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166
Antibody Neutralization and Escape by HIV-1
G M Shaw
Howard Hughes Med Inst, Univ of Alabama at Birmingham
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Background: Neutralizing antibodies (Nab) are a principal component of an effective human immune response to many pathogens yet their biological role in HIV-1 infection is unclear.
Method: Here, we utilize a sensitive, single-round viral infectivity assay together with a detailed genetic analysis of virus evolution to show that in patients (pts) with acute HIV-1 infection Nab exert sufficient viral inhibitory activity as to result in complete replacement of neutralization sensitive virus by successive populations of resistant virus.
Results: Autologous Nab were detected as early as 72 days following seroconversion and reached titers (50% inhibitory concentration, IC50) as high as 1:2,500 by 7 months. Escape virus, which exhibited >100-fold phenotypic resistance to autologous Nab, contained mutations in env that were unexpectedly sparse, did not map to known neutralization epitopes, and involved primarily changes in N-linked glycosylation. This pattern of escape, in the context of an exceptional density of HIV-1 envelope glycosylation generally, 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 neutralization escape from both autologous antibody and V3 loop specific monoclonal antibodies.
Conclusion: The dynamics of Nab generation and virologic escape observed in this study provide direct evidence for Nab-mediated virus selection in vivo and suggest a novel mechanism allowing for HIV-1 persistence in the face of an evolving antibody repertoire.
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