Thèse soutenue

Contrôle traductionnel des ARN génomiques de VIH-1 et VIH-2
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Auteur / Autrice : Ricardo Soto-Rifo
Direction : Théophile Ohlmann
Type : Thèse de doctorat
Discipline(s) : Sciences de la vie
Date : Soutenance en 2010
Etablissement(s) : Lyon, Ecole normale supérieure
Partenaire(s) de recherche : Laboratoire : Laboratoire de virologie humaine (Lyon)

Résumé

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Infections by Human immunodeficiency viruses type-1 and type-2 (HIV-1 and HIV-2) have an enormous impact in Human health as more than 33 million people is living with HIV/AIDS worldwide. The mechanisms controlling post-transcriptional events during the HIV life cycle have just started to capture the attention of scientists and most of the molecular processes allowing the genomic RNA to interact with the host machineries for translation, transport or decay are still obscure or in way to be determined. In this work, we contribute to the progress in the knowledge of the mechanisms controlling protein synthesis from the HIV-1 and HIV-2 genomic RNA. Results presented here provide evidence for the TAR RNA structure as a key player in controlling the interactions between the HIV-1 and HIV-2 genomic RNA with the host translational machinery. We also provide data for a new step during the HIV-2 life cycle that involves the accumulation of the genomic RNA in cytoplasmic granules containing several stress granules components. Finally, we present evidence for a potential mechanism by which nuclear export and protein synthesis are linked during the HIV-1 replication cycle. As such, we show that DEAD-box RNA helicase DDX3, previously implicated in Rev-mediated nuclear export, is absolutely required for HIV-1 genomic RNA translation. We determined the TAR structure as the viral determinant required for DDX3 function in translation. Strikingly, we also showed that DDX3 is specifically required for HIV-2 and SIV translation but not for FIV, HTLV-1, MLV or Line-1 suggesting that this function was acquired during primate lentiviruses evolution. Taken together, results obtained during this work highlight several key aspects of the HIV-1 and HIV-2 genomic RNA post-transcriptional control that may be critical for viral replication.