HTLV-II–Associated Cutaneous T-Cell Lymphoma in a Patient with HIV-1 Infection

Poiesz, Bernard J.; Dube, Dipak K.; Dube, Syamalima; Love, Jayne L.; Papsidero, Lawrence D.; Üner, Ayşegül; Hutchinson, Robert

doi:10.1056/nejm200003303421304

Cited by 58 publications

(28 citation statements)

References 30 publications

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“…[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.…”

Section: Introductionmentioning

confidence: 99%

PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo

Xie

Yamamoto

Haoudi

et al. 2006

Blood

100

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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...

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Section: Introductionmentioning

confidence: 99%

PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo

Xie

Yamamoto

Haoudi

et al. 2006

Blood

100

View full text Add to dashboard Cite

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“…2,3 In contrast, the correlation between HTLV-2 infection and hematopoietic malignancies is still controversial. [4][5][6][7] However, HTLV-2 infection of T cells in vitro results in spontaneous cell proliferation and transformation. 6,[8][9][10][11] In addition, HTLV-2 can be found in some patients with neurodegenerative and lymphoproliferative disorders and in a significant fraction (up to 10%) of intravenous drug users, frequently co-infected with human immunodeficiency virus (HIV)-1.…”

Section: Introductionmentioning

confidence: 99%

Human T-cell leukemia virus type 2 induces survival and proliferation of CD34+ TF-1 cells through activation of STAT1 and STAT5 by secretion of interferon-γ and granulocyte macrophage–colony-stimulating factor

Bovolenta

Pilotti

Mauri

et al. 2002

Blood

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“…Even if originally isolated from a case of atypical hairy T-cell leukemia (1,7) and capable of inducing the survival and proliferation of CD34 ϩ cells (8,9), of immortalizing human lymphocytes, or of transforming rat cells in vitro (10 -13), HTLV-2 has not been epidemiologically demonstrated to be the agent of a malignant hematological disease (14). There is in fact only one cutaneous T cell lymphoma case report where HTLV-2 was likely to be involved in the pathogenesis of the disease (15). Nevertheless, an overall increase of the CD8 ϩ T-cell population is often detected in HTLV-2-infected individuals (16).…”

mentioning

confidence: 99%

A 10-Amino Acid Domain within Human T-cell Leukemia Virus Type 1 and Type 2 Tax Protein Sequences Is Responsible for Their Divergent Subcellular Distribution

Meertens

Chevalier

Weil

et al. 2004

Journal of Biological Chemistry

116

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Human T-cell leukemia virus type 1 and type 2 (HTLV-1/2) are related retroviruses that infect Tlymphocytes. Whereas HTLV-1 infection can cause leukemia, HTLV-2 has not been demonstrated to be the agent of a hematological malignant disease. Nevertheless, the virally encoded Tax-1 and Tax-2 transactivators display a high percentage of similarity. Tax-1 is a shuttling protein that contains a noncanonical nuclear localization signal as well as a nuclear export signal. The presence of the nuclear localization signal and the nuclear export signal domains in the Tax-2 sequence has not been determined. The distribution of Tax-2 in infected cells is not known but has been assumed to be similar to that of Tax-1. By using a Tax-2-specific antibody, we report here that Tax-2 is located predominantly in the cytoplasm of the HTLV-2 immortalized or transformed infected T-cells. These results were confirmed after transient transfection of untagged Tax-1 and Tax-2 constructs, histidine tag Tax1/Tax2, GFPTax, and Tax-GFP fusion constructs in several cell lines. We show that this unanticipated localization is not due to a default in the Tax-2 nuclear localization signal functions nor to major differences in Tax-2 versus Tax-1 binding to the IKK␥/NEMO protein. In addition, we demonstrate that inhibiting the proteasome results in a relocalization of Tax-1 in the cytoplasm, similar to that of Tax-2. By using a series of Tax-1/Tax-2 chimeras, we determined that the minimal domain that is necessary for Tax-2 peculiar distribution encompasses amino acids 90 -100. Finally, we show a high correlation between intracellular localization of Tax and their NF-B or CREB transactivating ability.

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HTLV-II–Associated Cutaneous T-Cell Lymphoma in a Patient with HIV-1 Infection

Cited by 58 publications

References 30 publications

PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo

PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo

Human T-cell leukemia virus type 2 induces survival and proliferation of CD34+ TF-1 cells through activation of STAT1 and STAT5 by secretion of interferon-γ and granulocyte macrophage–colony-stimulating factor

A 10-Amino Acid Domain within Human T-cell Leukemia Virus Type 1 and Type 2 Tax Protein Sequences Is Responsible for Their Divergent Subcellular Distribution

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