Article | Published:

Stapled HIV-1 peptides recapitulate antigenic structures and engage broadly neutralizing antibodies

Nature Structural & Molecular Biology volume 21, pages 10581067 (2014) | Download Citation

Abstract

Hydrocarbon stapling can restore bioactive α-helical structure to natural peptides, yielding research tools and prototype therapeutics to dissect and target protein interactions. Here we explore the capacity of peptide stapling to generate high-fidelity, protease-resistant mimics of antigenic structures for vaccine development. HIV-1 has been refractory to vaccine technologies thus far, although select human antibodies can broadly neutralize HIV-1 by targeting sequences of the gp41 juxtamembrane fusion apparatus. To develop candidate HIV-1 immunogens, we generated and characterized stabilized α-helices of the membrane-proximal external region (SAH-MPER) of gp41. SAH-MPER peptides were remarkably protease resistant and bound to the broadly neutralizing 4E10 and 10E8 antibodies with high affinity, recapitulating the structure of the MPER epitope when differentially engaged by the two anti-HIV Fabs. Thus, stapled peptides may provide a new opportunity to develop chemically stabilized antigens for vaccination.

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Acknowledgements

We thank E. Smith for graphics assistance, D. Ekiert and E. Reinherz for insightful discussions, M. Connors (National Institute of Allergy and Infectious Diseases) for his generosity in providing us with a sample of 10E8 antibody and Y. Yang and P. Acharya for technical support. We are grateful to the US National Institutes of Health (NIH) AIDS Reagent Program for providing us with 4E10 and 10E8 antibodies. This work was supported by NIH grants 1R01 AI084102 (L.D.W.) and R01 AI084817 (I.A.W.); Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) grant UM1 AI100663 (I.A.W.); the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, IAVI Collaboration for AIDS Vaccine Discovery; the Bill and Melinda Gates Foundation; and the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH. Use of the 22-ID and 23-ID sectors at Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract nos. W-31-109-Eng-39 and DE-AC02-06CH11357.

Author information

Author notes

    • Gregory H Bird
    •  & Adriana Irimia

    These authors contributed equally to this work.

Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Gregory H Bird
    •  & Loren D Walensky
  2. Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Gregory H Bird
    •  & Loren D Walensky
  3. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

    • Gregory H Bird
    •  & Loren D Walensky
  4. Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California, USA.

    • Adriana Irimia
    •  & Ian A Wilson
  5. International AIDS Vaccine Initiative Neutralizing Antibody Center, Scripps Research Institute, La Jolla, California, USA.

    • Adriana Irimia
    •  & Ian A Wilson
  6. Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Scripps Research Institute, La Jolla, California, USA.

    • Adriana Irimia
    •  & Ian A Wilson
  7. Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Gilad Ofek
    •  & Peter D Kwong

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Contributions

G.H.B. and L.D.W. designed, synthesized and characterized SAH-MPER peptides and conducted the antibody binding, peptide proteolysis and MS analyses; A.I. and I.A.W. performed the structural studies of the 4E10 Fab–SAH-MPER complexes; and G.O. and P.D.K. conducted the structural analysis of the 10E8 Fab–SAH-MPER complex. L.D.W. wrote the manuscript with contributions from all authors.

Competing interests

L.D.W. is a scientific advisory board member and consultant for Aileron Therapeutics.

Corresponding author

Correspondence to Loren D Walensky.

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https://doi.org/10.1038/nsmb.2922

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