Polyclonal B cell responses to conserved neutralization epitopes in a subset of HIV-1-infected individuals.
A small proportion of HIV-infected individuals generate a neutralizing antibody (NAb) response of exceptional magnitude and breadth. A detailed analysis of the critical epitopes targeted by broadly neutralizing antibodies should help to define optimal targets for vaccine design. HIV-1-infected subjects with potent cross-reactive serum neutralizing antibodies were identified by assaying sera from 308 subjects against a multiclade panel of 12 "tier 2" viruses (4 each of subtypes A, B, and C). Various neutralizing epitope specificities were determined for the top 9 neutralizers, including clade A-, clade B-, clade C-, and clade A/C-infected donors, by using a comprehensive set of assays. In some subjects, neutralization breadth was mediated by two or more antibody specificities. Although antibodies to the gp41 membrane-proximal external region (MPER) were identified in some subjects, the subjects with the greatest neutralization breadth targeted gp120 epitopes, including the CD4 binding site, a glycan-containing quaternary epitope formed by the V2 and V3 loops, or an outer domain epitope containing a glycan at residue N332. The broadly reactive HIV-1 neutralization observed in some subjects is mediated by antibodies targeting several conserved regions on the HIV-1 envelope glycoprotein.
Tomaras, GD; Binley, JM; Gray, ES; Crooks, ET; Osawa, K; Moore, PL; Tumba, N; Tong, T; Shen, X; Yates, NL; Decker, J; Wibmer, CK; Gao, F; Alam, SM; Easterbrook, P; Abdool Karim, S; Kamanga, G; Crump, JA; Cohen, M; Shaw, GM; Mascola, JR; Haynes, BF; Montefiori, DC; Morris, L
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