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Role of the lineage-determining transcription factor PU.1 in the transcriptional activity of the Human Immunodeficiency Virus Type 1 (HIV-1) intragenic enhancer

par Hernalsteens, Olivier
Président du jury Droogmans, Louis
Promoteur Van Lint, Carine
Publication Non publié, 2023-12-01

Thèse de doctorat

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Résumé :

Human Immunodeficiency Virus type 1 (HIV-1) infection can be managed but not cured by the current combinatory antiretroviral therapy (cART). The replication rate of HIV-1, which is directly correlated to the rate of disease progression to Acquired Immunodeficiency Syndrome (AIDS), is controlled primarily at the transcription level of viral genes, which is not targeted by cART. The arrest of the cART is associated with a rapid viremia rebound due to the persistence of long-term reservoirs of virally infected cells, which cannot be eliminated by cART corresponding to cell types or tissue compartments where virally infected cells are maintained. These reservoirs are heterogeneous and principally composed of CD4+ T cells and myeloid cells, the latter understudied and poorly represented in cure-based efforts. Importantly, each reservoir harbors a unique regulation of HIV-1 gene expression. Even though most transcriptional studies on HIV-1 have only focused on the viral promoter 5’long terminal repeat (5’LTR), our laboratory has previously reported an intragenic cis-regulatory region (IRR), which the complete functional unit forming the HIV-1 IRR is composed, from 5’ to 3’, of three subdomains: the 5103 fragment, the hypersensitive site 7 (HS7), and the 5105 fragment. In this context, further deciphering the specific molecular mechanisms underlying HIV-1 gene expression in all host cell types (including myeloid cells) and from each transcriptional regulatory element (including the IRR) is crucial for a deeper understanding of HIV-1 biology and pathogenesis.In the first part of my PhD thesis, we determined the in vivo epigenetic landscape of the IRR in latent and reactivated conditions and in both T-lymphoid and myeloid-infected cells, representing the two major cellular contexts of HIV-1 infection. We demonstrated that the IRR harbored the characteristic features of an enhancer in these two physiological contexts. Second, we explored the contribution of the intragenic lineage-determining transcription factor (LDTF) PU.1 binding sites in the establishment of the IRR epigenetic and transcriptional landscape in myeloid HIV-1-infected cells. Finally, in the third part, since our results demonstrated that IRR also presented an epigenetic landscape of enhancers in T-lymphoid HIV-infected cells, we decided to identify and characterize the T cell-specific counterpart of PU.1, which is involved in the molecular regulation of the T-lymphoid IRR enhancer activity.Collectively, our findings expand our understanding of the molecular basis of the HIV-1 IRR epigenetic landscape and its contribution to viral transcriptional regulation. A better understanding of these molecular mechanisms should allow us to identify potential innovative therapeutic strategies aiming at HIV-1 remission/eradication and thereby decrease AIDS-associated morbidity.