Abstract
HIV-1 envelope glycoprotein gp41 undergoes large conformational changes to drive fusion of viral and target cell membranes, adopting at least three distinct conformations during the viral entry process. Neutralizing antibodies against gp41 block HIV-1 infection by targeting gp41′s membrane-proximal external region in a fusion-intermediate state. Here we report biochemical and structural evidence that non-neutralizing antibodies, capable of binding with high affinity to an immunodominant segment adjacent to the neutralizing epitopes in the membrane-proximal region, recognize a gp41 conformation that exists only when membrane fusion is complete. We propose that these non-neutralizing antibodies are induced in HIV-1–infected individuals by gp41 in a triggered, postfusion form and contribute to production of ineffective humoral responses. These results have important implications for gp41-based vaccine design.
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Acknowledgements
We thank S. Harrison, H. Peng, A. Carfi, A. Dey, J. Mascola, M. Alam and B.F. Haynes for advice and assistance, and the staff of the Northeastern Collaborative Access Team at Advanced Photon Source, Argonne National Laboratory, for assistance with X-ray data collection. We acknowledge support from US National Institutes of Health grants GM083680 (to B.C.), AI084794 (to B.C. and Dan H. Barouch) and AI36085 (to S.Z.-P.); a Collaboration for AIDS Vaccine Discovery grant (to Barton F. Haynes) from the Bill and Melinda Gates Foundation; the Center for HIV/AIDS Vaccine Immunology (to Barton F. Haynes); and the Department of Veterans Affairs. J.C. is supported by a fellowship from the Ragon Institute of MGH, MIT and Harvard.
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G.F., J.C. and B.C. designed research; G.F., J.C., S.R.-V. and M.M.F. performed the experiments; S.Z.-P. provided antibodies; G.F., J.C., S.R.-V., M.M.F. and B.C. analyzed data; and G.F., J.C., S.Z.-P. and B.C. wrote the manuscript.
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Frey, G., Chen, J., Rits-Volloch, S. et al. Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies. Nat Struct Mol Biol 17, 1486–1491 (2010). https://doi.org/10.1038/nsmb.1950
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DOI: https://doi.org/10.1038/nsmb.1950
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