IntroductionAdult T-cell leukemia (ATL) is an aggressive leukemic disorder of CD4 ϩ T cells caused by the human T-cell leukemia virus type 1 (HTLV-1). 1,2 It develops in 1% to 3% of infected individuals after more than 2 decades of viral persistence. 3,4 The contribution of the virus to the pathology of the disease is believed to involve 2 mechanisms. First, the virus directly stimulates the proliferation of the infected T cells independently of antigen. 5 Second, the HTLV-1 infection leads to chromosomal abnormalities and an increased mutation rate in infected cells. [6][7][8] In addition to its oncogenic properties, HTLV-1 induces a chronic neurologic disorder, termed HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP), 9-11 which primarily develops in patients with a specific HLA subtype. 12 As a complex retrovirus, HTLV-1 encodes the regulatory proteins Tax and Rex in addition to structural proteins. Rex is essential for the expression of the viral structural proteins, [13][14][15] and Tax acts as a transactivator of the viral promoter. [16][17][18] In addition, Tax influences multiple cellular functions including gene expression and proliferation and it increases the mutation rate. 19 Several lines of evidence indicate that the HTLV-1 regulatory protein p40 tax is responsible for the leukocyte transforming features of the virus. [20][21][22][23] The growth of primary human lymphocytes conditionally immortalized by Tax depends on Tax expression. The proliferation of these immortalized cells was reversibly arrested in the G 1 phase of the cell cycle by suppression of tax transcription, thus demonstrating that Tax stimulates the G 1 -to-S phase transition in immortalized T lymphocytes. 24 The mechanism by which Tax influences G 1 -to-S phase transition and the growth of transformed primary human T cells is not well understood and different Tax functions may cooperate in the stimulation of cell proliferation. This includes the property of Tax to directly interfere with the function of cell cycle-controlling proteins. [25][26][27][28] For instance, Tax inhibits the transactivating functions of the tumor suppressor p53 29,30 and activates cyclin-dependent kinases CDK4 and CDK6; these CDKs are essential for the control of the G 1 phase progression. 31,32 Tax has also been shown to interfere with DNA repair and in this way it possibly contributes to increase the cellular mutagenesis rate. 33 Thus, also this Tax function may be crucial for leukemogenesis. Tax-induced mutations, which accumulate during the decades of viral persistence, might affect growth-relevant genes and as a consequence of dysregulated signaling result in overexpressed genes. 8 Its function as a modulator of cellular transcription is believed to play a pivotal role in the stimulation of host cell proliferation, because Tax affects the gene expression of a variety of growthrelevant genes. It activates genes encoding proto-oncogenes, 34,35 the ␣-chain of the interleukin-2 (IL-2) receptor, [36][37][38] 28,46 Several of the mechani...

IntroductionThe human T cell leukemia virus type 1 (HTLV-1) infection is causally linked with the development of a severe and fatal lymphoproliferative disorder of CD4 ϩ T cells, the adult T cell leukemia (ATL), and of the neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). [1][2][3][4] Both diseases develop only after prolonged viral persistence. The HTLV-1 infection seems to stimulate growth and survival of the T-lymphocytes in carriers, since they expand to detectable clones, which can persist over many years even in nonleukemic individuals. 5,6 This notion is corroborated by the virus's capacity to stimulate permanent T-lymphocyte growth in vitro, resulting in T-cell immortalization. Hence, it is highly probable that viral gene functions are not only involved in immortalization of T-cell cultures, but also cause the clonal expansion of patient lymphocytes. Such growth-stimulating functions provide means to replicate the (pro-) viral genome without producing virus particles.Being a prototypic delta-retrovirus, HTLV-1 encodes the regulatory nonstructural proteins Tax and Rex, which are essential for viral replication, 7 and the accessory proteins p12, p30, and p13. While Rex acts at a posttranscriptional level 8,9 to control the expression of the structural proteins, Tax strongly enhances viral gene expression by transactivating the HTLV-1 long-terminalrepeat promoter. 10 Although the accessory proteins are important for viral infectivity and replication by influencing cellular signaling and gene expression, [11][12][13][14][15][16] p12, p13, and p30 are dispensable for lymphocyte immortalization. 17,18 Biochemically, Tax can stimulate transcription by affecting various pathways. Nuclear factor-B (NF-B) is activated by binding and stimulating IKK␥, a component of the inhibitor of kappa B kinase. 19 Transactivation of various cellular promoters is mediated by binding to the transcriptional activators CREB and SRF, and to the coactivators p300/CBP. 10,20 Tax also induces activator protein-1 (AP-1), a transcription factor complex composed of members of the Fos/Jun family, 21,22 and stimulates transcription via nuclear factor of activated T-cell (NF-AT) elements. [23][24][25] Tax confers the transforming properties on the virus. It is capable of immortalizing T cells 26,27 and is leukemogenic in transgenic mice. 28 It interferes with normal cell-cycle control by dysregulating control checkpoints. 29 In particular, Tax is capable of stimulating the G 1 phase by binding to and activating cyclindependent kinase holoenzymes; it also inhibits DNA repair and induces aneuploidy. [30][31][32][33][34][35] Importantly, it interferes with tumor suppressor functions; for instance, it inactivates p53. 36,37 Moreover, Tax can stimulate or repress the expression of cellular proteins involved in cell survival and proliferation. Among those are proto-oncogenes (c-FOS, EGR1), cytokines, and cytokine receptors, 20,25,38 as well as cell-cycle regulators (p21 WAF1/CIP1 ). Taxmediated modulati...

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