Human T Lymphotropic Virus Type I (HTLV-I) Oncogenesis: Molecular Aspects of Virus and Host Interactions in Pathogenesis of Adult T cell Leukemia/Lymphoma (ATL)

Document Type: Review Article

Authors

1 Research Centre for HIV/AIDS, HTLV and Viral Hepatitis, Iranian Academic Centre for Education, Culture & Research (ACECR), Mashhad Branch, Mashhad, Iran

2 Inflammation and Inflammatory diseases research Centre, Medical School, Mashhad University of Medical Science, Mashhad, Iran.

3 Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

4 Internal Medicine Dept, Medical School, Arak University of Medical Sciences, Arak- Iran

5 Immunology Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

 
 
The study of tumor viruses paves the way for understanding the mechanisms of virus pathogenesis, including those involved in establishing infection and dissemination in the host tumor affecting immune-compromised patients. The processes ranging from viral infection to progressing malignancy are slow and usually insufficient for establishment of transformed cells that develop cancer in only a minority of infected subjects. Therefore, viral infection is usually not the only cause of cancer, and further environmental and host factors, may be implicated.
HTLV-I, in particular, is considered as an oncovirus cause of lymphoproliferative disease such as adult T cell leukemia/lymphoma (ATL) and disturbs the immune responses which results in HTLV-I associated meylopathy/tropical spastic parapresis (HAM/TSP). HTLV-I infection causes ATL in a small proportion of infected subjects (2-5%) following a prolonged incubation period (15-30 years) despite a strong adaptive immune response against the virus.
 
Overall, these conditions offer a prospect to study the molecular basis of tumorgenicity in mammalian cells. In this review, the oncogencity of HTLV-I is being considered as an oncovirus in context of ATL.
 
 

Keywords


1. Chevaliez S, Pawlotsky JM. Diagnosis and management of chronic viral hepatitis: antigens, antibodies and viral genomes. Best Pract Res Clin Gastroenterol 2008; 22:1031-1048.

2. Moradi A, Khodabakhshi B, Sadeghipour M, Besharat S, Tabarraei A. Concurrent infections of hepatitis C and HIV in hepatitis B patients in the north-east of Iran. Trop Doct 2011; 41:129-131.

 

3. Ahmad B, Ali S, Ali I, Azam S, Bashir S. Response rates of standard interferon therapy in chronic HCV patients of Khyber Pakhtunkhwa (KPK). Virol J 2012; 9:18.

 

4. Pagano JS, Blaser M, Buendia MA, Damania B, Khalili K, Raab- Traub N,

 

 

et al

. Infectious agents and cancer: criteria for a causal relation. Semin Cancer Biol 2004; 14:453-471.

5. Hirase C, Maeda Y, Yamaguchi T, Miyatake J, Kanamaru A. mTOR inhibition and adult T-cell leukemia. Leuk Lymphoma 2009; 50:645-647.

6. Maeda E, Akahane M, Kiryu S, Kato N, Yoshikawa T, Hayashi N,et al. Spectrum of Epstein-Barr virus-related diseases: a pictorial review. Jpn J Radiol 2009; 27:4-19.

7. Shimamoto Y, Nomura S, Ishii K, Shimizu M, Ozaki Y, Ito T,

 

 

et al

. Adult T-cell leukemia after immunosuppressive therapy for systemic lupus erythematosus. Int J Hematol 2009 ; 89:128-129.

8. Rezaee SA, Cunningham C, Davison AJ, Blackbourn DJ. Kaposi’s sarcoma-associated herpesvirus immune modulation: an overview. J Gen Virol 2006; 87:1781-1804.

 

9. Verdonck K GE, Van Dooren S, Vandamme AM,Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis 2007; 7:266-281.

 

10. Trevino A, Aguilera A, Caballero E, Benito R, Parra P, Eiros JM,

 

 

et al

. Trends in the prevalence and distribution of HTLV-I and HTLV-II infections in Spain. Virol J 2012; 9:71.

11. Yamashiro T, Kamiya H, Miyara T, Gibo S, Ogawa K, Akamine T,

 

 

et al

. CT scans of the chest in carriers of human T-cell lymphotropic virus type 1: presence of interstitial pneumonia. Acad Radiol 2012; 19:952-957.

12. Naderi M, Paryan M, Azadmanesh K, Rafatpanah H, Rezvan H, Mirab Samiee S. Design and development of a quantitative real time PCR assay for monitoring of HTLV-I provirus in whole blood. J Clin Virol 2012; 53:302-307.

 

13. Sadeghian MH, Keramati MR, Ayatollahi H, Feizabadi AS, Tehranaian F, Shakibyee H. Is there any relationship between expressions of minor blood group antigens with HTLV-I infection? Transfus Apher Sci 2012; 47:151-154.

 

 

 

 

190

 

 

14. Rafatpanah H, Hedayati-Moghaddam MR, Fathimoghadam F, Bidkhori HR, Shamsian SK, Ahmadi S, Rezaee SA,

et al

. High prevalence of HTLV-I infection in Mashhad, Northeast Iran: a population-based seroepidemiology survey. J Clin Virol 2011; 52:172-176.

15. Saito M, Bangham CR. Immunopathogenesis of human T-cell leukemia virus type-1-associated myelopathy/tropical spastic paraparesis: recent perspectives. Leuk Res Treatment 2012; 2012:259045.

