Modulation des points de contrôle par la protéine Tax du virus T-lymphotrope humain de type 1 (HTLV-1) : vers une nouvelle approche thérapeutique

HTLV-1 infects approximately 20 million people worldwide and causes several diseases. This virus is responsible for the adult T-cell leukemia (ATL) and for a chronic neuropathology (TSP/HAM). There is currently no satisfactory treatment for these diseases. Among the proteins encoded by HTLV-1, Tax appears to play an important role in the mechanisms leading to pathogenicity. We are interested in the mechanisms of cell transformation by HTLV-1 and more particularly in the interplay between the viral Tax oncoprotein and the DNA damage response (DDR). We demonstrated that transient expression of Tax results in DNA damage, cell cycle arrest and activation of the ATM-Chk2-p53 axis of the DDR. In fibroblasts, cell cycle arrest occurs at the G1 and G2 phases depending on the p53 background. In contrast, HTLV-1 infected lymphocytes proliferate continuously and appear to be adapted to Chk2 and p53 checkpoints. This mechanism allows infected lymphocytes to proliferate despite the presence of genomic lesions. Our data shows that HTLV-1 infected cells use an alternative DNA repair pathway controlled by ATM and Chk1. This particularity may be used as novel therapeutic approach based on the principle of synthetic lethality.Thérapie de la leucémie à cellules T de l'adult