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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Data deposits

Coordinates and structure factors for PG9 Fab in complexes with V1/V2 from CAP45 and ZM109 strains of HIV-1 have been deposited with the Protein Data Bank under accession codes 3U4E and 3U2S, respectively. Coordinates and structure factors for unbound Fab structures of PG9, CH04, CH04H/CH02L (in two lattices) and PGT145 have been deposited with the Protein Data Bank under accession codes, 3U36, 3TCL, 3U46, 3U4B and 3U1S, respectively.


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We thank A. Changela and X. Wu for assistance with mapping the PG16 paratope, J. Sodroski for discussions, J. Stuckey for assistance with figures, and members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions and comments on the manuscript. Support for this work was provided by the Intramural Research Program of the National Institutes of Health (NIH), by the International AIDS Vaccine Initiative, by the Ragon Institute, by the Canadian Institute of Health Research and by grants from the NIH. The three-dimensional reconstructions were conducted at the National Resource for Automated Molecular Microscopy (NRAMM), which is supported by the NIH through the National Center for Research Resources' P41 program (RR017573). Use of sector 22 (Southeast Regional Collaborative Access Team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38.

Author information

Author notes

    • Jason S. McLellan
    •  & Marie Pancera

    These authors contributed equally to this work.


  1. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Jason S. McLellan
    • , Marie Pancera
    • , Jason Gorman
    • , Robert Louder
    • , Mallika Sastry
    • , Kaifan Dai
    • , Sijy O’Dell
    • , Syed Shahzad-ul-Hussan
    • , Yongping Yang
    • , Baoshan Zhang
    • , Tongqing Zhou
    • , Jiang Zhu
    • , Jeffrey C. Boyington
    • , Gwo-Yu Chuang
    • , Ivelin Georgiev
    • , Young Do Kwon
    • , Doyung Lee
    • , Mark K. Louder
    • , Stephanie Moquin
    • , Stephen D. Schmidt
    • , Zhi-Yong Yang
    • , John R. Mascola
    • , Gary J. Nabel
    •  & Peter D. Kwong
  2. Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA

    • Chris Carrico
    •  & William R. Schief
  3. Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA

    • Jean-Philippe Julien
    • , Reza Khayat
    • , Robert Pejchal
    • , Devan Diwanji
    • , Andrew B. Ward
    •  & Ian A. Wilson
  4. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Nikita Patel
    •  & James Arthos
  5. Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Syed Shahzad-ul-Hussan
    •  & Carole A. Bewley
  6. The Duke Human Vaccine Institute, Duke University School of Medicine, and Duke University Medical Center, Durham, North Carolina 27710, USA

    • Mattia Bonsignori
    •  & Barton F. Haynes
  7. Division of Infectious Diseases and International Health, Department of Medicine, and Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA

    • John A. Crump
  8. Kilimanjaro Christian Medical Centre and Kilimanjaro Christian Medical College, Tumaini University, Moshi, Tanzania

    • John A. Crump
    •  & Noel E. Sam
  9. Kilimanjaro Reproductive Health Programme, Moshi, Tanzania

    • Saidi H. Kapiga
    •  & Noel E. Sam
  10. Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA

    • Dennis R. Burton
    • , Laura M. Walker
    •  & William R. Schief
  11. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02129, USA

    • Dennis R. Burton
  12. International AIDS Vaccine Initiative (IAVI), New York, New York 10004, USA

    • Wayne C. Koff
    •  & Sanjay Phogat
  13. IAVI Neutralizing Antibody Center at TSRI, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA

    • Richard Wyatt
  14. Institute of Human Virology and Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA

    • Jared Orwenyo
    •  & Lai-Xi Wang


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J.S.M., M.P., M.S., T.Z., J.Z., J.A., C.A.B., J.R.M., G.J.N., W.R.S., A.B.W., I.A.W. and P.D.K. designed research and analysed the data; J.S.M., M.P., C.C., J.G., J.-P.J., R.K., R.L., R.P., M.S., K.D., S.O’D., N.P., S.S.H., Y.Y., T.Z., J.C.B., G.-Y.C., D.D., I.G., Y.D.K., D.L., M.K.L., S.M., S.D.S., Z.-Y.Y. and B.Z. performed research and are listed in four alphabetical groups: J.S.M. and M.P. performed the majority of research and, with C.C., J.G., J.-P.J., R.K., R.L., R.P. and M.S., determined structures, K.D., S.O’D., N.P., S.S.H., Y.Y., B.Z., T.Z. and J.Z. contributed substantial experiments, J.C.B., G.-Y.C., D.D., I.G., Y.D.K., D.L., M.K.L., S.M., S.D.S. and Z.-Y.Y. contributed supporting research; M.B., J.A.C., S.H.K., N.E.S. and B.F.H. contributed donor 0219 materials; D.R.B., W.C.K. and L.M.W. contributed donor 24 and donor 84 materials and T13 antibody; S.P. and R.W. contributed 16055 gp120; J.O. and L.-X.W. contributed polysaccharides; J.S.M., M.P., G.J.N., I.A.W. and P.D.K. wrote the paper, with all principal investigators providing comments or revisions.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Peter D. Kwong.

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