 

16. Abdelbary NH, Abdullah HM, Matsuzaki T, Hayashi D, Tanaka Y, Takashima H,

 

 

et al

. Reduced Tim-3 expression on human T-lymphotropic virus type I (HTLV-I) Tax-specific cytotoxic T lymphocytes in HTLV-I infection. J Infect Dis 2011; 203:948-959.

17. Rafatpanah H, Farid R, Golanbar G, Jabbari Azad F. HTLV-I Infection: virus structure, immune response to the virus and genetic association studies in HTLV-I-infected individuals. Iran J Allergy Asthma Immunol 2006; 5:153-166.

 

18. Franchini G, Tartaglia J, Markham P, Benson J, Fullen J, Wills M,

 

 

et al

. Highly attenuated HTLV type Ienv poxvirus vaccines induce protection against a cell-associated HTLV type I challenge in rabbits. AIDS Res Hum Retroviruses 1995; 11:307-313.

19. Ciminale V, Pavlakis GN, Derse D, Cunningham CP, Felber BK. Complex splicing in the human T-cell leukemia virus (HTLV) family of retroviruses: novel mRNAs and proteins produced by HTLV type I. J Virol 1992; 66:1737-1745.

 

20. Koralnik IJ, Gessain A, Klotman ME, Lo Monico A, Berneman ZN, Franchini G. Protein isoforms encoded by the pX region of human T-cell leukemia/lymphotropic virus type I. Proc Natl Acad Sci U S A 1992; 89:8813-8817.

 

21. Beimling P, Moelling K. Direct interaction of CREB protein with 21 bp Tax-response elements of HTLV-ILTR. Oncogene 1992; 7:257- 262.

 

22. Zhao LJ, Giam CZ. Human T-cell lymphotropic virus type I (HTLV-I) transcriptional activator, Tax, enhances CREB binding to HTLV-I 21-base-pair repeats by protein-protein interaction. Proc Natl Acad Sci U S A 1992; 89:7070-7074.

 

23. Paca-Uccaralertkun S, Zhao LJ, Adya N, Cross JV, Cullen BR, Boros IM,

 

 

et al

. In vitro selection of DNA elements highly responsive to the human T-cell lymphotropic virus type I transcriptional activator, Tax. Mol Cell Biol 1994; 14:456-462.

24. Adya N, Giam CZ. Distinct regions in human T-cell lymphotropic virus type I tax mediate interactions with activator protein CREB and basal transcription factors. J Virol 1995 ; 69:1834-1841.

 

25. Smith MR, Greene WC. Characterization of a novel nuclear localization signal in the HTLV-I tax transactivator protein. Virology 1992; 187:316-320.

 

26. Suzuki T, Hirai H, Fujisawa J, Fujita T, Yoshida M. A trans-activator Tax of human T-cell leukemia virus type 1 binds to NF-kappa B p50 and serum response factor (SRF) and associates with enhancer DNAs of the NF-kappa B site and CArG box. Oncogene 1993; 8:2391-2397.

 

27. Goren I, Semmes OJ, Jeang KT, Moelling K. The amino terminus of Tax is required for interaction with the cyclic AMP response element binding protein. J Virol 1995; 69:5806-5811.

 

28. Perini G, Wagner S, Green MR. Recognition of bZIP proteins by the human T-cell leukaemia virus transactivator Tax. Nature 1995; 376:602-605.

 

29. Harrod R, Tang Y, Nicot C, Lu HS, Vassilev A, Nakatani Y,

 

 

et al

. An exposed KID-like domain in human T-cell lymphotropic virus type 1 Tax is responsible for the recruitment of coactivators CBP/p300. Mol Cell Biol 1998; 18:5052-5061.

30. Kaida A, Ariumi Y, Ueda Y, Lin JY, Hijikata M, Ikawa S,

 

 

et al

. Functional impairment of p73 and p51, the p53-related proteins, by the human T-cell leukemia virus type 1 Tax oncoprotein. Oncogene 2000; 19:827-830.

31. Colgin MA, Nyborg JK. The human T-cell leukemia virus type 1 oncoprotein Tax inhibits the transcriptional activity of c-Myb through competition for the CREB binding protein. J Virol 1998; 72:9396-9399.

 

32. Sun SC, Maggirwar SB, Harhaj EW, Uhlik M. Binding of c-Rel to STAT5 target sequences in HTLV-I-transformed T cells. Oncogene 1999; 18:1401-1409.

 

33. Ng PW, Iha H, Iwanaga Y, Bittner M, Chen Y, Jiang Y,

 

 

et al

. Genome-wide expression changes induced by HTLV-I Tax: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-kappaB activation. Oncogene 2001; 20:4484-4496.

34. Franchini G, Fukumoto R, Fullen JR. T-cell control by human T-cell leukemia/lymphoma virus type 1. Int J Hematol 2003; 78:280- 296.

 

35. Grassmann R, Dengler C, Muller-Fleckenstein I, Fleckenstein B, McGuire K, Dokhelar MC. Transformation to continuous growth of primary human T lymphocytes by human T-cell leukemia virus type I X-region genes transduced by a Herpesvirus saimiri vector. Proc Natl Acad Sci U S A 1989; 86:3351-3355.

 

36. Pozzatti R, Vogel J, Jay G. The human T-lymphotropic virus type I tax gene can cooperate with the ras oncogene to induce neoplastic transformation of cells. Mol Cell Biol 1990; 10:413-417.

