Author
Listed:
- Peter D. Kwong
(National Institutes of Health
Columbia University)
- Michael L. Doyle
(GlaxoSmithKline Pharmaceuticals
Pharmaceutical Research Institute)
- David J. Casper
(GlaxoSmithKline Pharmaceuticals)
- Claudia Cicala
(National Institute of Allergy and Infectious Diseases, National Institutes of Health)
- Stephanie A. Leavitt
(Johns Hopkins University)
- Shahzad Majeed
(National Institutes of Health
Columbia University)
- Tavis D. Steenbeke
(National Institute of Allergy and Infectious Diseases, National Institutes of Health)
- Miro Venturi
(National Institutes of Health)
- Irwin Chaiken
(University of Pennsylvania)
- Michael Fung
(Cell Biology, Tanox)
- Hermann Katinger
(University of Agriculture and Forestry)
- Paul W. I. H. Parren
(Scripps Research Institute)
- James Robinson
(Tulane University Medical Center)
- Donald Van Ryk
(University of Pennsylvania)
- Liping Wang
(Harvard Medical School)
- Dennis R. Burton
(Scripps Research Institute)
- Ernesto Freire
(Johns Hopkins University)
- Richard Wyatt
(National Institutes of Health
Harvard Medical School)
- Joseph Sodroski
(Harvard Medical School
Harvard School of Public Health)
- Wayne A. Hendrickson
(Columbia University
Columbia University)
- James Arthos
(National Institute of Allergy and Infectious Diseases, National Institutes of Health)
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.
Suggested Citation
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 & Pau, 2002.
"HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites,"
Nature, Nature, vol. 420(6916), pages 678-682, December.
Handle:
RePEc:nat:nature:v:420:y:2002:i:6916:d:10.1038_nature01188
DOI: 10.1038/nature01188
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Citations
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Cited by:
- Kun-Wei Chan & Christina C. Luo & Hong Lu & Xueling Wu & Xiang-Peng Kong, 2021.
"A site of vulnerability at V3 crown defined by HIV-1 bNAb M4008_N1,"
Nature Communications, Nature, vol. 12(1), pages 1-12, December.
- Shuang Yang & Giorgos Hiotis & Yi Wang & Junjian Chen & Jia-huai Wang & Mikyung Kim & Ellis L. Reinherz & Thomas Walz, 2022.
"Dynamic HIV-1 spike motion creates vulnerability for its membrane-bound tripod to antibody attack,"
Nature Communications, Nature, vol. 13(1), pages 1-13, December.
- Catarina E Hioe & Terri Wrin & Michael S Seaman & Xuesong Yu & Blake Wood & Steve Self & Constance Williams & Miroslaw K Gorny & Susan Zolla-Pazner, 2010.
"Anti-V3 Monoclonal Antibodies Display Broad Neutralizing Activities against Multiple HIV-1 Subtypes,"
PLOS ONE, Public Library of Science, vol. 5(4), pages 1-14, April.
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