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. HendricksonJames Arthos

Research output: Contribution to journalArticlepeer-review

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 capacity. 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 footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, 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.

Original languageEnglish (US)
Pages (from-to)678-682
Number of pages5
JournalNature
Volume420
Issue number6916
DOIs
StatePublished - Dec 12 2002

ASJC Scopus subject areas

  • General

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