As the sole viral antigen on the HIV-1–virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1–Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer bound by a single CD4 without the typical antigenic hallmarks of CD4 induction. Antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens.

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We thank Y. Dai (The Scripps Research Institute) for ERV MuLV Gag plasmid, M. Murphy for SPR discussions, B. Whalen (Altravax) for the Rev plasmid, members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center for discussions and comments on the manuscript and the Weill Cornell Medical College, the Academic Medical Center of the University of Amsterdam and The Scripps Research Institute HIV Vaccine Research and Design Program for their contributions to the design and validation of near-native mimicry for soluble BG505 SOSIP.664 trimers. We thank J. Baalwa, D. Ellenberger, F. Gao, B. Hahn, K. Hong, J. Kim, F. McCutchan, D. Montefiori, L. Morris, J. Overbaugh, E. Sanders-Buell, G. Shaw, R. Swanstrom, M. Thomson, S. Tovanabutra, C. Williamson and L. Zhang for contributing the HIV-1–Env plasmids used in our neutralization panel. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health (NIH) (to J.A., A.B.M., J.R.M. and P.D.K.); the Division of AIDS, NIAID, NIH (P01-AI100151 to S.Z.-P., P01-AI104722 to L.S., R01-AI93278 to J.M.B., R21-AI100696 to W.M. and S.C.B., R21-AI112389 to K.K.L. and R33-AI84714 to J.M.B.); the US National Institutes of General Medical Sciences (P01-GM56550 to E.F., S.C.B. and W.M., R01-GM78031 to B.R.D. and R01-GM98859 to S.C.B.); the US National Institute of Heart, Lung and Blood (PO1-HL59725 to S.Z.-P.); the US National Science Foundation (MCB-1157506 to E.F.); the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (OPP1033102 to K.K.L.); the Australian Research Council (DP130102219 to L.K.L.); the Irvington Fellows Program of the Cancer Research Program (to J.B.M.); the Department of Veterans Affairs (to S.Z.-P.); and the China Scholarship Council–Yale World Scholars (fellowship to X.M.). This project was funded in part with Federal funds to U.B. from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-Eng-38.

Author information

Author notes

    • Young Do Kwon
    • , Marie Pancera
    • , Priyamvada Acharya
    •  & Ivelin S Georgiev

    These authors contributed equally to this work.


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

    • Young Do Kwon
    • , Marie Pancera
    • , Priyamvada Acharya
    • , Ivelin S Georgiev
    • , Jason Gorman
    • , M Gordon Joyce
    • , Sandeep Narpala
    • , Cinque Soto
    • , Yongping Yang
    • , Tongqing Zhou
    • , Robert T Bailer
    • , Michael Chambers
    • , Gwo-Yu Chuang
    • , Nicole A Doria-Rose
    • , Aliaksandr Druz
    • , Mark A Hallen
    • , Tatsiana Kirys
    • , Mark K Louder
    • , Sijy O'Dell
    • , Gilad Ofek
    • , Madhu Prabhakaran
    • , Mallika Sastry
    • , Guillaume B E Stewart-Jones
    • , Jonathan Stuckey
    • , Paul V Thomas
    • , Tishina Tittley
    • , Baoshan Zhang
    • , Lawrence Shapiro
    • , Adrian B McDermott
    • , John R Mascola
    •  & Peter D Kwong
  2. San Diego Biomedical Research Institute, San Diego, California, USA.

    • Emma T Crooks
    • , Keiko Osawa
    •  & James M Binley
  3. Department of Medicinal Chemistry, University of Washington, Seattle, Washington, USA.

    • Miklos Guttman
    •  & Kelly K Lee
  4. Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Xiaochu Ma
    • , James B Munro
    •  & Walther Mothes
  5. Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York, USA.

    • Daniel S Terry
    • , Hong Zhao
    • , Zhou Zhou
    •  & Scott C Blanchard
  6. Department of Biochemistry & Molecular Biophysics, Columbia University, New York, New York, USA.

    • Goran Ahlsen
    •  & Lawrence Shapiro
  7. Department of Systems Biology, Columbia University, New York, New York, USA.

    • Goran Ahlsen
  8. Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.

    • Mark A Hallen
    •  & Bruce R Donald
  9. Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.

    • Adam Harned
    •  & Ulrich Baxa
  10. New York University School of Medicine, New York, New York, USA.

    • Constance Williams
    •  & Susan Zolla-Pazner
  11. Department of Chemistry, Duke University, Durham, North Carolina, USA.

    • Bruce R Donald
  12. Department of Computer Science, Duke University, Durham, North Carolina, USA.

    • Bruce R Donald
  13. Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.

    • Lawrence K Lee
  14. New York Veterans Affairs Harbor Healthcare System, New York, New York, USA.

    • Susan Zolla-Pazner
  15. Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Arne Schön
    •  & Ernesto Freire
  16. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • James Arthos
  17. Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA.

    • James B Munro


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Y.D.K. headed the determination of the ligand-free trimer structure; M. Pancera coheaded the conformational fixation and led atomic-level investigations; P.A. coheaded the conformational fixation and led antigenic assessments; and I.S.G. headed the structural compatibility bioinformatics and designed the DS mutation. M. Pancera, T.Z., A.D. and P.D.K. contributed to structure determination; Y.D.K. and C.S. performed structural analysis; R.T.B. and M.K.L. assessed neutralization breadth; I.S.G., G.-Y.C., M.A.H., T.K., B.R.D. and L.K.L. performed structural-compatibility bioinformatics; M. Pancera, P.A., M.G.J., S.N., M.C., G.O., M. Prabhakaran, M.S., T.T., C.W., S.Z.-P. and A.B.M. performed antigenic analyses; J.G., G.B.E.S.-J., Y.Y., B.Z. and J.R.M. contributed to conformational fixation; A.H. and U.B. performed EM; M. Pancera, P.A., A.S. and E.F. performed calorimetry; Y.D.K., G.A. and L.S. performed ultracentrifugation; Y.D.K., M.G. and K.K.L. performed and analyzed HDX-MS; N.A.D.-R., S.O. and J.R.M. created and analyzed mutant virus; J.G., X.M., D.S.T., H.Z., Z.Z., J.A., J.B.M., S.C.B. and W.M. performed smFRET; P.A., M.G.J. and P.V.T. assessed physical and temporal stability; M. Pancera, E.T.C., K.O. and J.M.B. contributed VLP analysis; and I.S.G., J.S. and P.D.K. evaluated information flow. Y.D.K., M. Pancera, P.A., I.S.G. and P.D.K. assembled and wrote the paper, on which all principal investigators commented.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Peter D Kwong.

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