HTLV-1 is the etiological agent of adult T-cell leukemia (ATL), the neurological syndrome TSP/ HAM and certain other clinical disorders. The viral Tax protein is considered to play a central role in the process leading to ATL. Tax modulates the expression of many viral and cellular genes through the CREB/ATF-, SRF-and NF-κB-associated pathways. In addition, Tax employs the CBP/ p300 and p/CAF co-activators for implementing the full transcriptional activation competence of each of these pathways. Tax also affects the function of various other regulatory proteins by direct protein-protein interaction. Through these activities Tax sets the infected T-cells into continuous uncontrolled replication and destabilizes their genome by interfering with the function of telomerase and topoisomerase-I and by inhibiting DNA repair. Furthermore, Tax prevents cell cycle arrest and apoptosis that would otherwise be induced by the unrepaired DNA damage and enables, thereby, accumulation of mutations that can contribute to the leukemogenic process. Together, these capacities render Tax highly oncogenic as reflected by its ability to transform rodent fibroblasts and primary human T-cells and to induce tumors in transgenic mice. In this article we discuss these effects of Tax and their apparent contribution to the HTLV-1 associated leukemogenic process. Notably, however, shortly after infection the virus enters into a latent state, in which viral gene expression is low in most of the HTLV-1 carriers' infected T-cells and so is the level of Tax protein, although rare infected cells may still display high viral RNA. This low Tax level is evidently insufficient for exerting its multiple oncogenic effects. Therefore, we propose that the latent virus must be activated, at least temporarily, in order to elevate Tax to its effective level and that during this transient activation state the infected cells may acquire some oncogenic mutations which can enable them to further progress towards ATL even if the activated virus is re-suppressed after a while. We conclude this review by outlining an hypothetical flow of events from the initial virus infection up to the ultimate ATL development and comment on the risk factors leading to ATL development in some people and to TSP/HAM in others.

Previous reports have shown that, in certain cell types, p21 WAF-1 , which plays a central role in cell proliferation, can be activated by HTLV-I Tax protein and by TPA. Tax and TPA are also known to stimulate HTLV-I gene expression. Since cell proliferation has a major impact on HTLV-I replication, it was of interest to investigate their effect on p21 WAF-1 in human T cells, which are the main target of HTLV-I in human infection. This study demonstrates that p21 WAF-1 is activated in such cells by both factors, each acting through a different mechanism that does not influence the other. The effect of TPA is shown to require PKC activity. Notably, however, examination of different PKC isoforms revealed that PKC-a and PKC-e stimulated p21 WAF-1 expression, whereas PKC-g was rather inhibitory and PKC-b1 and b2 were ineffective. All these isoforms were found to be activated by TPA in the employed T cells, but this apparent paradox was resolved by the observation that when coexpressed together in these cells, the stimulatory PKCs override the inhibitory isoform. Further experiments demonstrated that the PKC-induced p21 WAF-1 activation was mediated by binding of Sp1-p53 complex to the second most upstream of the six Sp1 recognition sites present in its promoter and that this effect did not require the cooperation of an p53-binding site.

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In this study we investigated the effect of Tax on nucleotide excision repair (NER) in human T-cell lines by using the host cell repair analysis of UVC-irradiated reporter plasmid. This analysis revealed a p53-dpendent NER activity in wild type (w.t.) p53-containing T-cells and p53-independent NER in w.t. p53-lacking Tcells. Notably, in the w.t. p53-containing cells Tax exerted a dosedependent dual effect on NER. While low Tax doses markedly stimulated this repair, high Tax doses strongly reduced it. Further experiments demonstrated that the low Tax doses enhanced, in these cells, the level and the transcriptional function of their w.t. p53 protein. On the other hand, although the high Tax doses further increased the level of p53, they functionally inactivated its accumulating molecules. Both of these Tax effects on p53 proved to be mediated by Tax-induced NF-jB-related mechanisms. Together, these data suggest that by NF-jB activation Tax elevates the level of the cellular w.t. p53. However, while at low Tax doses the elevating w.t. p53 molecules are functionally active and capable of stimulating NER, intensifying further the NF-jB activation by the high Tax doses concomitantly evokes certain mechanism(s) which functionally inactivates the accumulating p53 protein. In contrast to this dual effect on the p53-dependent NER, Tax displayed only an inhibitory effect on the p53-independent NER by its high doses, whereas its low doses had no effect on this repair. The mechanisms of the NF-jB-associated effects on the level and function of the cellular w.t.p53 and of the p53-independent NER noted in our experimental systems are further investigated in our laboratory. ' 2007 Wiley-Liss, Inc.

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