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Pathogenesis and Immunity

Access of Antibody Molecules to the Conserved Coreceptor Binding Site on Glycoprotein gp120 Is Sterically Restricted on Primary Human Immunodeficiency Virus Type 1

Aran F. Labrijn, Pascal Poignard, Aarti Raja, Michael B. Zwick, Karla Delgado, Michael Franti, James Binley, Veronique Vivona, Christoph Grundner, Chih-Chin Huang, Miro Venturi, Christos J. Petropoulos, Terri Wrin, Dimiter S. Dimitrov, James Robinson, Peter D. Kwong, Richard T. Wyatt, Joseph Sodroski, Dennis R. Burton
Aran F. Labrijn
1Department of Immunology
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Pascal Poignard
1Department of Immunology
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Aarti Raja
2Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute
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Michael B. Zwick
1Department of Immunology
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Karla Delgado
1Department of Immunology
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Michael Franti
1Department of Immunology
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James Binley
1Department of Immunology
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Veronique Vivona
1Department of Immunology
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Christoph Grundner
2Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute
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Chih-Chin Huang
3Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda
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Miro Venturi
3Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda
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Christos J. Petropoulos
4ViroLogic, Inc., South San Francisco, California
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Terri Wrin
4ViroLogic, Inc., South San Francisco, California
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Dimiter S. Dimitrov
5Laboratory of Experimental and Computational Biology, National Cancer Institute-Frederick, National Institute of Health, Frederick, Maryland
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James Robinson
6Department of Pediatrics, Tulane University Medical Center, New Orleans, Louisiana
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Peter D. Kwong
3Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda
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Richard T. Wyatt
2Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute
3Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda
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Joseph Sodroski
2Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute
7Department of Pathology, Division of AIDS, Harvard Medical School
8Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts
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Dennis R. Burton
1Department of Immunology
9Department of Molecular Biology, The Scripps Research Institute, La Jolla
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  • For correspondence: burton@scripps.edu
DOI: 10.1128/JVI.77.19.10557-10565.2003
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ABSTRACT

Anti-human immunodeficiency virus type 1 (HIV-1) antibodies whose binding to gp120 is enhanced by CD4 binding (CD4i antibodies) are generally considered nonneutralizing for primary HIV-1 isolates. However, a novel CD4i-specific Fab fragment, X5, has recently been found to neutralize a wide range of primary isolates. To investigate the precise nature of the extraordinary neutralizing ability of Fab X5, we evaluated the abilities of different forms (immunoglobulin G [IgG], Fab, and single-chain Fv) of X5 and other CD4i monoclonal antibodies to neutralize a range of primary HIV-1 isolates. Our results show that, for a number of isolates, the size of the neutralizing agent is inversely correlated with its ability to neutralize. Thus, the poor ability of CD4i-specific antibodies to neutralize primary isolates is due, at least in part, to steric factors that limit antibody access to the gp120 epitopes. Studies of temperature-regulated neutralization or fusion-arrested intermediates suggest that the steric effects are important in limiting the binding of IgG to the viral envelope glycoproteins after HIV-1 has engaged CD4 on the target cell membrane. The results identify hurdles in using CD4i epitopes as targets for antibody-mediated neutralization in vaccine design but also indicate that the CD4i regions could be efficiently targeted by small molecule entry inhibitors.

  • Copyright © 2003 American Society for Microbiology
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Access of Antibody Molecules to the Conserved Coreceptor Binding Site on Glycoprotein gp120 Is Sterically Restricted on Primary Human Immunodeficiency Virus Type 1
Aran F. Labrijn, Pascal Poignard, Aarti Raja, Michael B. Zwick, Karla Delgado, Michael Franti, James Binley, Veronique Vivona, Christoph Grundner, Chih-Chin Huang, Miro Venturi, Christos J. Petropoulos, Terri Wrin, Dimiter S. Dimitrov, James Robinson, Peter D. Kwong, Richard T. Wyatt, Joseph Sodroski, Dennis R. Burton
Journal of Virology Sep 2003, 77 (19) 10557-10565; DOI: 10.1128/JVI.77.19.10557-10565.2003

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Access of Antibody Molecules to the Conserved Coreceptor Binding Site on Glycoprotein gp120 Is Sterically Restricted on Primary Human Immunodeficiency Virus Type 1
Aran F. Labrijn, Pascal Poignard, Aarti Raja, Michael B. Zwick, Karla Delgado, Michael Franti, James Binley, Veronique Vivona, Christoph Grundner, Chih-Chin Huang, Miro Venturi, Christos J. Petropoulos, Terri Wrin, Dimiter S. Dimitrov, James Robinson, Peter D. Kwong, Richard T. Wyatt, Joseph Sodroski, Dennis R. Burton
Journal of Virology Sep 2003, 77 (19) 10557-10565; DOI: 10.1128/JVI.77.19.10557-10565.2003
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KEYWORDS

CD4 Antigens
HIV Antibodies
HIV Envelope Protein gp120
HIV-1

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