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 XueLing; Zhou Tongqing; Jiang Zhu; Zhang BaoShan; Georgiev, I.; Wang, C.; Chen XueJun; Longo, NN.S.; Louder, M.; McKee, K.; O’Dell, S.; Perfetto, S.; Schmidt, S.D.; Wei Shi; Lan Wu; Yang YongPing; Yang ZhiYong; Yang ZhongJia; Zhang ZhenHai; Bonsignori, M.; Crump, J.A.; Kapiga, S.H.; Sam, N.E.; Haynes, B.F.; Simek, M.; Burton, D.R.; Koff, W.C.; Doria-Rose, N.A.; Connors, M.; Mullikin, J.C.; Nabel, G.J.; Roederer, M.; Shapiro, L.; Kwong, P.D.; Mascola, J.R. . Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing. Science (2011) 333 (6049) 1593-1602. [DOI: 10.1126/science.1207532]