Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity

Journal of Virology
Maxime VeilletteAndrés Finzi

Abstract

Anti-HIV-1 envelope glycoprotein (Env) antibodies without broadly neutralizing activity correlated with protection in the RV144 clinical trial, stimulating interest in other protective mechanisms involving antibodies, such as antibody-dependent cell-mediated cytotoxicity (ADCC). Env epitopes targeted by many antibodies effective at mediating ADCC are poorly exposed on the unliganded Env trimer. Here we investigated the mechanism of exposure of ADCC epitopes on Env and showed that binding of Env and CD4 within the same HIV-1-infected cell effectively exposes these epitopes. Env capacity to transit to the CD4-bound conformation is required for ADCC epitope exposure. Importantly, cell surface CD4 downregulation by Nef and Vpu accessory proteins and Vpu-mediated BST-2 antagonism modulate exposure of ADCC-mediating epitopes and reduce the susceptibility of infected cells to this effector function in vitro. Significantly, Env conformational changes induced by cell surface CD4 are conserved among Env from HIV-1 and HIV-2/SIVmac lineages. Altogether, our observations describe a highly conserved mechanism required to expose ADCC epitopes that might help explain the evolutionary advantage of downregulation of cell surface CD4 by the HIV-...Continue Reading

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Citations

Oct 30, 2014·AIDS Research and Human Retroviruses·Laurie-Anne BatravilleMichel Roger
Feb 13, 2016·EBioMedicine·Marjorie Robert-Guroff
Dec 10, 2015·Clinical and Experimental Immunology·S L GooneratneM S Parsons
Oct 21, 2015·Frontiers in Immunology·Mark A BrockmanZabrina L Brumme
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Sep 30, 2015·Nature·Yoshiko UsamiHeinrich G Göttlinger
Aug 16, 2014·Journal of Virological Methods·Jonathan RichardAndrés Finzi
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May 6, 2015·Proceedings of the National Academy of Sciences of the United States of America·Jonathan RichardAndrés Finzi
Jun 16, 2015·Frontiers in Immunology·Wen Shi LeeMarit Lichtfuss
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Aug 12, 2016·Journal of Virology·Philip MwimanziMark A Brockman

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