K., Kong, Xiang-Peng, and Hioe, Catarina E. Wed . "Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL". United States. doi:10.1128/JVI.01280-15. https://www.osti.gov/servlets/purl/1213730.
@article{osti_1213730,
title = {Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL},
author = {Kumar, Rajnish and Pan, Ruimin and Upadhyay, Chitra and Mayr, Luzia and Cohen, Sandra and Wang, Xiao-Hong and Balasubramanian, Preetha and Nádas, Arthur and Seaman, Michael S. and Zolla-Pazner, Susan and Gorny, Miroslaw K. and Kong, Xiang-Peng and Hioe, Catarina E.},
abstractNote = {The V3 region of HIV-1 gp120 is important for virus-coreceptor interaction and highly immunogenic. Although most anti-V3 antibodies neutralize only the sensitive tier 1 viruses, anti-V3 antibodies effective against the more resistant viruses exist, and a better understanding of these antibodies and their epitopes would be beneficial for the development of novel vaccine immunogens against HIV. The HIV-1 isolate JRFL with its cryptic V3 is resistant to most V3-specific monoclonal antibodies (MAbs). However, the V3 MAb 2424 achieves 100% neutralization against JRFL. 2424 is encoded by IGHV3-53 and IGLV2-28 genes, a pairing rarely used by the other V3 MAbs. 2424 also has distinct binding and neutralization profiles. Studies of 2424-mediated neutralization of JRFL produced with a mannosidase inhibitor further revealed that its neutralizing activity is unaffected by the glycan composition of the virus envelope. To understand the distinct activity of 2424, we determined the crystal structure of 2424 Fab in complex with a JRFL V3 peptide and showed that the 2424 epitope is located at the tip of the V3 crown (307IHIGPGRAFYT319), dominated by interactions with HisP308, ProP313, and ArgP315. The binding mode of 2424 is similar to that of the well-characterized MAb 447-52D, although 2424 is more side chain dependent. The 2424 epitope is focused on the very apex of V3, away from nearby glycans, facilitating antibody access. Lastly, this feature distinguishes the 2424 epitope from the other V3 crown epitopes and indicates that the tip of V3 is a potential site to target and incorporate into HIV vaccine immunogens.},
doi = {10.1128/JVI.01280-15},
journal = {Journal of Virology},
issn = {0022-538X},
number = 17,
volume = 89,
place = {United States},
year = {2015},
month = {6}
}

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

Citation Metrics:
Cited by: 9 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

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


Broad and potent HIV-1 neutralization by a human antibody that binds the gp41–gp120 interface
journal, September 2014

  • Huang, Jinghe; Kang, Byong H.; Pancera, Marie
  • Nature, Vol. 515, Issue 7525
  • DOI: 10.1038/nature13601

Structure of Antibody F425-B4e8 in Complex with a V3 Peptide Reveals a New Binding Mode for HIV-1 Neutralization
journal, January 2008

  • Bell, Christian H.; Pantophlet, Ralph; Schiefner, André
  • Journal of Molecular Biology, Vol. 375, Issue 4
  • DOI: 10.1016/j.jmb.2007.11.013

Broad neutralization coverage of HIV by multiple highly potent antibodies
journal, September 2011

  • Walker, Laura M.; Huber, Michael; Doores, Katie J.
  • Nature, Vol. 477, Issue 7365
  • DOI: 10.1038/nature10373

Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design
journal, October 2011


Distinct Mechanisms Regulate Exposure of Neutralizing Epitopes in the V2 and V3 Loops of HIV-1 Envelope
journal, August 2014

  • Upadhyay, C.; Mayr, L. M.; Zhang, J.
  • Journal of Virology, Vol. 88, Issue 21
  • DOI: 10.1128/JVI.02125-14

A broad range of mutations in HIV-1 neutralizing human monoclonal antibodies specific for V2, V3, and the CD4 binding site
journal, August 2015


Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein
journal, July 2012

  • Klein, Florian; Gaebler, Christian; Mouquet, Hugo
  • The Journal of Experimental Medicine, Vol. 209, Issue 8
  • DOI: 10.1084/jem.20120423

Cross-clade neutralizing antibodies against HIV-1 induced in rabbits by focusing the immune response on a neutralizing epitope
journal, September 2009


Prevention of HIV-1 infection in chimpanzees by gpl20 V3 domain-specific monoclonal antibody
journal, February 1992

  • Emini, E. A.; Schleif, W. A.; Nunberg, J. H.
  • Nature, Vol. 355, Issue 6362
  • DOI: 10.1038/355728a0

