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

Jason S. McLellan, Marie Pancera, Chris Carrico, Jason Gorman, Jean-Philippe Julien, Reza Khayat, Robert Louder, Robert Pejchal, Mallika Sastry, Kaifan Dai, Sijy O’Dell, Nikita Patel, Syed Shahzad-ul-Hussan, Yongping Yang, Baoshan Zhang, Tongqing Zhou, Jiang Zhu, Jeffrey C. Boyington, Gwo-Yu Chuang, Devan Diwanji, Ivelin Georgiev, Young Do Kwon, Doyung Lee, Mark K. Louder, Stephanie Moquin, Stephen D. Schmidt, Zhi-Yong Yang, Mattia Bonsignori, John A. Crump, Saidi H. Kapiga, Noel E. Sam, Barton F. Haynes, Dennis R. Burton, Wayne C. Koff, Laura M. Walker, Sanjay Phogat, Richard Wyatt, Jared Orwenyo, Lai-Xi Wang, James Arthos, Carole A. Bewley, John R. Mascola, Gary J. Nabel, William R. Schief, Andrew B. Ward, Ian A. Wilson and Peter D. Kwong ()
Additional contact information
Jason S. McLellan: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Marie Pancera: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Chris Carrico: University of Washington, Seattle, Washington 98195, USA
Jason Gorman: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Jean-Philippe Julien: The Scripps Research Institute, La Jolla, California 92037, USA
Reza Khayat: The Scripps Research Institute, La Jolla, California 92037, USA
Robert Louder: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Robert Pejchal: The Scripps Research Institute, La Jolla, California 92037, USA
Mallika Sastry: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Kaifan Dai: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Sijy O’Dell: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Nikita Patel: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Syed Shahzad-ul-Hussan: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Yongping Yang: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Baoshan Zhang: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Tongqing Zhou: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Jiang Zhu: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Jeffrey C. Boyington: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Gwo-Yu Chuang: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Devan Diwanji: The Scripps Research Institute, La Jolla, California 92037, USA
Ivelin Georgiev: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Young Do Kwon: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Doyung Lee: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Mark K. Louder: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Stephanie Moquin: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Stephen D. Schmidt: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Zhi-Yong Yang: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Mattia Bonsignori: The Duke Human Vaccine Institute, Duke University School of Medicine, and Duke University Medical Center, Durham, North Carolina 27710, USA
John A. Crump: Duke University Medical Center, Durham, North Carolina 27710, USA
Saidi H. Kapiga: Kilimanjaro Reproductive Health Programme
Noel E. Sam: Kilimanjaro Christian Medical Centre and Kilimanjaro Christian Medical College, Tumaini University
Barton F. Haynes: The Duke Human Vaccine Institute, Duke University School of Medicine, and Duke University Medical Center, Durham, North Carolina 27710, USA
Dennis R. Burton: The Scripps Research Institute, La Jolla, California 92037, USA
Wayne C. Koff: International AIDS Vaccine Initiative (IAVI), New York, New York 10004, USA
Laura M. Walker: The Scripps Research Institute, La Jolla, California 92037, USA
Sanjay Phogat: International AIDS Vaccine Initiative (IAVI), New York, New York 10004, USA
Richard Wyatt: IAVI Neutralizing Antibody Center at TSRI, The Scripps Research Institute, La Jolla, California 92037, USA
Jared Orwenyo: University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
Lai-Xi Wang: University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
James Arthos: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Carole A. Bewley: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
John R. Mascola: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Gary J. Nabel: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
William R. Schief: University of Washington, Seattle, Washington 98195, USA
Andrew B. Ward: The Scripps Research Institute, La Jolla, California 92037, USA
Ian A. Wilson: The Scripps Research Institute, La Jolla, California 92037, USA
Peter D. Kwong: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

Nature, 2011, vol. 480, issue 7377, 336-343

Abstract: 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.

Date: 2011
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DOI: 10.1038/nature10696

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