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Epigenetic and Transcriptional Mechanisms of Human Immunodeficiency Virus type 1 Persistence in T-lymphoid and Myeloid Reservoirs

par Verdikt, Roxane
Président du jury Vanhamme, Luc
Promoteur Van Lint, Carine
Publication Non publié, 2019-05-28

Thèse de doctorat

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Résumé :

HIV-1 infections can be treated but not cured by the current antiretroviral therapy regimens. One of the major barriers to HIV-1 eradication is the persistence of the virus in treated HIV+ individuals under the form of reservoirs. A continuum of molecular mechanisms, at the epigenetic, transcriptional and post-transcriptional levels maintains HIV-1 gene expression silent in its reservoirs. A better understanding of HIV-1 molecular mechanisms of persistence thus allows to devise novel therapeutic approaches to eradicate the virus. In this context, our thesis aimed at characterizing the molecular mechanisms of HIV-1 persistence in its T-lymphoid and myeloid reservoirs. More specifically, we have studied the epigenetic and transcriptional mechanisms of HIV-1 persistence at three different levels. First, we have investigated the DNA methylation-mediated mechanisms underlying the heterogeneity of the DNA methylation inhibitor 5-aza-2’-deoxycytidine potency in the reactivation of HIV-1 gene expression from latently-infected CD4+ T cells. Second, we have studied the contribution of the intragenic binding sites for the cellular PU.1 transcription factor in the specific regulation of HIV-1 gene expression in myeloid lineages. Finally, in a third study, we have designed a new tool to study the transcriptional landscape of HIV-1 in LTRs-suppressed proviruses. Collectively, our work has offered individual insights into the molecular mechanisms underlying the heterogeneity of HIV-1 T-lymphoid and myeloid reservoirs, with the ultimate goal of developing new HIV-1 curative strategies and improving the quality of life of HIV+ individuals.