The genome of HTLV-1 and the major transcripts are shown in Fig. 1. In addition to the gag, pol and env gene products found in other exogenous replication-competent retroviruses, HTLV-1 encodes at least 7 regulatory gene products which control the proviral transcription, mRNA splicing and transport, and the expression of certain host genes. The functions of these regulatory Linsitinib genes of HTLV-1 have been reviewed elsewhere [19] and [20]. Among these genes, two, tax and HBZ, appear to play a particularly important role in regulating the expression of viral and host genes and the activation and proliferation of the host cell [20] and [21]. The transcriptional transactivator Tax recruits host

cell transcription factors, notably CBP/p300, and activates transcription of the virus itself, from the promoter/enhancer in the 5′ long-terminal repeat (LTR) ( Fig. 1), creating a strong positive feedback loop. In addition, Tax activates the NF-κB and AKT pathways, thereby upregulating many host genes [22]. This widespread gene activation results in activation and proliferation

of the host cell [20] and [23] and transmission of HTLV-1 to other host cells via the virological synapse [24] and [25]. HTLV-1 Tax protein has a remarkable range of actions on the host cell, promoting DNA replication and cell-cycle progression, structural damage to the host cell DNA, inhibition of DNA repair and cell-cycle and and DNA damage checkpoints, and centrosome over-duplication. check details Understandably, Tax has therefore been believed to be necessary and sufficient to cause ATLL. Tax is indeed sufficient

to immortalize rat fibroblasts in culture, and Tax-transgenic mice develop a variety of tumours [26], [27] and [28]. However, mouse cells appear to be transformed more readily than human cells [29], and attempts to transform human cells in vitro with Tax have failed. A second paradox concerning the putative oncogenic role of Tax is the fact that some 60% of ATLL clones do not express Tax, although the transformed cell typically retains the phenotype (CD25+ FoxP3+ GITR+, etc.) of the Tax-expressing cell. The loss of Tax results from one of 3 mechanisms: deletion or methylation of the 5′ LTR, or mutation of the provirus [20] and [21]. It is thought that the pressure to lose Tax expression is exerted by the strong host cytotoxic T lymphocyte (CTL) response to the Tax protein [30]. In 2002 a new gene was discovered in HTLV-1 [31]. The HTLV-1 bZIP factor, HBZ, is expressed from the negative strand of the provirus (Fig. 1), driven by the transcription factor Sp1 from a promoter in the 3′ LTR. In contrast with Tax, HBZ appears to be expressed at a constant (albeit low) level in most if not all HTLV-1-infected cells, both non-transformed and malignantly transformed [32]. HBZ has important actions at both the protein and mRNA levels [20].