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

Finzi, A.

doi:10.1128/JVI.03230-13

Titre

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

Type

article

Institution

Externe

Périodique

Journal of Virology

Auteur(s)

Veillette, M.

Auteure/Auteur

Désormeaux, A.

Auteure/Auteur

Medjahed, H.

Auteure/Auteur

Gharsallah, N.E.

Auteure/Auteur

Coutu, M.

Auteure/Auteur

Baalwa, J.

Auteure/Auteur

Guan, Y.

Auteure/Auteur

Lewis, G.

Auteure/Auteur

Ferrari, G.

Auteure/Auteur

Hahn, B.H.

Auteure/Auteur

Haynes, B.F.

Auteure/Auteur

Robinson, J.E.

Auteure/Auteur

Kaufmann, D.E.

Auteure/Auteur

Bonsignori, M.

Auteure/Auteur

Sodroski, J.

Auteure/Auteur

Finzi, A.

Auteure/Auteur

Liens vers les personnes

Kaufmann, Daniel

ISSN

1098-5514

Statut éditorial

Publié

Date de publication

2014-03

Volume

88

Numéro

5

Première page

2633

Dernière page/numéro d’article

2644

Peer-reviewed

Oui

Langue

anglais

Notes

Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish

Résumé

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-1 Vpu and Nef proteins.
HIV-1 envelope epitopes targeted by many antibodies effective at mediating antibody-dependent cell-mediated cytotoxicity (ADCC) are poorly exposed on the unliganded envelope trimer. Here we investigated the mechanism of exposure of these epitopes and found that envelope interaction with the HIV-1 CD4 receptor is required to expose some of these epitopes. Moreover, our results suggest that HIV-1 CD4 downregulation might help avoid the killing of HIV-1-infected cells by this immune mechanism.