 

37. Tanaka A, Takahashi C, Yamaoka S, Nosaka T, Maki M, Hatanaka M. Oncogenic transformation by the tax gene of human T-cell leukemia virus type I in vitro. Proc Natl Acad Sci U S A 1990; 87:1071- 1075.

 

38. Grassmann R, Berchtold S, Radant I, Alt M, Fleckenstein B, Sodroski JG,

 

 

et al

. Role of human T-cell leukemia virus type 1 X region proteins in immortalization of primary human lymphocytes in culture. J Virol 1992; 66:4570-4575.

39. Akagi T, Shimotohno K. Proliferative response of Tax1-transduced primary human T cells to anti-CD3 antibody stimulation by an interleukin-2-independent pathway. J Virol 1993 ; 67:1211-1217.

 

40. Grossman WJ, Kimata JT, Wong FH, Zutter M, Ley TJ, Ratner L. Development of leukemia in mice transgenic for the tax gene of human T-cell leukemia virus type I. Proc Natl Acad Sci U S A 1995; 92:1057-1061.

 

41. Nagashima K, Yoshida M, Seiki M. A single species of pX mRNA of human T-cell leukemia virus type I encodes trans-activator p40x and two other phosphoproteins. J Virol 1986; 60:394-399.

 

42. Inoue Y, Kuroda N, Shiraki H, Sato H, Maeda Y. Neutralizing activity of human antibodies against the structural protein of human T-cell lymphotropic virus type I. Int J Cancer 1992; 52:877-880.

 

43. Hidaka T, Nakahata S, Hatakeyama K, Hamasaki M, Yamashita K, Kohno T,

 

 

et al

. Down-regulation of TCF8 is involved in the leukemogenesis of adult T-cell leukemia/lymphoma. Blood 2008;112:383-393.

44. Ballaun C, Farrington GK, Dobrovnik M, Rusche J, Hauber J, Bohnlein E. Functional analysis of human T-cell leukemia virus type I rex-response element: direct RNA binding of Rex protein correlates with in vivo activity. J Virol 1991; 65:4408-4413.

 

45. Yoshida M, Osame M, Usuku K, Matsumoto M, Igata A. Viruses detected in HTLV-I-associated myelopathy and adult T-cell leukaemia are identical on DNA blotting. Lancet 1987; 1:1085-1086.

 

46. Hanly SM, Rimsky LT, Malim MH, Kim JH, Hauber J, Duc Dodon M,

 

 

et al

. Comparative analysis of the HTLV-I Rex and HIV-1 Rev trans-regulatory proteins and their RNA response elements. Genes Dev 1989; 3:1534-1544.

47. Derse D, Mikovits J, Ruscetti F. X-I and X-II open reading frames of HTLV-I are not required for virus replication or for immortalization of primary T-cells in vitro. Virology 1997; 237:123-128.

 

48. Robek MD, Wong FH, Ratner L. Human T-cell leukemia virus type 1 pX-I and pX-II open reading frames are dispensable for the immortalization of primary lymphocytes. J Virol 1998; 72:4458- 4462.

 

49. Collins ND, Newbound GC, Albrecht B, Beard JL, Ratner L, Lairmore MD. Selective ablation of human T-cell lymphotropic virus type 1 p12I reduces viral infectivity in vivo. Blood 1998; 91:4701- 4707.

 

50. Franchini G, Mulloy JC, Koralnik IJ, Lo Monico A, Sparkowski JJ, Andresson T,

 

 

et al

. The human T-cell leukemia/lymphotropic virus type I p12I protein cooperates with the E5 oncoprotein of bovine papillomavirus in cell transformation and binds the 16-kilodalton subunit of the vacuolar H+ ATPase. J Virol 1993; 67:7701-7704.

51. Mulloy JC, Crownley RW, Fullen J, Leonard WJ, Franchini G. The human T-cell leukemia/lymphotropic virus type 1 p12I proteins

 

 

 

 

191

 

 

bind the interleukin-2 receptor beta and gammac chains and affects their expression on the cell surface. J Virol 1996; 70:3599- 3605.

52. Albrecht B, Collins ND, Burniston MT, Nisbet JW, Ratner L, Green PL,

et al

. Human T-lymphotropic virus type 1 open reading frame I p12(I) is required for efficient viral infectivity in primary lymphocytes. J Virol 2000; 74:9828-9835.

53.Trovato R, Mulloy JC, Johnson JM, Takemoto S, de Oliveira MP, Franchini G. A lysine-to-arginine change found in natural alleles of the human T-cell lymphotropic/leukemia virus type 1 p12(I) protein greatly influences its stability. J Virol 1999; 73:6460-6467.

 

54. Jacobson S, Shida H, McFarlin DE, Fauci AS, Koenig S. Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease. Nature 1990; 348:245-248.

 

55. Igakura T, Stinchcombe JC, Goon PK, Taylor GP, Weber JN, Griffiths GM,

 

 

et al

. Spread of HTLV-I Between Lymphocytes by Virus-Induced Polarization of the Cytoskeleton. Science 2003; 299:1713- 1716.

56. Manel N, Kim FJ, Kinet S, Taylor N, Sitbon M, Battini JL. The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV. Cell 2003; 115:449-459.

 

57. Jones KS, Akel S, Petrow-Sadowski C, Huang Y, Bertolette DC, Ruscetti FW. Induction of human T cell leukemia virus type I receptors on quiescent naive T lymphocytes by TGF-beta. J Immunol 2005; 174:4262-4270.

