Checkpoints modulation by the human T-lymphotropic virus type 1 (HTLV-1) Tax protein : towards new therapeutic approaches

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 demonstrate 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. Despite Tax expression hampers cell cycle progression, neither pro-apoptotic nor pro-senescent effects are observed. In contrast, HTLV-1 infected lymphocytes proliferate continuously and appear to be adapted to the checkpoints. This mechanism allows infected lymphocytes to proliferate despite the presence of genomic lesions. Those cells might thus rely on effective DNA repair mechanisms. Indeed, we show that Tax expressing cells activate the error free repair mechanism homologous recombination (HR). Inhibition of ATM, involved in DDR and DNA repair by HR, impedes Tax-mediated cellular transformation.
Depending on these observations, we propose a novel therapeutic approach based on the principle of synthetic lethality.