Abstract

Broadly neutralizing antibodies (bNAbs) against HIV-1 Env V1V2 arise in multiple donors. However, atomic-level interactions had previously been determined only with antibodies from a single donor, thus making commonalities in recognition uncertain. Here we report the cocrystal structure of V1V2 with antibody CH03 from a second donor and model Env interactions of antibody CAP256-VRC26 from a third donor. These V1V2-directed bNAbs used strand-strand interactions between a protruding antibody loop and a V1V2 strand but differed in their N-glycan recognition. Ontogeny analysis indicated that protruding loops develop early, and glycan interactions mature over time. Altogether, the multidonor information suggested that V1V2-directed bNAbs form an 'extended class', for which we engineered ontogeny-specific antigens: Env trimers with chimeric V1V2s that interacted with inferred ancestor and intermediate antibodies. The ontogeny-based design of vaccine antigens described here may provide a general means for eliciting antibodies of a desired class.

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Acknowledgements

We thank members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, NIH, for discussions and comments on the manuscript, and Weill Cornell Medical College, The Scripps Research Institute, Academic Medical Center and the HIV Vaccine Research and Design team comprising investigators from these three institutions 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 contributions to HIV-1-Env plasmids used in neutralization assessments. We thank R. Sanders for providing the PGDM1400–1412 sequences and the International AIDS Vaccine Initiative (IAVI) for PG9, PG16 and PGT141–145. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, US National Institute of Allergy and Infectious Diseases (NIAID) (to A.B.M., J.R. Mascola and P.D.K.); the Division of AIDS, NIAID, NIH (1U01-AI116086-01 to P.L.M., L.M., J.R. Mascola and P.D.K.; R21-AI112389 to K.K.L.); the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (OPP1033102 to K.K.L.); IAVI; and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery grant (CHAVI-ID; UM1 AI100645 to M.B. and B.F.H.). 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 number W-31-109-Eng-38. Modeling and molecular dynamics were carried out through the NIH's Biowulf computing cluster.

Author information

Affiliations

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

    • Jason Gorman
    • , Cinque Soto
    • , Max M Yang
    • , Robert T Bailer
    • , Michael Chambers
    • , Gwo-Yu Chuang
    • , Brandon J DeKosky
    • , Nicole A Doria-Rose
    • , Aliaksandr Druz
    • , Michael J Ernandes
    • , Ivelin S Georgiev
    • , Marissa C Jarosinski
    • , M Gordon Joyce
    • , Sherman Leung
    • , Mark K Louder
    • , Sandeep Narpala
    • , Marie Pancera
    • , Jonathan Stuckey
    • , Xueling Wu
    • , Yongping Yang
    • , Baoshan Zhang
    • , Tongqing Zhou
    • , Adrian B McDermott
    • , Lawrence Shapiro
    • , John R Mascola
    •  & Peter D Kwong
  2. Department of Medicinal Chemistry, University of Washington, Seattle, Washington, USA.

    • Thaddeus M Davenport
    • , Miklos Guttman
    •  & Kelly K Lee
  3. Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.

    • Brandon J DeKosky
    • , Jonathan R McDaniel
    •  & George Georgiou
  4. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA.

    • Thomas M Lemmin
  5. NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.

    • NISC Comparative Sequencing Program
    •  & James C Mullikin
  6. Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.

    • Ulrich Baxa
  7. Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

    • Mattia Bonsignori
    •  & Barton F Haynes
  8. Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa.

    • Penny L Moore
    •  & Lynn Morris
  9. Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

    • Penny L Moore
    •  & Lynn Morris
  10. Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, South Africa.

    • Penny L Moore
    •  & Lynn Morris
  11. Department of Biochemistry & Molecular Biophysics, Columbia University, New York, New York, USA.

    • Lawrence Shapiro
  12. Department of Systems Biology, Columbia University, New York, New York, USA.

    • Lawrence Shapiro

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Contributions

J.G. headed the determination of the V1V2-bound CH03 and CH04 crystal structures, revertant neutralization strategy and chimeric SOSIP design and assessment, and assisted with VRC26 model development; C.S. headed the next-generation-sequencing lineage analysis and VRC26 modeling; M.M.Y. assisted with crystallization. T.M.D., M.G. and K.K.L. performed HDX experiments and analyzed the data; R.T.B. and M.K.L. and J.R. Mascola assessed neutralization breadth; S.N., M.C. and A.B.M. performed antigenic analyses; G.-Y.C. performed frequentist probability analysis; B.J.D., J.R. McDaniel, G.G., X.W., J.C.M. and J.R. Mascola and NISC contributed next-generation sequencing data; J.G., C.S., M.P., N.A.D.-R., M.J.E., M.C.J. and B.Z. contributed to paratope mapping; A.D. expressed V1V2 scaffold and antibodies; J.G., I.S.G., Y.Y. and S.L. contributed to V1V2 scaffold design and assessment; C.S., T.M.L. and J.G. contributed to MDFF analysis; M.P. assisted with chimeric SOSIP design; J.S. assisted with figure conception and design; U.B. performed EM; T.Z. and M.G.J. contributed to reverted VRC01 experiments; M.B. and B.F.H. contributed CH0219 materials; P.L.M. and L.M. contributed CAP256 materials; J.G., C.S., L.S. 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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https://doi.org/10.1038/nsmb.3144

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