| Autor: |
Francis Corazza, Le Douce, Christian Schwartz, Van Lint C, Nestola L, Caroline Vanhulle, Pereira Bittencourt Passaes C, Amina Ait-Ammar, Avettand-Fenoel, Christine Rouzioux, François Fuks, Maryam Bendoumou, Ben Berkhout, Alexander O. Pasternak, Coca Valentina Necsoi, Sophie Bouchat, Gilles Darcis, Plant E, Rohr O, Gautier, De Wit S, Nadège Delacourt, Cicilionyte A, Asier Sáez-Cirión, Roxane Verdikt, Martin Bizet |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.1101/2021.06.15.448539 |
| Popis: |
The multiplicity, heterogeneity and dynamic nature of HIV-1 latency mechanisms are reflected in the current lack of functional cure for HIV-1 and in the various reported ex vivo potencies of latency- reversing agents. Here, we investigated the molecular mechanisms underlying the potency of the DNA methylation inhibitor 5-aza-2’-deoxycytidine (5-AzadC) in HIV-1 latency reversal. Doing so, we uncovered specific demethylation CpG signatures induced by 5-AzadC in the HIV-1 promoter. By analyzing the binding modalities to these CpG, we revealed the recruitment of the epigenetic integrator UHRF1 to the HIV-1 promoter. We further demonstrated the role of UHRF1 in DNA methylation- mediated silencing of the latent HIV-1 promoter. As a proof-of-concept to this molecular characterization, we showed that pharmacological downregulation of UHRF1 in ex vivo HIV+ patient cell cultures resulted in potent reactivation of latent HIV-1. Together, we identify UHRF1 as a novel actor in HIV-1 gene silencing and highlight that it constitutes a new molecular target for HIV-1 curative strategies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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