Abstract

The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 Å resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation.

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Accessions

Primary accessions

Protein Data Bank

Data deposits

Coordinates and structure factors for BG505 SOSIP.664 in complex with PGT122 and 35O22 Fabs have been deposited with the Protein Data Bank under accession code 4TVP.

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Acknowledgements

We thank J. Binley for the JR-FL plasmid used in smFRET; D. Burton and W. Koff for PGT122; J. Chrzas and SER-CAT staff for assistance with data collection; B. Graham for discussions on RSV; R. Sanders for furin plasmid; R. Schwartz and the Vaccine Production Program for antibody VRC01; J. Sodroski for information on C34-Ig; I. Wilson for discussions on pre-fusion Env structure; Z. Yang for assistance with cloning; G. Nabel, G. Scott and members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions and comments on the manuscript; and the WCMC/AMC/TSRI HIVRAD team 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 envelope plasmids used in our neutralization panel. The authors acknowledge the contributions of the Center for HIV/AIDS Vaccine Discovery (CHAVI) Clinical Core Team for recruiting study participants and carrying out all aspects of the CHAVI001 and CHAVI008 protocols at Chapel Hill, North Carolina (J. Eron); Blantyre, Malawi (J. Kumwenda, T. Taha); Lilongwe, Malawi (I. Hoffman, G. Kaminga); Johannesburg, South Africa (H. Rees); Durban, South Africa (S. Abdool Karim); Moshi, Tanzania (S. Noel, S. Kapiga, J. Crump); and London, UK (S. Fidler). Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); and by grants from the Division of AIDS, NIAID, NIH (R21-AI100696, CHAVI-AI0678501, and CHAVI-Immunogen Discovery-AI100645), from the National Institutes of General Medical Sciences (PO1-GM56550 and RO1-GM098859), from the Irvington Fellows Program of the Cancer Research Program, and from the International AIDS Vaccine Initiative’s (IAVI’s) Neutralizing Antibody Consortium. IAVI's work is made possible by support from many donors including: the Bill & Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation (NORAD); the UK Department for International Development (DFID): and the United States Agency for International Development (USAID). The full list of IAVI donors is available at http://www.iavi.org. 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 number W-31-109-Eng-38.

Author information

Affiliations

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

    • Marie Pancera
    • , Tongqing Zhou
    • , Aliaksandr Druz
    • , Ivelin S. Georgiev
    • , Cinque Soto
    • , Jason Gorman
    • , Priyamvada Acharya
    • , Gwo-Yu Chuang
    • , Gilad Ofek
    • , Guillaume B. E. Stewart-Jones
    • , Jonathan Stuckey
    • , Robert T. Bailer
    • , M. Gordon Joyce
    • , Mark K. Louder
    • , Yongping Yang
    • , Baoshan Zhang
    • , John R. Mascola
    •  & Peter D. Kwong
  2. HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Jinghe Huang
    •  & Mark Connors
  3. Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Sandringham, Johannesburg 2131, South Africa

    • Nancy Tumba
    •  & Lynn Morris
  4. Departments of Medicine, Epidemiology, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • Myron S. Cohen
  5. Duke University Human Vaccine Institute, Departments of Medicine, Surgery, Pediatrics and Immunology, Duke University School of Medicine, and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery at Duke University, Durham, North Carolina 27710, USA

    • Barton F. Haynes
  6. University of the Witwatersrand, Braamfontein, Johannesburg 2000, South Africa

    • Lynn Morris
  7. Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban 4041, South Africa

    • Lynn Morris
  8. Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536, USA

    • James B. Munro
    •  & Walther Mothes
  9. Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York 10021, USA

    • Scott C. Blanchard

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Contributions

M.P., T.Z., A.D. and P.D.K. determined the trimer structure, with M.P. heading structure determination; and with T.Z. assisting with solution and refinement, A.D. with protein production, and P.D.K. with data collection. I.S.G. and C.S. performed bioinformatics analysis, J.G. performed conformational analysis, P.A., G.-Y.C., G.O., G.B.E.S.-J. and J.S. performed antigenic and mechanistic analyses, R.T.B., M.G.J., M.K.L., N.T., Y.Y., B.Z., M.S.C., B.F.H., J.R.M. and L.M. performed cohort analysis, J.B.M., S.C.B. and W.M. performed smFRET analysis, and J.H. and M.C. provided antibody 35O22. M.P. and P.D.K. 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.

Extended data

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    Supplementary Information

    This file contains Supplementary Tables 1-4.

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DOI

https://doi.org/10.1038/nature13808

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