 

58. Okochi H, Kurita K, Sugui K, Sugiyama I, Takahashi M. [Discussion. Consequences of the research on re-evaluation of public heath activities]. Hokenfu Zasshi 1984; 40:876-896.

 

59. Akashi-Tanaka S, Fukutomi T, Sato N, Iwamoto E, Watanabe T, Katsumata N,

 

 

et al

. The use of contrast-enhanced computed tomography before neoadjuvant chemotherapy to identify patients likely to be treated safely with breast-conserving surgery. Ann Surg 2004; 239:238-243.

60. Etoh K, Tamiya S, Yamaguchi K, Okayama A, Tsubouchi H, Ideta T,

 

 

et al

. Persistent clonal proliferation of human T-lymphotropic virus type I-infected cells in vivo. Cancer Res 1997; 57:4862-4867.

61. Okayama A, Stuver S, Matsuoka M, Ishizaki J, Tanaka G, Kubuki Y,

 

 

et al

. Role of HTLV-I proviral DNA load and clonality in the development of adult T-cell leukemia/lymphoma in asymptomatic carriers. Int J Cancer 2004; 110:621-625.

62. Barnard AL, Igakura T, Tanaka Y, Taylor GP, Bangham CR. Engagement of specific T-cell surface molecules regulates cytoskeletal polarization in HTLV-I-infected lymphocytes. Blood 2005; 106:988-995.

 

63. Bangham J, Chapman T, Smith HK, Partridge L. Influence of female reproductive anatomy on the outcome of sperm competition in Drosophila melanogaster. Proc Biol Sci 2003; 270:523-520.

 

64. Mesnard JM, Barbeau B, Devaux C. HBZ, a new important player in the mystery of adult T-cell leukemia. Blood 2006; 108:3979-3982.

 

65. Tabakin-Fix Y, Azran I, Schavinky-Khrapunsky Y, Levy O, Aboud M. Functional inactivation of p53 by human T-cell leukemia virus type 1 Tax protein: mechanisms and clinical implications. Carcinogenesis 2006; 27:673-681.

 

66. Cesarman E, Chadburn A, Inghirami G, Gaidano G, Knowles DM. Structural and functional analysis of oncogenes and tumor suppressor genes in adult T-cell leukemia/lymphoma shows frequent p53 mutations. Blood 1992; 80:3205-3216.

 

67. Satoh M, Toma H, Sugahara K, Etoh K, Shiroma Y, Kiyuna S,

 

 

et al

. Involvement of IL-2/IL-2R system activation by parasite antigen in polyclonal expansion of CD4(+)25(+) HTLV-I-infected T-cells in human carriers of both HTLV-I and S. stercoralis. Oncogene 2002; 21:2466-2475.

68. Jacobson S. Cellular immune responses to HTLV-I: immunopathogenic role in HTLV-I-associated neurologic disease. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 13:S100-6.

 

69. Brauweiler A, Garrus JE, Reed JC, Nyborg JK. Repression of bax gene expression by the HTLV-I Tax protein: implications for suppression of apoptosis in virally infected cells. Virology 1997; 231:135-40.

 

70. Yamada T, Yamaoka S, Goto T, Nakai M, Tsujimoto Y, Hatanaka M. The human T-cell leukemia virus type I Tax protein induces apoptosis which is blocked by the Bcl-2 protein. J Virol 1994; 68:3374- 3379.

 

71. Mulloy JC, Kislyakova T, Cereseto A, Casareto L, LoMonico A, Fullen J,

 

 

et al

. Human T-cell lymphotropic/leukemia virus type 1 Tax abrogates p53-induced cell cycle arrest and apoptosis through its CREB/ATF functional domain. J Virol 1998; 72:8852-8860.

72. Furnia A, Lal R, Maloney E, Wiktor S, Pate E, Rudolph D,

 

 

et al

. Estimating the time of HTLV-I infection following mother-to-child transmission in a breast-feeding population in Jamaica. J Med Virol 1999; 59:541-546.

73. Manns A, Hisada M, La Grenade L. Human T-lymphotropic virus type I infection. Lancet 1999; 353:1951-1958.

 

74. Manns A, Miley WJ, Waters D, Hanchard B, Wharfe G, Cranston B,

 

 

et al

. Prognostic significance of quantitative viral markers in adult T-cell leukemia/lymphoma. Blood 1999; 94:372-373.

75. Manns A, Miley WJ, Wilks RJ, Morgan OS, Hanchard B, Wharfe G,

 

 

et al

. Quantitative proviral DNA and antibody levels in the natural history of HTLV-I infection. J Infect Dis 1999; 180:1487-1493.

76. Nagai M, Usuku K, Matsumoto W, Kodama D, Takenouchi N, Moritoyo T,

 

 

et al

. Analysis of HTLV-I proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV-I carriers: high proviral load strongly predisposes to HAM/TSP. J Neurovirol 1998; 4:586-593.

77. Sugimoto M, Kitaichi M, Ikeda A, Nagai S, Izumi T. Chronic bronchioloalveolitis associated with human T-cell lymphotrophic virus type I infection. Curr Opin Pulm Med 1998; 4:98-102.

 

78. Yoshida M, Seiki M, Yamaguchi K, Takatsuki K. Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. Proc Natl Acad Sci U S A 1984; 81:2534- 2537.

