IntroductionHuman T-cell leukemia virus type 1 (HTLV-1) infection causes adult T-cell leukemia/lymphoma and is associated with a variety of lymphocyte-mediated diseases. 1 Although infected subjects develop a vigorous and sustained immune response against the virus, infection is typically lifelong. The positive sense RNA genome of HTLV-1 encodes the typical retroviral structural and enzymatic genes Gag, Pol, and Env, the positive regulatory gene products Tax and Rex, and several accessory gene products, p12 I , p27 I , p13 II , and p30 II , which are important for viral infectivity and persistence in vivo. [2][3][4] Tax, the transcriptional activator, is an important modulator of both viral and cellular gene expression, 5 and its expression is essential for HTLV-mediated cellular transformation of T lymphocytes. 6-8 Tax transactivates not only the viral gene promoter, but many host cellular promoters through cAMP response elementbinding protein (CREB), nuclear factor B (NF-B), and serum response factor (SRF) pathways. 9,10 The stimulation of such pathways by Tax leads to unregulated protein expression and heightened activation in signaling cascades, including Janus kinase/ signal transducer and activator of transcription (JAK/STAT), phosphatidylinositol 3-kinase (PI3K), and c-Jun N-terminal kinase (JNK). [11][12][13][14] It has also been shown that Tax can bind to cyclindependent kinase holoenzymes, inactivate tumor supressors such as p53 and discs large protein (DLG), and has the ability to silence cellular checkpoints. [15][16][17][18][19] These pleiotropic effects of Tax on the cell have suggested that there may be differences between the initiation and maintenance of transformation. 20 The majority of retroviral gene products are encoded by the sense strand of the genome. However, natural antisense viral transcripts have been recognized in retroviruses, including HTLV-1, HIV, and feline immunodeficiency virus (FIV). [21][22][23] The novel HTLV-1 protein HBZ (HTLV-1 b-ZIP factor) is encoded by a minus-strand mRNA that is transcribed by a functional promoter present in the antisense strand of the HTLV-1 proviral genome (Larocca et al 21 and Cavanagh et al 24 ). Since exogenously overexpressed HBZ down-regulates Tax-induced HTLV-1 transcription and interacts with and disrupts the DNA binding activity of JunB and c-Jun (AP-1 components), 25,26 it has been hypothesized that HBZ may play an important role in HTLV-1 biology by counteracting the effects of Tax at the transcriptional level and attenuating the activation of AP-1.In this study, we evaluated the functional role of HBZ in the context of an infectious molecular clone and determined its contribution to viral-induced immortalization in vitro and viral replication kinetics and persistence in vivo. Our findings indicated that the reported repressive effects of HTLV-1 HBZ on Tax and AP-1 were not sufficient to disrupt the capacity of the virus to immortalize primary T lymphocytes in vitro, but rather, enhanced infectivity and modified virus persistence in vivo...
HTLV-1 cellular transformation and disease induction is dependent on expression of the viral Tax oncoprotein. PDZ is a modular protein interaction domain used in organizing signaling complexes in eukaryotic cells through recognition of a specific binding motif in partner proteins. Tax-1, but not Tax-2, contains a PDZ-binding domain motif (PBM) that promotes the interaction with several cellular PDZ proteins. Herein, we investigate the contribution of the Tax-1 PBM in HTLV-induced proliferation and immortalization of primary T cells in vitro and viral survival in an infectious rabbit animal model. We generated several HTLV-1 and HTLV-2 Tax viral mutants, including HTLV-1⌬PBM, HTLV-2؉C22(؉PBM), and HTLV-2؉ C18(⌬PBM). All Tax mutants maintained the ability to significantly activate the CREB/ATF or NFB signaling pathways. Microtiter proliferation assays revealed that the Tax-1 PBM significantly increases both HTLV-1-and HTLV-2-induced primary T-cell proliferation. In addition, Tax-1 PBM was responsible for the micronuclei induction activity of Tax IntroductionHTLV-1 and HTLV-2 are highly related complex retroviruses that immortalize and transform T lymphocytes in cell culture and persist in infected individuals. However, the clinical manifestations of infection with these 2 viruses differ. HTLV-1 is associated with adult T-cell leukemia and a variety of immune-mediated disorders, including the chronic neurologic disease termed HTLV-1-associated myelopathy/tropical spastic paraparesis. [1][2][3][4] In contrast, HTLV-2 is much less pathogenic with only a few cases of variant hairy cell leukemia and neurologic disease associated with infection. [5][6][7][8][9] Both HTLV-1 and HTLV-2 encode the essential Tax protein. Tax acts in trans to activate transcription initiation from the viral promoter. 10,11 Tax also modulates the expression or activity of various cellular factors involved in growth and differentiation and disrupts cell-cycle control and DNA repair processes. [12][13][14] Strong evidence suggests that these pleiotropic effects of Tax on cellular processes are required for the transforming or oncogenic capacity of HTLV. 15 Indeed, mutational analysis directly demonstrated that Tax of both HTLV-1 and HTLV-2 is essential for viral-mediated cellular transformation of primary human T cells in culture. [16][17][18] Comparative studies of Tax-1 and Tax-2 revealed that these proteins display many similarities but also some major differences. Tax-1 has a higher intrinsic transactivation activity for the viral promoter than Tax-2. 19 Tax-1, but not Tax-2, is a potent inducer of micronuclei (MN) formation, which is a marker of genetic instability. 20 Tax-2, in contrast to Tax-1, fails to suppress the maturation of CD34 ϩ cells in vitro. 21 Tax-1 has been shown to inhibit p53 function more efficiently than Tax-2. 22,23 Tax-1 morphologically transforms rat fibroblasts with higher efficiency than Tax-2. 24,25 This phenotypic property was attributed to a C-terminal PDZ binding motif (PBM) that is present in Tax-1 but not Ta...
Human T-cell leukemia virus (HTLV) regulatory protein, Rex, functions to increase the expression of the viral structural and enzymatic gene products. The phosphorylation of two serine residues (S151 and S153) at the C terminus is important for the function of HTLV-2 Rex (Rex-2). The Rex-2 phosphomimetic double mutant (S151D, S153D) is locked in a functionally active conformation. Since rex and tax genes overlap, Rex S151D and S153D mutants were found to alter the Tax oncoprotein coding sequence and transactivation activities. Therefore, additional Rex-2 mutants including P152D, A157D, S151Term, and S158Term were generated and characterized ("Term" indicates termination codon). All Rex-2 mutants and wild-type (wt) Rex-2 localized predominantly to the nucleus/nucleolus, but in contrast to the detection of phosphorylated and unphosphorylated forms of wt Rex-2 (p26 and p24), mutant proteins were detected as a single phosphoprotein species. We found that Rex P152D, A157D, and S158Term mutants are more functionally active than wt Rex-2 and that the Rex-2 C terminus and its specific phosphorylation state are required for stability and optimal expression. In the context of the provirus, the more active Rex mutants (A157D or S158Term) promoted increased viral protein production, increased viral infectious spread, and enhanced HTLV-2-mediated cellular proliferation. Moreover, these Rex mutant viruses replicated and persisted in inoculated rabbits despite higher antiviral antibody responses. Thus, we identified in Rex-2 a novel C-terminal inhibitory domain that regulates functional activity and is positively regulated through phosphorylation. The ability of this domain to modulate viral replication likely plays a key role in the infectious spread of the virus and in virus-induced cellular proliferation.
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