Abstract

Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination.

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Accessions

Data deposits

The GenBank accession numbers for 292 CH505 Env proteins are KC247375KC247667, and accessions for 459 VHDJH and 174 VLJL sequences of antibody members in the CH103 clonal lineage are KC575845KC576303 and KC576304KC576477, respectively. Atomic coordinates and structure factors for unbound CH103 Fab as well as CH103 Fab in complex with the ZM176.66 outer domain have been deposited with the Protein Data Bank under accession codes 4JAM for CH103 Fab, and 4JAN for the CH103–gp120 complex.

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Acknowledgements

This study was supported by the National Institutes of Allergy and Infectious Diseases (NIAID) and by intramural National Institutes of Health (NIH) support for the NIAID Vaccine Research Center, by grants from the NIH, NIAID, AI067854 (the Center for HIV/AIDS Vaccine Immunology) and AI100645 (the Center for Vaccine Immunology-Immunogen Discovery). The authors thank J. Pritchett, H. Chen, D. Pause, M. Cooper, E. Solomon, J. Blinn, K. Yarborough, E. Friberg, M. Smith, A. Hogan, C. Peckels, A. Foulger and T. Jeffries for technical assistance, and J. Kircherr and C. Andrews for project management. 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. The opinions herein are those of the authors and should not be construed as official or representing the views of the US Department of Health and Human Services, National Institute for Allergy and Infectious Diseases.

Author information

Author notes

    • Hua-Xin Liao
    • , Rebecca Lynch
    • , Tongqing Zhou
    •  & Feng Gao

    These authors contributed equally to this work.

Affiliations

  1. Duke University Human Vaccine Institute, Departments of Medicine and Immunology, Duke University School of Medicine, Durham, North Carolina 27710, USA

    • Hua-Xin Liao
    • , Feng Gao
    • , S. Munir Alam
    • , Kevin Wiehe
    • , Garnett Kelsoe
    • , Guang Yang
    • , Shi-Mao Xia
    • , David C. Montefiori
    • , Robert Parks
    • , Krissey E. Lloyd
    • , Richard M. Scearce
    • , Kelly A. Soderberg
    • , Yue Chen
    • , Fangping Cai
    • , Sheri Chen
    •  & Barton F. Haynes
  2. Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Durham, North Carolina 27710, USA

    • Hua-Xin Liao
    • , Feng Gao
    • , S. Munir Alam
    • , Kevin Wiehe
    • , Garnett Kelsoe
    • , Guang Yang
    • , Shi-Mao Xia
    • , David C. Montefiori
    • , Robert Parks
    • , Krissey E. Lloyd
    • , Richard M. Scearce
    • , Kelly A. Soderberg
    • , Yue Chen
    • , Fangping Cai
    • , Sheri Chen
    •  & Barton F. Haynes
  3. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Rebecca Lynch
    • , Tongqing Zhou
    • , Jiang Zhu
    • , Lawrence Shapiro
    • , Mark K. Louder
    • , Lillian M. Tran
    • , Stephanie Moquin
    • , Xiulian Du
    • , M. Gordon Joyce
    • , Sanjay Srivatsan
    • , Baoshan Zhang
    • , Anqi Zheng
    • , Peter D. Kwong
    •  & John R. Mascola
  4. Department of Pathology, Stanford University, Palo Alto, California 94305, USA

    • Scott D. Boyd
    • , Andrew Z. Fire
    •  & Krishna M. Roskin
  5. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA

    • Chaim A. Schramm
    • , Zhenhai Zhang
    •  & Lawrence Shapiro
  6. NISC Comparative Sequencing Program, NIH, Bethesda, Maryland 20892, USA

    • Jesse Becker
    • , Betty Benjamin
    • , Robert Blakesley
    • , Gerry Bouffard
    • , Shelise Brooks
    • , Holly Coleman
    • , Mila Dekhtyar
    • , Michael Gregory
    • , Xiaobin Guan
    • , Jyoti Gupta
    • , Joel Han
    • , April Hargrove
    • , Shi-ling Ho
    • , Taccara Johnson
    • , Richelle Legaspi
    • , Sean Lovett
    • , Quino Maduro
    • , Cathy Masiello
    • , Baishali Maskeri
    • , Jenny McDowell
    • , Casandra Montemayor
    • , James Mullikin
    • , Morgan Park
    • , Nancy Riebow
    • , Karen Schandler
    • , Brian Schmidt
    • , Christina Sison
    • , Mal Stantripop
    • , James Thomas
    • , Pam Thomas
    • , Meg Vemulapalli
    •  & Alice Young
  7. NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA

    • James C. Mullikin
  8. Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87544, USA

    • S. Gnanakaran
    • , Peter Hraber
    •  & Bette T. M. Korber
  9. Departments of Medicine, Epidemiology and Microbiology and Immunology, University of North Carolina, North Carolina 27599, USA

    • Myron Cohen
  10. University of North Carolina Project, Kamuzu Central Hospital, Lilongwe, Malawi

    • Gift Kamanga
  11. Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • George M. Shaw
    •  & Beatrice H. Hahn
  12. Department of Microbiology, Boston University, Boston, Massachusetts 02215, USA

    • Thomas B. Kepler

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Contributions

H.-X.L., R.L., T.Z. and F.G. contributed equally to this work. H.-X.L. led production of antibodies and Env proteins, designed assays, analysed data and edited the paper; R.L. generated antibodies and performed assays; T.Z. co-led the structural biology team, performed structural studies, analysed data, and edited the paper; F.G. generated autologous Env sequences and viruses; S.M.A. performed surface plasmon reasonance analysis; S.D.B., A.Z.F., J.C.M. and K.M.R. performed pyrosequencing; C.A.S., Z.Z., J.Z. and L.S. analysed pyrosequences; S.G., P.H., B.T. and M.K. performed antibody and Env sequence analysis, and edited the paper; G.K. and G.Y. performed polyreactivity assays and analysis; S.-M.X. and D.C.M. performed neutralization assays and analysis; R.P., K.E.L. and R.M.S developed and performed ELISAs; K.A.S., M.C. and G.K. performed cohort development, patient recruitment, management and sampling; M.K.L. and L.M.T. performed neutralization assays; Y.C., F.C. and S.C. performed Env cloning and sequencing, S.M., X.D., M.G.J., S.S., B.Z. and A.Z. performed experiments related to crystallization, structure determination, and structural analysis; G.M.S. and B.H.H. generated autologous Env sequences and edited the paper; T.B.K. performed antibody gene sequence analysis and inferred ancestor and intermediate antibodies and edited the paper; P.D.K. co-led the structural biology team and collected and analysed data, and edited the paper; J.R.M. isolated antibodies, designed assays, analysed data, and edited the paper; B.F.H. designed and directed the study, read and interpreted antinuclear antibody assays, analysed data, and wrote and edited the paper.

Competing interests

H.-X.L., R.L., T.Z., F.G., S.D.B., B.H.H., T.B.K., J.R.M., P.D.K. and B.F.H. have filed patent applications on monoclonal antibodies and their sequences and/or CH505 Env proteins and their sequences used in this study.

Corresponding authors

Correspondence to Hua-Xin Liao or Barton F. Haynes.

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https://doi.org/10.1038/nature12053

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