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Interactions entre CCR5 et trois récepteurs couplés aux protéines G : EBI2, A2A et S1P1 : effets sur l'infection par le VIH-1, mécanismes d'action et perspectives thérapeutiques

Abstract : It was shown in the laboratory that CCR5 density at the surface of primary CD4+ T cells strongly determines their R5 HIV-1 productive infectability. This is due to the fact that viral envelope - CCR5 interaction triggers signals that boost the viral life cycle. Our working hypothesis was that other G-protein coupled receptors (GPCR) co-expressed with CCR5 might also modulate HIV replicative cycle. To test this hypothesis, the GPCR coexpressed with CCR5 in CD4+ T cells have been identified, and the ability of the most highly expressed of them to dimerize with CCR5 and to interfere with the infection has been determined. During this thesis, I have initiated the study of two of these GPCR, EBI2 and A2A, and participated in the study of another one, S1P1.I have shown that the presence of EBI2 or A2A that each heterodimerize with CCR5, boosts the viral production in HOS and MT4 cells, similarly to S1P1. Analyzing the stages of HIV life cycle modified by the expression and triggering of these GPCR, I unveiled that the major effect was an increase in HIV genome transcription. Furthermore, we have shown that S1P1 signaling activates the transcription factor NFKB and thereby the HIV promoter. Moreover, triggering S1P1 in an in vitro model of HIV reservoir cells results in the reversion of the viral latency. These findings suggest that S1P1 agonists might be used as latency reversing agents to purge the HIV reservoir.
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Adeline Guigues. Interactions entre CCR5 et trois récepteurs couplés aux protéines G : EBI2, A2A et S1P1 : effets sur l'infection par le VIH-1, mécanismes d'action et perspectives thérapeutiques. Médecine humaine et pathologie. Université Montpellier, 2017. Français. ⟨NNT : 2017MONTT048⟩. ⟨tel-01684257⟩

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