Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing |
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| Authors: | Wu Xueling,Zhou Tongqing,Zhu Jiang,Zhang Baoshan,Georgiev Ivelin,Wang Charlene,Chen Xuejun,Longo Nancy S,Louder Mark,McKee Krisha,O'Dell Sijy,Perfetto Stephen,Schmidt Stephen D,Shi Wei,Wu Lan,Yang Yongping,Yang Zhi-Yong,Yang Zhongjia,Zhang Zhenhai,Bonsignori Mattia,Crump John A,Kapiga Saidi H,Sam Noel E,Haynes Barton F,Simek Melissa,Burton Dennis R,Koff Wayne C,Doria-Rose Nicole A,Connors Mark NISC Comparative Sequencing Program,Mullikin James C,Nabel Gary J,Roederer Mario,Shapiro Lawrence,Kwong Peter D,Mascola John R |
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| Affiliation: | Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA. |
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| Abstract: | 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. |
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