Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing.
Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.
Wu, X; Zhou, T; Zhu, J; Zhang, B; Georgiev, I; Wang, C; Chen, X; Longo, NS; Louder, M; McKee, K; O'Dell, S; Perfetto, S; Schmidt, SD; Shi, W; Wu, L; Yang, Y; Yang, Z-Y; Yang, Z; Zhang, Z; Bonsignori, M; Crump, JA; Kapiga, SH; Sam, NE; Haynes, BF; Simek, M; Burton, DR; Koff, WC; Doria-Rose, NA; Connors, M; NISC Comparative Sequencing Program, ; Mullikin, JC; Nabel, GJ; Roederer, M; Shapiro, L; Kwong, PD; Mascola, JR
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