par Bendoumou, Maryam
Président du jury Vanhamme, Luc
Promoteur Van Lint, Carine
Publication Non publié, 2026-04-09
Thèse de doctorat
Résumé : Despite antiretroviral therapy, the human immunodeficiency virus type 1 (HIV-1) persists in latently infected cells through mechanisms that remain incompletely understood. The poor clinical efficacy of latency-reversing agents is attributed to incomplete knowledge of the molecular regulators maintaining HIV-1 latency. This thesis identifies novel factors and molecular mechanisms that sustain HIV-1 latency. KLF16 was identified as a new HIV-1 repressor that competes with Sp1 and recruits repressive epigenetic machinery to the viral promoter. The epigenetic integrator UHRF1 was discovered to function as a multifunctional repressor, operating at epigenetic, transcriptional initiation, and elongation levels by inducing proteasomal degradation of critical HIV-1 transcription components. The importance of post-transcriptional blocks during latency in patient samples was demonstrated, with UHRF1 shown to modulate HIV-1 gene expression post-transcriptionally by affecting RNA stability, splicing, and export. The molecular mechanisms underlying non-cytotoxic CD8⁺ T cell-mediated HIV-1 suppression were explored, revealing coordinated molecular remodelling in both CD8⁺ and CD4⁺ T cells that promotes latency. CD8⁺ T cells impose repressive chromatin at the HIV-1 5'LTR by recruiting epigenetic machinery (UHRF1, KLF16, EZH2, G9a) while sculpting a "survival-optimized" state in infected CD4⁺ T cells with maintained metabolic capacity but suppressed inflammatory circuits (TNF-α, IL-2/STAT5). Proteomic profiling reveals that suppressive CD8⁺ T cells transform into a non-cytolytic regulatory state with downregulated cytotoxic machinery but enhanced translational capacity. These findings illuminate multiple interconnected molecular layers governing HIV-1 latency, offering potential therapeutic targets for innovative cure strategies

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