PATHOGENESIS AND EVOLUTION OF HUMAN T CELL LEUKEMIA/LYMPHOTROPIC VIRUSES

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HTLV-I transformation of human T-cell occurs through the selection of permissive cells, both in vitro and in vivo. We are investigating the viral and cellular genetic determinants involved in the mechanism of human T-cell transformation in vitro, with emphasis on their relevance in the development of adult T-cell leukemia (ATL). Because HTLV-II also transforms T-cells, but does not cause disease, different genetic determinants may be involved in the ability of both viruses to induce T-cell transformation in vitro. Indeed, we have found that in HTLV-I, a protein encoded from the pX region binds to the IL-2R and chains, but none of the proteins from the HTLV-II pX region do. In addition, while in vitro transformation by HTLV-I corresponds to a constitutive activation of the IL-2R (JAK/STAT) pathway, this is not the case in HTLV-II. Interestingly, by studying the functional status of the JAK/STAT pathway in uncultured ATL samples, we found that, in 70% of the cases, STAT proteins are activated, but in other cases they are not, indicating that the biochemical events which determine ATL cells differ. Presently, the research focus is to understand the mechanism of JAK/STAT activation in vivo and in vitro. CDNA for JAK, STAT3 and the cytoplasmic portion of the chain from uncultured leukemic cells and HTLV-I transformed cell lines are being analyzed for the presence of activating mutations. The sites of interaction of p12 and the and chains of the IL- 2R have been finely mapped and evidence on the lack of effect of p12I on the JAK-STAT pathway have been obtained in a reconstituted IL-2 signaling system in Cos-cells. Investigation on the possible effect of p12 on the ras-pathway are in progress. In addition, we have obtained evidence that the viral transactivation protein, Tax, trans-represses p53 transcriptional activity in lymphoid and non-lymphoid cells and we are investigating the mechanisms. Finally, we have demonstrated that the late-phase of HTLV-I transformation in vitro is associated with constitutive activation of the cyclin E-CDK2 complex, an event that correlates with limiting amount of the p27kip1 inhibitor in the cyclin E-CDK2 complex.