Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9


Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded ß-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which—with PG9—involves a site of vulnerability comprising just two glycans and a strand.


Arthos, J.; Bewley, C.A.; Bonsignori, M.; Boyington, J.C.; Burton, D.R.; Carrico, C.; Chuang GwoYu; Crump, J.A.; Devan Diwanji; Doyung Lee; Georgiev, I.; Gorman, J.; Haynes, B.F.; Jiang Zhu; Julien, J.P.; Kaifan Dai; Kapiga, S.H.; Koff, W.C.; Kwong, P.D.; Louder, M.K.; Louder, R.; Mascola, J.R.; McLellan, J.S.; Moquin, S.; Nabel, G.J.; O’Dell, S.; Orwenyo, J.; Pancera, M.; Patel, N.; Pejchal, R.; Khayat, R.; Sam, N.E.; Phogat, S.; Sastry, M.; Schief, W.R.; Schmidt, S.D.; Shahzad-ul-Hussan, S.; Tongqing Zhou; Walker, L.M.; Wang LaiXi; Ward, A.B.; Wilson, I.A.; Wyatt, R.; Yang YongPing; Yang ZhiYong; Young Do Kwon; Zhang BaoShan. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature (2011) 480 (7377) 336-343. [DOI: 10.1038/nature10696]

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