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Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding

Author

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  • Daniel W. Kulp

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
    Vaccine and Immune Therapy Center, The Wistar Institute)

  • Jon M. Steichen

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute)

  • Matthias Pauthner

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute)

  • Xiaozhen Hu

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute)

  • Torben Schiffner

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute)

  • Alessia Liguori

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute)

  • Christopher A. Cottrell

    (IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
    The Scripps Research Institute)

  • Colin Havenar-Daughton

    (Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
    Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology)

  • Gabriel Ozorowski

    (IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
    The Scripps Research Institute)

  • Erik Georgeson

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute)

  • Oleksandr Kalyuzhniy

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute)

  • Jordan R. Willis

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute)

  • Michael Kubitz

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute)

  • Yumiko Adachi

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute)

  • Samantha M. Reiss

    (Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
    Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology)

  • Mia Shin

    (IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
    The Scripps Research Institute)

  • Natalia Val

    (IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
    The Scripps Research Institute)

  • Andrew B. Ward

    (IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
    The Scripps Research Institute)

  • Shane Crotty

    (Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
    Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology
    University of California, San Diego)

  • Dennis R. Burton

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
    The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University)

  • William R. Schief

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
    The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University)

Abstract

Elicitation of broadly neutralizing antibodies (bnAbs) is a primary HIV vaccine goal. Native-like trimers mimicking virion-associated spikes present nearly all bnAb epitopes and are therefore promising vaccine antigens. However, first generation native-like trimers expose epitopes for non-neutralizing antibodies (non-nAbs), which may hinder bnAb induction. We here employ computational and structure-guided design to develop improved native-like trimers that reduce exposure of non-nAb epitopes in the V3-loop and trimer base, minimize both CD4 reactivity and CD4-induced non-nAb epitope exposure, and increase thermal stability while maintaining bnAb antigenicity. In rabbit immunizations with native-like trimers of the 327c isolate, improved trimers suppress elicitation of V3-directed and tier-1 neutralizing antibodies and induce robust autologous tier-2 neutralization, unlike a first-generation trimer. The improved native-like trimers from diverse HIV isolates, and the design methods, have promise to assist in the development of a HIV vaccine.

Suggested Citation

  • Daniel W. Kulp & Jon M. Steichen & Matthias Pauthner & Xiaozhen Hu & Torben Schiffner & Alessia Liguori & Christopher A. Cottrell & Colin Havenar-Daughton & Gabriel Ozorowski & Erik Georgeson & Oleksa, 2017. "Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01549-6
    DOI: 10.1038/s41467-017-01549-6
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    Cited by:

    1. Yi-Nan Zhang & Jennifer Paynter & Aleksandar Antanasijevic & Joel D. Allen & Mor Eldad & Yi-Zong Lee & Jeffrey Copps & Maddy L. Newby & Linling He & Deborah Chavez & Pat Frost & Anna Goodroe & John Du, 2023. "Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimers as HIV-1 vaccine candidates," Nature Communications, Nature, vol. 14(1), pages 1-29, December.
    2. Ziyang Xu & Susanne Walker & Megan C. Wise & Neethu Chokkalingam & Mansi Purwar & Alan Moore & Edgar Tello-Ruiz & Yuanhan Wu & Sonali Majumdar & Kylie M. Konrath & Abhijeet Kulkarni & Nicholas J. Turs, 2022. "Induction of tier-2 neutralizing antibodies in mice with a DNA-encoded HIV envelope native like trimer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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