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

Academic Article
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Overview

authors

  • Kwong, P. D.
  • Doyle, M. L.
  • Casper, D. J.
  • Cicala, C.
  • Leavitt, S. A.
  • Majeed, S.
  • Steenbeke, T. D.
  • Venturi, M.
  • Chaiken, I.
  • Fung, M.
  • Katinger, H.
  • Parren, P .W. I. H.
  • Robinson, J.
  • Van Ryk, D.
  • Wang, L. P.
  • Burton, Dennis
  • Freire, E.
  • Wyatt, Richard
  • Sodroski, J.
  • Hendrickson, W. A.
  • Arthos, J.

publication date

  • December 2002

journal

  • Nature  Journal

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.

subject areas

  • Antibody Affinity
  • Antigens, CD4
  • Binding Sites
  • Calorimetry
  • Entropy
  • Epitopes
  • Glycosylation
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV-1
  • Humans
  • Models, Molecular
  • Neutralization Tests
  • Protein Conformation
  • Receptors, HIV
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Identity

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature01188

PubMed ID

  • 12478295
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Additional Document Info

start page

  • 678

end page

  • 682

volume

  • 420

issue

  • 6916

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