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

Nature volume 420, pages 678–682 (2002)Cite this article

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.

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Figure 1: HIV-1 gp120: structure, receptor binding, antigenicity and entropy of antibody binding.
Figure 2: Thermodynamic cycles of 17b and 48d with CD4.

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Acknowledgements

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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Author notes

  1. Michael L. Doyle & Wayne A. Hendrickson

    Present address: Biopharmaceuticals Department H13-07, Bristol-Myers Squibb PRI, Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey, 08543-4000, USA

Authors and Affiliations

  1. Vaccine Research Center, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Peter D. Kwong, Shahzad Majeed, Miro Venturi & Richard Wyatt

  2. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Claudia Cicala, Tavis D. Steenbeke & James Arthos

  3. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, 10032, USA

    Peter D. Kwong, Shahzad Majeed & Wayne A. Hendrickson

  4. Howard Hughes Medical Institute, Columbia University, USA, New York, 10032, New York

    Wayne A. Hendrickson

  5. Department of Structural Biology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, 19406, USA

    Michael L. Doyle & David J. Casper

  6. Department of Biology, Johns Hopkins University, Baltimore, Maryland, 21218, USA

    Stephanie A. Leavitt & Ernesto Freire

  7. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Irwin Chaiken & Donald Van Ryk

  8. Cell Biology, Tanox, Houston, Texas, 77025, USA

    Michael Fung

  9. Institute for Applied Microbiology, University of Agriculture and Forestry, A-1190, Vienna, Austria

    Hermann Katinger

  10. Departments of Immunology and Molecular Biology, Scripps Research Institute, La Jolla, California, 92037, USA

    Paul W. I. H. Parren & Dennis R. Burton

  11. Department of Pediatrics, Tulane University Medical Center, New Orleans, Louisiana, 70112, USA

    James Robinson

  12. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Pathology, Division of AIDS, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Liping Wang, Richard Wyatt & Joseph Sodroski

  13. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, 02115, USA

    Joseph Sodroski

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Correspondence to Peter D. Kwong.

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Kwong, P., Doyle, M., Casper, D. et al. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature 420, 678–682 (2002). https://doi.org/10.1038/nature01188

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