 

79. Taylor GP, Tosswill JH, Matutes E, Daenke S, Hall S, Bain BJ,

 

 

et al

. Prospective study of HTLV-I infection in an initially asymptomatic cohort. J Acquir Immune Defic Syndr 1999; 22:92-100.

80. Kubota R, Fujiyoshi T, Izumo S, Yashiki S, Maruyama I, Osame M,

 

 

et al

. Fluctuation of HTLV-I proviral DNA in peripheral blood mononuclear cells of HTLV-I-associated myelopathy. J Neuroimmunol 1993; 4:147-154.

81.Ohshima K, Mukai Y, Shiraki H, Suzumiya J, Tashiro K, Kikuchi M. Clonal integration and expression of human T-cell lymphotropic virus type I in carriers detected by polymerase chain reaction and inverse PCR. Am J Hematol 1997; 54:306-312.

 

82. Hara S, Yokote T, Akioka T, Oka S, Yamano T, Tsuji M,

 

 

et al

. [Graft-versus-ATLL effect induced by abrupt discontinuation of immunosuppression following allogeneic bone marrow transplantation]. Gan To Kagaku Ryoho 2005; 32:867-871.

83. Yamano Y, Nagai M, Brennan M, Mora CA, Soldan SS, Tomaru U,

 

 

et al

. Correlation of human T-cell lymphotropic virus type 1 (HTLV-I) mRNA with proviral DNA load, virus-specific CD8(+) T cells, and disease severity in HTLV-I-associated myelopathy (HAM/TSP). Blood 2002; 99:88-94.

84. Kamihira S, Dateki N, Sugahara K, Hayashi T, Harasawa H, Minami S,

 

 

et al

. Significance of HTLV-I proviral load quantification by real-time PCR as a surrogate marker for HTLV-I-infected cell count. Clin Lab Haematol 2003; 25:111-117.

85. Bangham CR, Hall SE, Jeffery KJ, Vine AM, Witkover A, Nowak MA,

 

 

et al

. Genetic control and dynamics of the cellular immune response to the human T-cell leukaemia virus, HTLV-I. Philos Trans R Soc Lond B Biol Sci 1999; 354:691-700.

86. Nitta T, Tanaka M, Sun B, Hanai S, Miwa M. The genetic background as a determinant of human T-cell leukemia virus type 1 proviral load. Biochem Biophys Res Commun 2003; 309:161-165.

 

87. Nishimura M, Maeda M, Yasunaga J, Kawakami H, Kaji R, Adachi A,

 

 

et al

. Influence of cytokine and mannose binding protein gene polymorphisms on human T-cell leukemia virus type I (hTLV-I) provirus load in HTLV-I asymptomatic carriers. Hum Immunol 2003; 64:453-457.

88. Kodama D, Saito M, Matsumoto W, Sabouri AH, Izumo S, Arimura K,

 

 

et al. Longer dinucleotide repeat polymorphism in matrix me

 

192

 

 

talloproteinase-9 (MMP-9) gene promoter which correlates with higher HTLV-I Tax mediated transcriptional activity influences the risk of HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). J Neuroimmunol 2004; 156:188-194.

89. Sabouri AH, Saito M, Lloyd AL, Vine AM, Witkover AW, Furukawa Y,

et al

. Polymorphism in the interleukin-10 promoter affects both provirus load and the risk of human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis. J Infect Dis 2004; 190:1279-1285.

90. Saito M, Usuku K, Nobuhara Y, Matsumoto W, Kodama D, Sabouri AH,

 

 

et al

. Serum concentration and genetic polymorphism in the 5’-untraslated region of VEGF is not associated with susceptibility to HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-I infected individuals. J Neurol Sci 2004; 219:157-1561.

91. Iwanaga M, Watanabe T, Utsunomiya A, Okayama A, Uchimaru K, Koh KR,

 

 

et al

. Human T-cell leukemia virus type I (HTLV-I) proviral load and disease progression in asymptomatic HTLV-I carriers: a nationwide prospective study in Japan. Blood 2010; 116:1211-1219.

92. Gao L, Deng H, Zhao H, Hirbe A, Harding J, Ratner L,

 

 

et al

. HTLV-I Tax transgenic mice develop spontaneous osteolytic bone metastases prevented by osteoclast inhibition. Blood 2005; 106:4294- 4302.

93. Zhao TM, Hague B, Caudell DL, Simpson RM, Kindt TJ. Quantification of HTLV-I proviral load in experimentally infected rabbits. Retrovirology 2005; 2:34.

 

94. Giam CZ, Jeang KT. HTLV-I Tax and adult T-cell leukemia. Front Biosci 2007; 12:1496-14507.

 

95. Merling R, Chen C, Hong S, Zhang L, Liu M, Kuo YL,

 

 

et al

. HTLV-I Tax mutants that do not induce G1 arrest are disabled in activating the anaphase promoting complex. Retrovirology 2007; 4:35.

96. Zehender G, Ebranati E, Bernini F, De Maddalena C, Giambelli C, Collins J,

 

 

et al

. Phylogeny of human T cell lymphotropic virus type 1 in Peru: a high degree of evolutionary relatedness with South African isolates. AIDS Res Hum Retroviruses 2007; 23:1146- 1149.

97. Armstrong AP, Franklin AA, Uittenbogaard MN, Giebler HA, Nyborg JK. Pleiotropic effect of the human T-cell leukemia virus Tax protein on the DNA binding activity of eukaryotic transcription factors. Proc Natl Acad Sci U S A 1993; 90:7303-7307.

