PATHOGENESIS AND EVOLUTION OF HUMAN T CELL LEUKEMIA/LYMPHOTROPIC VIRUSES

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Some of the steps involved in the mechanism of T-cell transformation by human T-cell leukemia/lymphotropic virus (HTLV)-I and HTLV-II are becoming understood. Investigation of the proteins encoded by the 3' end of the HTLV-I and HTLV-II genome revealed important differences. HTLV-I encodes a protein of 12 kilodalton which carries at least four putative SH3 binding domains and behaves as a weak oncogene in mouse fibroblast. P12(I) interacts with the interleukin 2 receptor (IL-2R) beta and gamma but not alpha chains. In the presence of p12(I), downregulation of the cell surface expression of the IL-2R beta chain occurs. Preliminary data suggest that the amino terminal region of p12(I), which contains one of the SH3 binding domains, is involved in this event. Mapping of the IL-2R and p12(I) genetic determinant involved in this interaction is ongoing. A protein equivalent to p12 in HTLV-II has not been identified. However, it appears that in HTLV-I- and HTLV-II-transformed T-cells, different pathways, both leading to T-cell growth, might be activated. In HTLV-I, IL-2 independent T-cells, the JAK/STAT pathway is constitutively activated. However, this is not the case in HTLV-II IL-2 independent T-cells. Studies on the SHC-GRAB-2, MAPK pathway in HTLV- transformed cells is now underway. In both HTLV-I- and HTLV-II-transformed T-cell, alteration of cell cycle inhibitors like the p21(waf/cip1) and p53 gene appears to occur frequently. The consequence of these alterations on the Rb and Abelson proteins are also being investigated. A new simian T-cell leukemia/lymphotropic virus type I, isolated last year, has been cloned and its DNA sequence obtained. The putative amino acid sequence will be used to generate reagents that may uncover other related retroviruses in humans.