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HIV-1 Vpr mediates the depletion of the cellular repressor CTIP2 to counteract viral gene silencing (C. Van Lint, O. Rohr and C. Schwartz are co-corresponding authors)

par Forouzanfar, Faezeh;Ali, Shahid;Wallet, Clementine;De Rovere, Marco;Ducloy, Camille;El Mekdad, Hala;El Maassarani, Mahmoud;Aït-Ammar, Amina;Van Assche, Jeanne;Boutant, Emmanuel;Daouad, Fadoua;Margottin-Goguet, Florence;Moog, Christiane;Van Lint, Carine ;Schwartz, Christian;Rohr, Olivier
Référence Scientific reports, 9, 1, 13154
Publication Publié, 2019-12-01

Article révisé par les pairs

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Résumé :

Mammals have evolved many antiviral factors impacting different steps of the viral life cycle. Associated with chromatin-modifying enzymes, the cellular cofactor CTIP2 contributes to HIV-1 gene silencing in latently infected reservoirs that constitute the major block toward an HIV cure. We report, for the first time, that the virus has developed a strategy to overcome this major transcriptional block. Productive HIV-1 infection results in a Vpr-mediated depletion of CTIP2 in microglial cells and CD4+ T cells, two of the major viral reservoirs. Associated to the Cul4A-DDB1-DCAF1 ubiquitin ligase complex, Vpr promotes CTIP2 degradation via the proteasome pathway in the nuclei of target cells and notably at the latent HIV-1 promoter. Importantly, Vpr targets CTIP2 associated with heterochromatin-promoting enzymes dedicated to HIV-1 gene silencing. Thereby, Vpr reactivates HIV-1 expression in a microglial model of HIV-1 latency. Altogether our results suggest that HIV-1 Vpr mediates the depletion of the cellular repressor CTIP2 to counteract viral gene silencing.