 

98. Wagner S, Green MR. HTLV-I Tax protein stimulation of DNA binding of bZIP proteins by enhancing dimerization. Science 1993; 262:395-399.

 

99. Beck A, Lima MC, Castro MC, Drummond DX, Oliveira ML, Oelemann W,

 

 

et al

. Performance of HTLV-I screening assays in Brazil. Zentralbl Bakteriol. 1996 ; 283:340-346.

100. Ge T, Wang G, Zhao B. [HTLV-I associated myelopathy]. Zhonghua Shen Jing Jing Shen Ke Za Zhi 1992; 25:182-184.

 

101. Fujisawa J, Hirai H, Suzuki T, Yoshida M. [Mechanism of transcriptional activation by HTLV-I Tax]. Hum Cell 1993; 6:266-272.

 

102. Adya N, Zhao LJ, Huang W, Boros I, Giam CZ. Expansion of CREB’s DNA recognition specificity by Tax results from interaction with Ala-Ala-Arg at positions 282-284 near the conserved DNA-binding domain of CREB. Proc Natl Acad Sci U S A 1994; 91:5642-5646.

 

103. [HTLV-I AND HTLV-II in Spain]. An Med Interna 1995; 12:299-306.

 

104. Baranger AM, Palmer CR, Hamm MK, Giebler HA, Brauweiler A, Nyborg JK,

 

 

et al

. Mechanism of DNA-binding enhancement by the human T-cell leukaemia virus transactivator Tax. Nature 1995; 376:606-608.

105. Kimzey AL, Dynan WS. Identification of a human T-cell leukemia virus type I tax peptide in contact with DNA. J Biol Chem 1999; 274:34226-34232.

 

106. Lenzmeier BA, Giebler HA, Nyborg JK. Human T-cell leukemia virus type 1 Tax requires direct access to DNA for recruitment of CREB binding protein to the viral promoter. Mol Cell Biol 1998; 18:721-731.

 

107. Bex F, Gaynor RB. Regulation of gene expression by HTLV-I Tax protein. Methods. 1998; 16:83-94.

 

108. Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev 2004; 18:2195-2224.

 

109. Cartier L, Araya F, Castillo JL, Zaninovic V, Hayami M, Miura T,

 

 

et al

. Southernmost carriers of HTLV-I/II in the world. Jpn J Cancer Res 1993; 84:1-3.

110. Chu ZL, DiDonato JA, Hawiger J, Ballard DW. The tax oncoprotein of human T-cell leukemia virus type 1 associates with and persistently activates IkappaB kinases containing IKKalpha and IKKbeta. J Biol Chem 1998; 273:15891-1584.

 

111. Harhaj EW, Good L, Xiao G, Sun SC. Gene expression profiles in HTLV-I-immortalized T cells: deregulated expression of genes involved in apoptosis regulation. Oncogene 1999; 18:1341-1349.

 

112. Harhaj EW, Good L, Xiao G, Uhlik M, Cvijic ME, Rivera-Walsh I,

 

 

et al

. Somatic mutagenesis studies of NF-kappa B signaling in human T cells: evidence for an essential role of IKK gamma in NF-kappa B activation by T-cell costimulatory signals and HTLV-I Tax protein. Oncogene 2000; 19:1448-1456.

113. Fassati A, Bardoni A, Sironi M, Wells DJ, Bresolin N, Scarlato G,

 

 

et al

. Insertion of two independent enhancers in the long terminal repeat of a self-inactivating vector results in high-titer retroviral vectors with tissue-specific expression. Hum Gene Ther 1998; 9:2459-2468.

114. Akiyama N, Ohtake H, Ohwada A, Kajiwara K, Hayama M, Kohri M,

 

 

et al

. [Successful radiotherapy for the thoracic cord infiltration of adult T-cell leukemia/lymphoma]. Rinsho Ketsueki 2003; 44:1095-10100.

115. Abbaszadegan MR, Gholamin M, Tabatabaee A, Farid R, Houshmand M, Abbaszadegan M. Prevalence of human T-lymphotropic virus type 1 among blood donors from Mashhad, Iran. J Clin Microbiol 2003; 41:2593-2595.

 

116. Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G,

 

 

et al

. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 2001 ; 293:1495-1499.

117. Uhlik M, Good L, Xiao G, Harhaj EW, Zandi E, Karin M,

 

 

et al

. NF-kappaB-inducing kinase and IkappaB kinase participate in human T-cell leukemia virus I Tax-mediated NF-kappaB activation. J Biol Chem 199; 273:21132-21136.

118. Geleziunas R, Ferrell S, Lin X, Mu Y, Cunningham ET, Jr., Grant M,

 

 

et al

. Human T-cell leukemia virus type 1 Tax induction of NF-kappaB involves activation of the IkappaB kinase alpha (IKKalpha) and IKKbeta cellular kinases. Mol Cell Biol 1998; 18:5157-5165.

119. Doi K, Wu X, Taniguchi Y, Yasunaga J, Satou Y, Okayama A,

 

 

et al

. Preferential selection of human T-cell leukemia virus type I provirus integration sites in leukemic versus carrier states. Blood 2005; 106:1048-1053.

120. Osato M, Yamaguchi K, Tamiya S, Yamasaki H, Okubo T, Suzushima H,

 

 

et al

. A human T-cell lymphotropic virus type-I carrier with chronic renal failure, aplastic anemia, myelopathy, uveitis, Sjogren’s syndrome and panniculitis. Intern Med 1996; 35:742-745.

