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

Abstract

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 β-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. The crystal structure of V1/V2, the only unresolved portion of the HIV-1 gp120 envelope glycoprotein, is reported in complex with human antibody PG9 and reveals a paradigm of antibody recognition with implications for vaccine development. The V1/V2 variable region of the gp120 envelope glycoprotein of HIV-1, with its extraordinary sequence diversity and N-linked glycosylation, exemplifies the ability of the virus to evade antibody recognition. It has also resisted structural determination. Now Peter Kwong and colleagues have determined the atomic-level structure of gp120 V1/V2 by using an antibody called PG9, which can neutralize most strains of HIV. Instead of being confounded by the N-linked glycan that shields most of gp120 from immune recognition, PG9 uses N-linked glycan for binding through a mechanism shared by a number of antibodies capable of effective HIV neutralization. The structure shows that the antibody recognizes glycopeptide conjugates and avoids diversity in V1/V2 by making sequence-independent interactions, such as hydrogen bonds.