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Letters to Nature

Nature 422, 307-312 (20 March 2003) | doi:10.1038/nature01470; Received 6 December 2002; Accepted 30 January 2003

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Antibody neutralization and escape by HIV-1

Xiping Wei1, Julie M. Decker1, Shuyi Wang1, Huxiong Hui2, John C. Kappes2,3, Xiaoyun Wu2, Jesus F. Salazar-Gonzalez2, Maria G. Salazar2, J. Michael Kilby2, Michael S. Saag2, Natalia L. Komarova4, Martin A. Nowak4, Beatrice H. Hahn2,3, Peter D. Kwong5 & George M. Shaw1,2,3

  1. Howard Hughes Medical Institute, University of Alabama at Birmingham, 720 South 20th Street, KAUL 816, Birmingham, Alabama 35294-0024, USA
  2. Department of Medicine, University of Alabama at Birmingham, 720 South 20th Street, KAUL 816, Birmingham, Alabama 35294-0024, USA
  3. Department of Microbiology, University of Alabama at Birmingham, 720 South 20th Street, KAUL 816, Birmingham, Alabama 35294-0024, USA
  4. Institute for Advanced Study, Princeton, New Jersey 08540, USA
  5. Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA

Correspondence to: George M. Shaw1,2,3 Correspondence and requests for materials should be addressed to G.M.S. (e-mail: Email: gshaw@uab.edu).

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Neutralizing antibodies (Nab) are a principal component of an effective human immune response to many pathogens, yet their role in HIV-1 infection is unclear1, 2, 3, 4, 5, 6. To gain a better understanding of this role, we examined plasma from patients with acute HIV infection. Here we report the detection of autologous Nab as early as 52 days after detection of HIV-specific antibodies. The viral inhibitory activity of Nab resulted in complete replacement of neutralization-sensitive virus by successive populations of resistant virus. Escape virus contained mutations in the env gene that were unexpectedly sparse, did not map generally to known neutralization epitopes, and involved primarily changes in N-linked glycosylation. This pattern of escape, and the exceptional density of HIV-1 envelope glycosylation generally7, 8, led us to postulate an evolving 'glycan shield' mechanism of neutralization escape whereby selected changes in glycan packing prevent Nab binding but not receptor binding. Direct support for this model was obtained by mutational substitution showing that Nab-selected alterations in glycosylation conferred escape from both autologous antibody and epitope-specific monoclonal antibodies. The evolving glycan shield thus represents a new mechanism contributing to HIV-1 persistence in the face of an evolving antibody repertoire.