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

Shuang Yang, Giorgos Hiotis, Yi Wang, Junjian Chen, Jia-huai Wang, Mikyung Kim, Ellis L. Reinherz () and Thomas Walz ()
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Shuang Yang: The Rockefeller University
Giorgos Hiotis: The Rockefeller University
Yi Wang: Dana-Farber Cancer Institute
Junjian Chen: Dana-Farber Cancer Institute
Jia-huai Wang: Dana-Farber Cancer Institute
Mikyung Kim: Dana-Farber Cancer Institute
Ellis L. Reinherz: Dana-Farber Cancer Institute
Thomas Walz: The Rockefeller University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34008-y

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