121. Hayase H, Ishizu A, Ikeda H, Miyatake Y, Baba T, Higuchi M,

 

 

et al

. Aberrant gene expression by CD25+CD4+ immunoregulatory T cells in autoimmune-prone rats carrying the human T cell leukemia virus type-I gene. Int Immunol 2005; 17:677-684.

122. Horie R, Watanabe T, Morishita Y, Ito K, Ishida T, Kanegae Y,

 

 

et al

. Ligand-independent signaling by overexpressed CD30 drives NF-kappaB activation in Hodgkin-Reed-Sternberg cells. Oncogene 2002; 21:2493-24503.

123. de La Fuente C, Deng L, Santiago F, Arce L, Wang L, Kashanchi F. Gene expression array of HTLV type 1-infected T cells: Up-regulation of transcription factors and cell cycle genes. AIDS Res Hum Retroviruses 2000; 16:1695-1700.

 

124. Abrieu A, Magnaghi-Jaulin L, Kahana JA, Peter M, Castro A, Vigneron S,

 

 

et al

. Mps1 is a kinetochore-associated kinase essential for the vertebrate mitotic checkpoint. Cell 2001; 106:83-93.

125. Kuroda Y, Matsui M, Yukitake M, Kurohara K, Takashima H, Takashima Y,

 

 

et al

. Assessment of MRI criteria for MS in Japanese MS and HAM/TSP. Neurology 1995; 45:30-33.

126. Imaizumi M, Tatewaki SY, Kimoto K, Takaki Y, Nakatsuka K, Furushima M,

 

 

et al

. Disappearance of puncta after uveitis in an eye with fundus albipunctatus. Retina 2005; 25:1096-1098.

127. Higuchi M, Tsubata C, Kondo R, Yoshida S, Takahashi M, Oie M,

 

 

et al. Cooperation of NF-kappaB2/p100 activation and the PDZ do

 

193

 

 

main binding motif signal in human T-cell leukemia virus type 1 (HTLV-I) Tax1 but not HTLV-II Tax2 is crucial for interleukin-2-independent growth transformation of a T-cell line. J Virol 2007; 81:11900-1197.

128. Merino F, Robert-Guroff M, Clark J, Biondo-Bracho M, Blattner WA, Gallo RC. Natural antibodies to human T-cell leukemia/lymphoma virus in healthy Venezuelan populations. Int J Cancer 198; 34:501-506.

129. Michael B, Nair AM, Datta A, Hiraragi H, Ratner L, Lairmore MD. Histone acetyltransferase (HAT) activity of p300 modulates human T lymphotropic virus type 1 p30II-mediated repression of LTR transcriptional activity. Virology 2006; 354:225-239.

130. Michael B, Nair AM, Hiraragi H, Shen L, Feuer G, Boris-Lawrie K,

et al

. Human T lymphotropic virus type-1 p30II alters cellular gene expression to selectively enhance signaling pathways that activate T lymphocytes. Retrovirology 2004; 1:39.

131. Maruyama K, Fukushima T, Mochizuki S, Kawamura K, Miyauchi M. Human T-cell leukemia virus type I as agent inducing genetic changes in infected human lymphocytes. Leukemia 1992; 6:60S- 63S.

 

132. Leclercq I, Mortreux F, Rabaaoui S, Jonsson CB, Wattel E. Naturally occurring substitutions of the human T-cell leukemia virus type 1 3’ LTR influence strand-transfer reaction. J Virol Methods 2003; 109:105-117.

 

133. Mortreux F, Kazanji M, Gabet AS, de Thoisy B, Wattel E. Two-step nature of human T-cell leukemia virus type 1 replication in experimentally infected squirrel monkeys (Saimiri sciureus). J Virol 2001; 75:1083-1089.

 

134. Murphy EL, Hanchard B, Figueroa JP, Gibbs WN, Lofters WS, Campbell M,

 

 

et al

. Modelling the risk of adult T-cell leukemia/lymphoma in persons infected with human T-lymphotropic virus type I. Int J Cancer 1989; 43:250-253.

135. Yamaguchi K KT, Futami G, Ishii T, Takatsuki K. . Pathogenesis of adult T-cell leukemia from clinical pathologic features. Hum Retrovirol 1990; 163-71.

 

136. SHino. ATL development after adult infection of HTLV-I? . J Cancer Res 1989; 80.

 

137. Kinoshita K AT, Ikeda S. Preleukemic state of adult T cell leukemia: abnormal T lymphocytosis induced by human adult T cell leukemia-lymphoma virus. Blood 1985; 66:120-127.

 

138. Rhew DC GC, Daar ES, Zakowski PC, Said J. Infections in patients with chronic adult T-cell leukemia/lymphoma: case report and review. Clin Infect Dis 1995; 21:1014-1016.

 

139. Kchour G, Tarhini M, Kooshyar MM, El Hajj H, Wattel E, Mahmoudi M, Rezaee SA,

 

 

et al

. Phase 2 study of the efficacy and safety of the combination of arsenic trioxide, interferon alpha, and zidovudine in newly diagnosed chronic adult T-cell leukemia/lymphoma (ATL). Blood 2009; 113:6528-6532.

140. Jeang KT. Functional activities of the human T-cell leukemia virus type I Tax oncoprotein: cellular signaling through NF-kappa B. Cytokine Growth Factor Rev 2001; 12:207-217.

