Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of two diseases: adult T-cell leukemia (ATL), a fatal T-lymphoproliferative disorder, and tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM), a chronic progressive disease of the central nervous system. ATL was initially identified in Japan (Uchiyama et al., 1977) and is characterized by a malignant proliferation of a mature T lymphocyte with a CD2+, CD3+, CD4+, CD8J, CD25+, and HLA-DR+ phenotype. Leukemic cells have lobulated nuclei and are referred to as flower cells. The association of TSP/HAM with HTLV-1 infection was first reported by Gessain et al.(1985). TSP/HAM is characterized by a progressive demyelination of the spinal cord, but the mechanism involved in the tissue damage of the central nervous system remains unknown. HTLV-1 has also been described to be associated with other disorders such as uveitis, arthropathy, infective dermatitis, and polymyositis. Here we review recent results concerning the involvement of HTLV-1 Tax protein in molecular events controlling cell proliferation. Taken together, these observations provide further insight into the mechanisms by which HTLV-1 induces cell transformation. The expression of the HTLV-1 genome is controlled by two regulatory genes, the rex and tax genes, located in the 3! region of the viral genome. Rex is a 27-kDa protein that acts at the posttranscriptional level by modulating the transport of the viral RNAs and hence by promoting the translation of unspliced and singly spliced mRNA encoding the gag-pol and env gene products, respectively (Hidaka et al., 1988). Tax is a 40-kDa protein that functions in association with the activating transcription factor/CRE-binding protein (ATF/CREB) family (Zhao and Giam, 1992; Suzuki et al., 1993; Adya and Giam, 1995; Yin et al., 1995; Reddy et al., 1997; Gachon et al., 1998) to enhance viral transcription. This trans-activation operates through three imperfect cAMP response element (CRE)-containing 21-bp regulatory sequences in the HTLV-1 long terminal repeat (LTR). Tax also upregulates the expression of several cellular genes by activating different signaling pathways that stimulate effectors such as the serum responsive factor and the NF-κB/Rel factors (for review see Hiscott et al., 1995; Yoshida et al., 1995). Moreover, Tax can repress the transcription of cellular genes through factors of the basic helix-loophelix family (Uittenbogaard et al., 1994; Lemasson et al., 1997).

The mode of leukemic transformation by HTLV-1 is poorly understood. HTLV-1 does not code for a known cellular proto-oncogene and has no preferential site of integration, which could explain why a transformation process is initiated. Some published results suggest that Tax not only is a transcriptional activator, but also contributes to the development of ATL. Indirect evidence for the role of Tax in leukemogenesis comes from studies on malignant cells from ATL patients, which have defective proviruses retaining the 3!-end of the HTLV-1 genome (Korber et al., 1991). From experiments on primary human T-lymphocyte immortalization by a recombinant herpesvirus vector carrying the HTLV-1 3! region (Grassmann et al., 1989), it has been shown that the tax gene is necessary and sufficient for cell immortalization (Grassmann et al., 1992). Tax can also transform established rodent fibroblasts (Tanaka et al., 1990; Smith and Greene, 1991; Yamaoka et al., 1992, 1996). In addition, cotransfection of Tax with Ras can also induce transformation of primary rat embryo fibroblasts (Pozzatti et al., 1990). Finally, Tax transgenic mice develop several pathologies including leukemia, mesenchymal …