Quantitative assessment of masking of neutralization epitopes in HIV-1
journal, September 2011


Human Anti-V3 HIV-1 Monoclonal Antibodies Encoded by the VH5-51/VL Lambda Genes Define a Conserved Antigenic Structure
journal, December 2011


HIV-1 Entry Cofactor: Functional cDNA Cloning of a Seven-Transmembrane, G Protein-Coupled Receptor
journal, May 1996


A systematic study of the N-glycosylation sites of HIV-1 envelope protein on infectivity and antibody-mediated neutralization
journal, February 2013


Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody
journal, June 1998

  • Kwong, Peter D.; Wyatt, Richard; Robinson, James
  • Nature, Vol. 393, Issue 6686
  • DOI: 10.1038/31405

Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals
journal, March 2009

  • Scheid, Johannes F.; Mouquet, Hugo; Feldhahn, Niklas
  • Nature, Vol. 458, Issue 7238
  • DOI: 10.1038/nature07930

Identification of a major co-receptor for primary isolates of HIV-1
journal, June 1996

  • Deng, HongKui; Liu, Rong; Ellmeier, Wilfried
  • Nature, Vol. 381, Issue 6584
  • DOI: 10.1038/381661a0

Production of site-selected neutralizing human monoclonal antibodies against the third variable domain of the human immunodeficiency virus type 1 envelope glycoprotein.
journal, April 1991

  • Gorny, M. K.; Xu, J. Y.; Gianakakos, V.
  • Proceedings of the National Academy of Sciences, Vol. 88, Issue 8
  • DOI: 10.1073/pnas.88.8.3238

Evaluating Neutralizing Antibodies Against HIV, SIV, and SHIV in Luciferase Reporter Gene Assays
journal, December 2004


Neutralizing antibody responses to subtype B and C adjuvanted HIV envelope protein vaccination in rabbits
journal, April 2009


Vaccine-induced Human Antibodies Specific for the Third Variable Region of HIV-1 gp120 Impose Immune Pressure on Infecting Viruses
journal, November 2014


Antibody 2G12 Recognizes Di-Mannose Equivalently in Domain- and Nondomain-Exchanged Forms but Only Binds the HIV-1 Glycan Shield if Domain Exchanged
journal, August 2010

  • Doores, Katie J.; Fulton, Zara; Huber, Michael
  • Journal of Virology, Vol. 84, Issue 20
  • DOI: 10.1128/JVI.01110-10

HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5
journal, June 1996

  • Dragic, Tatjana; Litwin, Virginia; Allaway, Graham P.
  • Nature, Vol. 381, Issue 6584
  • DOI: 10.1038/381667a0

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


Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Assessment of Neutralizing Antibodies
journal, November 2009

  • Seaman, M. S.; Janes, H.; Hawkins, N.
  • Journal of Virology, Vol. 84, Issue 3
  • DOI: 10.1128/JVI.02108-09

XDS
journal, January 2010

  • Kabsch, Wolfgang
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
  • DOI: 10.1107/S0907444909047337

Clonal analysis of human anti-V3 monoclonal antibodies selected by a V3 tetramer
journal, March 2013

  • Li, Liuzhe; Wang, Xiao-Hong; Banerjee, Sagarika
  • Human Antibodies, Vol. 21, Issue 3-4
  • DOI: 10.3233/HAB-130264

Anti-V3 Monoclonal Antibodies Display Broad Neutralizing Activities against Multiple HIV-1 Subtypes
journal, April 2010


Variable Loop Glycan Dependency of the Broad and Potent HIV-1-Neutralizing Antibodies PG9 and PG16
journal, August 2010

  • Doores, Katie J.; Burton, Dennis R.
  • Journal of Virology, Vol. 84, Issue 20
  • DOI: 10.1128/JVI.00552-10

Conserved sequence and structural elements in the HIV-1 principal neutralizing determinant
journal, August 1990


High Prevalence of Antibodies to the gp120 V3 Region Principal Neutralizing Determinant of HIV-1 MN in Sera from Africa and the Americas
journal, October 1991

  • Carrow, Emily W.; Vujcic, Luba K.; Glass, Wendy L.
  • AIDS Research and Human Retroviruses, Vol. 7, Issue 10
  • DOI: 10.1089/aid.1991.7.831

Coot model-building tools for molecular graphics
journal, November 2004

  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
  • DOI: 10.1107/S0907444904019158

