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Importance des facteurs cellulaires LSD1 et HIC1 dans la restriction de l'expression du VIH-1 dans les cellules microgliales

Abstract : Even though current multitherapies maintain HIV infection under control, they unfortunately do not achieve viral eradication due to the existence of latently infected cell reservoirs. Microglial cells are resident macrophages and the main HIV-1 target in brain. They have been described as a long-lived HIV-1 cell reservoir, and so appear as a one of the main obstacle to viral clearance. Thus, understanding of the mechanisms implicated in the establishment and maintaining of viral latency in these cells is a critical step on the way towards an HIV cure. Our team already demonstrated the implication of the cellular transcription factor CTIP2 in the establishment of HIV-1 silencing. In this work, I present two other cellular factors, LSD1 and HIC1 as new HIV-1 transcriptionnal expression inhibitors in microglial cells. LSD1 cooperates with CTIP2 to promote the establishment of epigenetic marks associated to heterochromatin structure at the viral promoter. LSD1 act as an anchoring plateform for CTIP2, and so the CTIP2-associated mutli-enzymatic chromatin remodeling complex, but also recruits the COMPASS methyltransferase complex. Unlike CTIP2 and LSD1, the tumor suppressor HIC1 disrupts the TAT-mediated transactivation cycle. HIC1 is beforehand modified post-translationnaly by the deacetylase SIRT1 and then counteracts TAT activity in order to limit viral transcription reactivation. Thus, while CTIP2 and LSD1 favour latency establishment, HIC1 maintains provirus silencing in microglial cells. All together, the results presented in this work introduce two new viral expression restriction factors and new potential therapeutic targets in reservoir purge strategies.
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Submitted on : Monday, April 15, 2013 - 11:47:12 AM
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Valentin Le Douce. Importance des facteurs cellulaires LSD1 et HIC1 dans la restriction de l'expression du VIH-1 dans les cellules microgliales. Biochimie, Biologie Moléculaire. Université de Strasbourg, 2012. Français. ⟨NNT : 2012STRAJ081⟩. ⟨tel-00813219⟩

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