Abstract
Apart from mediating viral entry, the function of the free HIV-1 envelope protein (gp120) has yet to be elucidated. Our group previously showed that EP2 derived from one β-strand in gp120 can form amyloid fibrils that increase HIV-1 infectivity. Importantly, gp120 contains ~30 β-strands. We examined whether gp120 might serve as a precursor protein for the proteolytic release of amyloidogenic fragments that form amyloid fibrils, thereby promoting viral infection. Peptide array scanning, enzyme degradation assays, and viral infection experiments in vitro confirmed that many β-stranded peptides derived from gp120 can indeed form amyloid fibrils that increase HIV-1 infectivity. These gp120-derived amyloidogenic peptides, or GAPs, which were confirmed to form amyloid fibrils, were termed gp120-derived enhancers of viral infection (GEVIs). GEVIs specifically capture HIV-1 virions and promote their attachment to target cells, thereby increasing HIV-1 infectivity. Different GAPs can cross-interact to form heterogeneous fibrils that retain the ability to increase HIV-1 infectivity. GEVIs even suppressed the antiviral activity of a panel of antiretroviral agents. Notably, endogenous GAPs and GEVIs were found in the lymphatic fluid, lymph nodes, and cerebrospinal fluid (CSF) of AIDS patients in vivo. Overall, gp120-derived amyloid fibrils might play a crucial role in the process of HIV-1 infectivity and thus represent novel targets for anti-HIV therapeutics.
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Acknowledgements
We thank Yelena Oksov for her help in performing the TEM experiment. This work was supported by grants from the Natural Science Foundation of China (82072276 and 81772194 to ST, 82073898 and 31370781 to SL, and 81630090 to SJ).
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S.T., S.L., and S.J. conceived the study. S.T., W.L., C.Y., S.L., and S.J. contributed to the methodology. S.T., W.L., C.Y., Q.Z., K.L., J.L., Z.L., and F.Y. performed the experiments and analyzed the data. Y.Y.L., Y.X.D., J.L., Y.M.J., J.S.B., L.W., Y.T.Z., T.Z., and J.W. collected the clinical samples. S.T., S.L., and S.J. acquired the funding S.T., S.L., and S.J. supervised the study. S.T., W.L., and C.Y. drafted the manuscript. S.T., S.L., S.J., L.L., and L.L. reviewed and edited the manuscript.
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Tan, S., Li, W., Yang, C. et al. gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity. Cell Mol Immunol 21, 479–494 (2024). https://doi.org/10.1038/s41423-024-01144-y
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DOI: https://doi.org/10.1038/s41423-024-01144-y