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Dynamic HIV-1 spike motion creates vulnerability for its membrane-bound tripod to antibody attack

Author

Listed:
  • Shuang Yang

    (The Rockefeller University)

  • Giorgos Hiotis

    (The Rockefeller University
    The Rockefeller University)

  • Yi Wang

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Junjian Chen

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Jia-huai Wang

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Mikyung Kim

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Ellis L. Reinherz

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Thomas Walz

    (The Rockefeller University)

Abstract

Vaccines targeting HIV-1’s gp160 spike protein are stymied by high viral mutation rates and structural chicanery. gp160’s membrane-proximal external region (MPER) is the target of naturally arising broadly neutralizing antibodies (bnAbs), yet MPER-based vaccines fail to generate bnAbs. Here, nanodisc-embedded spike protein was investigated by cryo-electron microscopy and molecular-dynamics simulations, revealing spontaneous ectodomain tilting that creates vulnerability for HIV-1. While each MPER protomer radiates centrally towards the three-fold axis contributing to a membrane-associated tripod structure that is occluded in the upright spike, tilting provides access to the opposing MPER. Structures of spike proteins with bound 4E10 bnAb Fabs reveal that the antibody binds exposed MPER, thereby altering MPER dynamics, modifying average ectodomain tilt, and imposing strain on the viral membrane and the spike’s transmembrane segments, resulting in the abrogation of membrane fusion and informing future vaccine development.

Suggested Citation

  • Shuang Yang & Giorgos Hiotis & Yi Wang & Junjian Chen & Jia-huai Wang & Mikyung Kim & Ellis L. Reinherz & Thomas Walz, 2022. "Dynamic HIV-1 spike motion creates vulnerability for its membrane-bound tripod to antibody attack," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34008-y
    DOI: 10.1038/s41467-022-34008-y
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    References listed on IDEAS

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    Cited by:

    1. Kemin Tan & Junjian Chen & Yu Kaku & Yi Wang & Luke Donius & Rafiq Ahmad Khan & Xiaolong Li & Hannah Richter & Michael S. Seaman & Thomas Walz & Wonmuk Hwang & Ellis L. Reinherz & Mikyung Kim, 2023. "Inadequate structural constraint on Fab approach rather than paratope elicitation limits HIV-1 MPER vaccine utility," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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