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.
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We thank M. Dybul for providing primary isolates pi102, pi104, pi202 and pi204; M. A. Gawinowisc for matrix-assisted laser desorption/ionization–time of flight analysis; Z. Moodie and A. Palmer for help with error analysis; A. Fauci, S. Harrison, A. Miranker, R. Seder and L. Shapiro for discussions; and D. Dimitrov, B. Kwong, N. Letvin, J. Mascola, G. Nabel and Q. Sattentau for comments. This work was supported by grants from the National Institutes of Health and by a Center for AIDS Research grant to the Dana-Farber Cancer Institute. The Dana-Farber Cancer Institute is also the recipient of a Cancer Center Grant from the National Institutes of Health. Columbia University is a participant in a Center for AIDS Research. R.W. was a fellow of the American Foundation for AIDS Research and P.D.K. was a recipient of a Burroughs Wellcome Career Development award.
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