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Nature 420, 678-682 (12 December 2002) | doi:10.1038/nature01188; Received 28 May 2002; Accepted 23 September 2002

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

Peter D. Kwong1,2, Michael L. Doyle3,4, David J. Casper3, Claudia Cicala5, Stephanie A. Leavitt6, Shahzad Majeed1,2, Tavis D. Steenbeke5, Miro Venturi1, Irwin Chaiken7, Michael Fung8, Hermann Katinger9, Paul W. I. H. Parren10, James Robinson11, Donald Van Ryk7, Liping Wang12, Dennis R. Burton10, Ernesto Freire6, Richard Wyatt1,12, Joseph Sodroski12,13, Wayne A. Hendrickson2,14 & James Arthos5

  1. Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA
  2. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
  3. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA
  4. Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA
  5. Department of Structural Biology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA
  6. Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, USA
  7. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
  8. Cell Biology, Tanox, Houston, Texas 77025, USA
  9. Institute for Applied Microbiology, University of Agriculture and Forestry, A-1190 Vienna, Austria
  10. Departments of Immunology and Molecular Biology, Scripps Research Institute, La Jolla, California 92037, USA
  11. Department of Pediatrics, Tulane University Medical Center, New Orleans, Louisiana 70112, USA
  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
  13. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA
  14. Present address: Biopharmaceuticals Department H13-07, Bristol-Myers Squibb PRI, Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA.

Correspondence to: Peter D. Kwong1,2 Correspondence and requests for materials should be addressed to P.D.K. (e-mail: Email: pdkwong@nih.gov).

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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.

  1. Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA
  2. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
  3. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA
  4. Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA
  5. Department of Structural Biology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA
  6. Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, USA
  7. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
  8. Cell Biology, Tanox, Houston, Texas 77025, USA
  9. Institute for Applied Microbiology, University of Agriculture and Forestry, A-1190 Vienna, Austria
  10. Departments of Immunology and Molecular Biology, Scripps Research Institute, La Jolla, California 92037, USA
  11. Department of Pediatrics, Tulane University Medical Center, New Orleans, Louisiana 70112, USA
  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
  13. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA
  14. Present address: Biopharmaceuticals Department H13-07, Bristol-Myers Squibb PRI, Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA.

Correspondence to: Peter D. Kwong1,2 Correspondence and requests for materials should be addressed to P.D.K. (e-mail: Email: pdkwong@nih.gov).