HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites

Peter D. Kwong (), Michael L. Doyle, David J. Casper, Claudia Cicala, Stephanie A. Leavitt, Shahzad Majeed, Tavis D. Steenbeke, Miro Venturi, Irwin Chaiken, Michael Fung, Hermann Katinger, Paul W. I. H. Parren, James Robinson, Donald Van Ryk, Liping Wang, Dennis R. Burton, Ernesto Freire, Richard Wyatt, Joseph Sodroski, Wayne A. Hendrickson and James Arthos
Additional contact information
Peter D. Kwong: National Institutes of Health
Michael L. Doyle: GlaxoSmithKline Pharmaceuticals
David J. Casper: GlaxoSmithKline Pharmaceuticals
Claudia Cicala: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Stephanie A. Leavitt: Johns Hopkins University
Shahzad Majeed: National Institutes of Health
Tavis D. Steenbeke: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Miro Venturi: National Institutes of Health
Irwin Chaiken: University of Pennsylvania
Michael Fung: Cell Biology, Tanox
Hermann Katinger: University of Agriculture and Forestry
Paul W. I. H. Parren: Scripps Research Institute
James Robinson: Tulane University Medical Center
Donald Van Ryk: University of Pennsylvania
Liping Wang: Harvard Medical School
Dennis R. Burton: Scripps Research Institute
Ernesto Freire: Johns Hopkins University
Richard Wyatt: National Institutes of Health
Joseph Sodroski: Harvard Medical School
Wayne A. Hendrickson: Columbia University
James Arthos: National Institute of Allergy and Infectious Diseases, National Institutes of Health

Nature, 2002, vol. 420, issue 6916, 678-682

Abstract: Abstract The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity1. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint2 and should therefore be accessible for antibody binding. Because gp120–receptor interactions involve conformational reorganization3, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor–antibody thermodynamic cycles suggested a receptor-binding-site ‘conformational masking’ mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus–receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.

Date: 2002
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DOI: 10.1038/nature01188

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