Abstract
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 âglycan shieldâ 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.
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Acknowledgements
We thank S. Zolla-Pazner for HIV-1 V3 specific monoclonal antibodies; D. Burton, B. Korber, J. Mascola, D. Montefiore, J. Moore, L. Shapiro and R. Wyatt for discussions; S. Meleth for assistance with statistical analyses; and W. Abbott for artwork and technical assistance. This work was supported by the Acute Infection Early Disease Research Program of the National Institutes of Allergy and Infectious Diseases, the UAB Center for AIDS Research, the UAB General Clinical Research Center, and the National Institutes of Health. We also thank Bristol-Myers Squibb, GlaxoSmithKline, Agouron and Merck for continuing support of acute HIV-1 infection studies.
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Wei, X., Decker, J., Wang, S. et al. Antibody neutralization and escape by HIV-1. Nature 422, 307â312 (2003). https://doi.org/10.1038/nature01470
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DOI: https://doi.org/10.1038/nature01470
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