Human T-cell leukemia virus type I (HTLV-I IntroductionAdult T-cell leukemia (ATL) is an aggressive malignancy of CD4 ϩ T cells, and its development is closely associated with human T-cell leukemia virus type I (HTLV-I) infection. [1][2][3] In vitro, HTLV-I transforms primary human CD4 ϩ T cells in interleukin-2 (IL-2)-dependent and IL-2-independent manners. Although the mechanism of transformation and leukemogenesis is not fully elucidated, there is evidence to suggest that the viral Tax protein plays a crucial role in these processes. For instance, like HTLV-I, Tax immortalizes primary human CD4 ϩ T cells in vitro and transforms rat fibroblast cell lines. 4,5 In addition, Tax inhibits apoptosis induced by various stimuli in T-cell lines. 6 Tax activates viral gene expression through the binding sequence for cAMP response element binding protein (CREB)/ activating transcription factor (ATF) in the 21-bp repeats of the HTLV-I long terminal repeat (LTR). Tax has been shown to activate the expression of a number of cellular genes through several distinct transcription factors, such as NF-B/Rel, AP-1, and serum response factor. 7-9 The cellular genes induced by Tax include cytokines/chemokines (IL-1␣, IL-6, IL-8, tumor necrosis factor-␤, monocyte chemoattractant protein-1, granulocyte macrophage-colony stimulating factor, and granulocyte colonystimulating factor), their receptors (the ␣ chain of IL-2 receptor [IL-2R] and IL-15R), cell adhesion molecule (OX40), matrix metalloproteinase (MMP-9), apoptosis inhibitor (Bcl-x L ), and G1-cyclins (cyclin D1 and cyclin D2). 7,10-21 The transcriptional activation of cellular genes, including those listed above, by Tax is thought to contribute to deregulated proliferation of HTLV-Iinfected cells.Accumulating evidence suggests that activation of cellular genes by Tax through NF-B is a critical process in the transforming activity as well as the inhibition of apoptosis. For instance, a Tax mutant inactive for NF-B cannot immortalize primary human T cells in vitro. 22 NF-B2, a member of the IB protein family, abrogates the transformation of a rat fibroblast cell line by Tax. 5 Tax inhibits apoptosis induced by IL-2 withdrawal in mouse factor-dependent T-cell lines, and such inhibition correlates with the activation of NF-B and induction of the antiapoptotic gene Bcl-x L through the NF-B pathway. 23,24 In resting T cells, NF-B is sequestered in the cytoplasm in an inactive form by association with an inhibitory IB subunit. Activation of NF-B generally involves phosphorylation and degradation of IBs, followed by nuclear translocation of NF-B and subsequent activation of the genes containing NF-B binding sites. IBs are phosphorylated by a multisubunit IB kinase (IKK) complex, which is composed of 2 catalytic subunits, IKK␣ and IKK␤, and a noncatalytic subunit, IKK␥/NEMO. Tax Reprints: Naoki Mori, Department of Virology, Faculty of Medicine, University of the Ryukyus, 207, Uehara, Nishihara, Okinawa 903-0215, Japan; e-mail: n-mori@med.u-ryukyu.ac.jp.The publication costs of this ar...

Human T-cell leukemia virus type I (HTLV-I

Our aim was to examine the involvement of G1 cell‐cycle regulators in cell growth dysregulation induced by HTLV‐I. Compared to uninfected cells, higher expression levels of cyclin D1 and D2 mRNA were detected in HTLV‐I–infected T‐cell lines, which were at least in part mediated by the viral transforming protein Tax since Tax activated both cyclin D1 and D2 promoters in the human T‐cell line Jurkat. A Tax mutant that did not activate NF‐κB failed to activate cyclin D1 and D2 promoters. Inhibitors of NF‐κB (dominant negative IκBs mutants) suppressed Tax‐dependent activation of cyclin D1 and D2 promoters, indicating that Tax‐induced activation was mediated by NF‐κB. Wild‐type and mutant Tax capable of activating NF‐κB, but not Tax mutant incapable of activating NF‐κB, converted cell growth of a T‐cell line from being IL‐2–dependent to being IL‐2–independent; and this conversion was associated with IL‐2–independent induction of cyclins D1 and D2. Our data suggest that induction of cyclins D1 and D2 by Tax is involved in IL‐2–independent cell‐cycle progression as well as IL‐2–independent transformation of primary human T cells by HTLV‐I. High expression levels of cyclin D1 and D2 mRNAs were also detected in some patients with ATL. Our findings link HTLV‐I infection to changes in cellular D‐type cyclin gene expression, transformation of T cells and subsequent development of T‐cell leukemia. © 2002 Wiley‐Liss, Inc.

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL), which is an aggressive form of human T-cell malignancy. The viral protein, Tax, immortalizes human T-cells and inhibits various types of apoptosis, and is thought to play crucial roles in the development of ATL. We have recently demonstrated that Tax induces the constitutive expression of the anti-apoptotic protein, Bcl-xL, in a mouse T-cell line. The mouse, however, is not a natural host of HTLV-I, and HTLV-I does not induce this malignancy in mice. We thus examined whether Tax also activates the expression of Bcl-xL in human T-cells. Expression of Tax in a human T-cell line, Jurkat, induced the expression of the Bcl-xL gene, but did not significantly affect the expression of the other apoptosis-related genes, Bcl-2 and Bax. Transient transfection assays showed that Tax stimulated human Bcl-xL promoter activity in Jurkat cells. Deletion of the two potential nuclear factor (NF)-kappaB binding sites in the human Bcl-xL promoter significantly decreased Tax-induced transactivation. In addition to NF-kappaB, Tax activates transcription through the c-AMP responsive element binding protein (CREB). Tax mutants segregating these two pathways showed that both the NF-kappaB and CREB pathways of Tax are required for maximum activation of a human Bcl-xL promoter, nevertheless, NF-kappaB alone was sufficient for that of a mouse Bcl-xL promoter. Northern blot analysis showed that all the human T-cell lines expressing Tax had higher levels of Bcl-xL mRNA than HTLV-I-uninfected ones. Furthermore, the sample from one patient with ATL expressed higher levels of Bcl-xL mRNA compared with levels from uninfected peripheral blood mononuclear cells. Our results suggest that Tax induces the expression of Bc-xL through the NF-kappaB and CREB pathways in HTLV-I-infected human T-cells, and then inhibits apoptosis, and such inhibition is necessary for the infected cells to advance to the leukemia in vivo.

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