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


Structural Rationale for the Broad Neutralization of HIV-1 by Human Monoclonal Antibody 447-52D
journal, February 2004


A Human Antibody to the CD4 Binding Site of gp120 Capable of Highly Potent but Sporadic Cross Clade Neutralization of Primary HIV-1
journal, August 2013


ICM?A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation
journal, May 1994

  • Abagyan, Ruben; Totrov, Maxim; Kuznetsov, Dmitry
  • Journal of Computational Chemistry, Vol. 15, Issue 5
  • DOI: 10.1002/jcc.540150503

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding.
journal, August 1991

  • Sattentau, Q. J.; Moore, J. P.
  • The Journal of Experimental Medicine, Vol. 174, Issue 2
  • DOI: 10.1084/jem.174.2.407

A Potent and Broad Neutralizing Antibody Recognizes and Penetrates the HIV Glycan Shield
journal, October 2011


The V1, V2, and V3 Regions of the Human Immunodeficiency Virus Type 1 Envelope Differentially Affect the Viral Phenotype in an Isolate-Dependent Manner
journal, July 2005


Structure of 2G12 Fab2 in Complex with Soluble and Fully Glycosylated HIV-1 Env by Negative-Stain Single-Particle Electron Microscopy
journal, June 2014

  • Murin, C. D.; Julien, J. -P.; Sok, D.
  • Journal of Virology, Vol. 88, Issue 17
  • DOI: 10.1128/JVI.01229-14

The Effects of Somatic Hypermutation on Neutralization and Binding in the PGT121 Family of Broadly Neutralizing HIV Antibodies
journal, November 2013


Autoreactivity in Human IgG+ Memory B Cells
journal, February 2007


Progress in HIV-1 vaccine development
journal, July 2014

  • Haynes, Barton F.; Moody, M. Anthony; Alam, Munir
  • Journal of Allergy and Clinical Immunology, Vol. 134, Issue 1
  • DOI: 10.1016/j.jaci.2014.04.025

Conserved structural elements in the V3 crown of HIV-1 gp120
journal, July 2010

  • Jiang, Xunqing; Burke, Valicia; Totrov, Maxim
  • Nature Structural & Molecular Biology, Vol. 17, Issue 8
  • DOI: 10.1038/nsmb.1861

Induction of CD4-dependent cell fusion by the HTLV-III/LAV envelope glycoprotein
journal, October 1986

  • Lifson, Jeffrey D.; Feinberg, Mark B.; Reyes, Gregory R.
  • Nature, Vol. 323, Issue 6090
  • DOI: 10.1038/323725a0

Role of Complex Carbohydrates in Human Immunodeficiency Virus Type 1 Infection and Resistance to Antibody Neutralization
journal, March 2010

  • Binley, James M.; Ban, Yih-En Andrew; Crooks, Emma T.
  • Journal of Virology, Vol. 84, Issue 11
  • DOI: 10.1128/JVI.00105-10

The V3 Loop Is Accessible on the Surface of Most Human Immunodeficiency Virus Type 1 Primary Isolates and Serves as a Neutralization Epitope
journal, March 2004


HIV-1 gp120 Vaccine Induces Affinity Maturation in both New and Persistent Antibody Clonal Lineages
journal, May 2012

  • Moody, M. A.; Yates, N. L.; Amos, J. D.
  • Journal of Virology, Vol. 86, Issue 14
  • DOI: 10.1128/JVI.00426-12

Preferential use of the VH5-51 gene segment by the human immune response to code for antibodies against the V3 domain of HIV-1
journal, February 2009


Diversity Considerations in HIV-1 Vaccine Selection
journal, June 2002

  • Gaschen, Brian; Taylor, Jesse; Yusim, Karina
  • Science, Vol. 296, Issue 5577, p. 2354-2360
  • DOI: 10.1126/science.1070441

Structural Basis of the Cross-Reactivity of Genetically Related Human Anti-HIV-1 mAbs: Implications for Design of V3-Based Immunogens
journal, November 2009


Complete Nucleotide Sequences of Functional Clones of the AIDS Virus
journal, January 1987

  • Ratner, Lee; Fisher, Amanda; Jagodzinski, Linda L.
  • AIDS Research and Human Retroviruses, Vol. 3, Issue 1
  • DOI: 10.1089/aid.1987.3.57

    Works referencing / citing this record:

    Difficult-to-neutralize global HIV-1 isolates are neutralized by antibodies targeting open envelope conformations
    journal, July 2019