Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9 |
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Authors: | McLellan Jason S Pancera Marie Carrico Chris Gorman Jason Julien Jean-Philippe Khayat Reza Louder Robert Pejchal Robert Sastry Mallika Dai Kaifan O'Dell Sijy Patel Nikita Shahzad-ul-Hussan Syed Yang Yongping Zhang Baoshan Zhou Tongqing Zhu Jiang Boyington Jeffrey C Chuang Gwo-Yu Diwanji Devan Georgiev Ivelin Kwon Young Do Lee Doyung Louder Mark K Moquin Stephanie Schmidt Stephen D Yang Zhi-Yong Bonsignori Mattia Crump John A Kapiga Saidi H Sam Noel E Haynes Barton F Burton Dennis R Koff Wayne C Walker Laura M Phogat Sanjay Wyatt Richard Orwenyo Jared Wang Lai-Xi Arthos James Bewley Carole A |
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Institution: | Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. |
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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. |
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