Novel Role of UHRF1 in DNA methylation-mediated repression of latent HIV-1

Verdikt, R.; Bouchat, S.; Pasternak, A. O.; Nestola, L.; Darcis, G.; Avettand-Fenoel, V.; Vanhulle, C.; Ait-Ammar, A.; Bendoumou, M.; Plant, E.; Le Douce, V.; Delacourt, N.; Cicilionyte, A.; Necsoi, C.; Corazza, F.; Pereira Bittencourt Passaes, C.; Schwartz, C.; Bizet, M.; Fuks, F.; Saez-Cirion, A.; Rouzioux, C.; De Wit, S.; Berkhout, B.; Gautier, V.; ROHR, O.; Van Lint, C.

doi:10.1101/2021.06.15.448539

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bioRxiv · 10.1101/2021.06.15.448539

Novel Role of UHRF1 in DNA methylation-mediated repression of latent HIV-1

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Abstract

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.

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Verdikt, R., Bouchat, S., Pasternak, A. O., Nestola, L., Darcis, G., Avettand-Fenoel, V., Vanhulle, C., Ait-Ammar, A., Bendoumou, M., Plant, E., Le Douce, V., Delacourt, N., Cicilionyte, A., Necsoi, C., Corazza, F., Pereira Bittencourt Passaes, C., Schwartz, C., Bizet, M., Fuks, F., Saez-Cirion, A., Rouzioux, C., De Wit, S., Berkhout, B., Gautier, V., ROHR, O., Van Lint, C.. 2021-06-15. Novel Role of UHRF1 in DNA methylation-mediated repression of latent HIV-1. https://doi.org/10.1101/2021.06.15.448539

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