141. Younis I, Green PL. The human T-cell leukemia virus Rex protein. Front Biosci 2005; 10:431-445.

 

142. Yoshida M. Multiple viral strategies of HTLV-I for dysregulation of cell growth control. Annu Rev Immunol 2001; 19:475-496.

 

143. Tanaka M, Yano T, Ichikawa Y, Kaji M. [A case of subacute necrotizing lymphadenitis with localized interstitial pneumonia]. Nihon Kyobu Shikkan Gakkai Zasshi 1990; 28:1234-1238.

 

144. Smith MR, Greene WC. Type I human T cell leukemia virus tax protein transforms rat fibroblasts through the cyclic adenosine monophosphate response element binding protein/activating transcription factor pathway. J Clin Invest 1991; 88:1038-1042.

 

145. Yamaoka S, Tobe T, Hatanaka M. Tax protein of human T-cell leukemia virus type I is required for maintenance of the transformed phenotype. Oncogene. 1992 Mar;7(3):433-7.

 

146. Takeda S, Maeda M, Morikawa S, Taniguchi Y, Yasunaga J, Nosaka K,

 

 

et al

. Genetic and epigenetic inactivation of tax gene in adult T-cell leukemia cells. Int J Cancer 2004; 109:559-567.

147. Tamiya S, Matsuoka M, Etoh K, Watanabe T, Kamihira S, Yamaguchi K,

 

 

et al

. Two types of defective human T-lymphotropic virus type I provirus in adult T-cell leukemia. Blood 1996; 88:3065-3073.

148. Koiwa T H-UA, Ishida T, Okayama A, Yamaguchi K, Kamihira S, Watanabe T. 5’-long terminal repeat-selective CpG methylation of latent human T-cell leukemia virus type 1 provirus in vitro and in vivo. . J Virol 2002; 76:9389-9397.

 

149. Seiki M, Eddy R, Shows TB, Yoshida M. Nonspecific integration of the HTLV provirus genome into adult T-cell leukaemia cells. Nature 1984; 309:640-642.

 

150. Lemoine FJ, Marriott SJ. Accelerated G(1) phase progression induced by the human T cell leukemia virus type I (HTLV-I) Tax oncoprotein. J Biol Chem 2001; 276:31851-3187.

 

151. Cereseto A, Washington Parks R, Rivadeneira E, Franchini G. Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells. Oncogene 1999; 18:2441-2450.

 

152. Yamada YHY, Murata K, Sugawara K, Ikeda S, Mine M, Maeda T,

 

 

et al

. Deletions of p15 and/or p16 genes as a poor-prognosis factor in adult T-cell leukemia. J Clin Oncol 1997; 15:1778-1785.

153. Sasaki H NI, Shiraga T, Akamatsu E, Fukami T, Hidaka T, Kubuki Y,

 

 

et al

. Okayama A, Hamada K, Okabe H, Murakami Y, Tsubouchi H, Morishita K. Overexpression of a cell adhesion molecule, TSLC1, as a possible molecular marker for acute-type adult T-cell leukemia.. Blood 2005; 105:1204-1213.

154. Kuramochi M, Fukuhara H, Nobukuni T, Kanbe T, Maruyama T, Ghosh HP,

 

 

et al

. TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. Nat Genet 2001; 27:427-430.

155. Toyota M, Ho C, Ahuja N, Jair KW, Li Q, Ohe-Toyota M,

 

 

et al

. Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res 1999; 59:2307-2312.

156. Yasunaga J, Taniguchi Y, Nosaka K, Yoshida M, Satou Y, Sakai T,

 

 

et al

. Identification of aberrantly methylated genes in association with adult T-cell leukemia. Cancer Res 2004; 64:6002-6009.

157. Mittelstadt PR, Ashwell JD. Cyclosporin A-sensitive transcription factor Egr-3 regulates Fas ligand expression. Mol Cell Biol 1998; 18:3744-3751.

 

158. Krueger A, Fas SC, Baumann S, Krammer PH. The role of CD95 in the regulation of peripheral T-cell apoptosis. Immunol Rev 2003; 193:58-69.

 

159. Waldele K, Schneider G, Ruckes T, Grassmann R. Interleukin-13 overexpression by tax transactivation: a potential autocrine stimulus in human T-cell leukemia virus-infected lymphocytes. J Virol 2004; 78:6081-6090.

 

160. Marriott SJ, Lemoine FJ, Jeang KT. Damaged DNA and miscounted chromosomes: human T cell leukemia virus type I tax oncoprotein and genetic lesions in transformed cells. J Biomed Sci 2002; 9:292-298.

 

161. Schmitt I, Rosin O, Rohwer P, Gossen M, Grassmann R. Stimulation of cyclin-dependent kinase activity and G1- to S-phase transition in human lymphocytes by the human T-cell leukemia/lymphotropic virus type 1 Tax protein. J Virol 1998; 72:633-640.

 

162. Liang MH, Geisbert T, Yao Y, Hinrichs SH, Giam CZ. Human T-lymphotropic virus type 1 oncoprotein tax promotes S-phase entry but blocks mitosis. J Virol 2002; 76:4022-4033.

 

163. Neuveut C, Jeang KT. Cell cycle dysregulation by HTLV-I: role of the tax oncoprotein. Front Biosci 2002; 7:d157-63.

 

164. Iwanaga R, Ohtani K, Hayashi T, Nakamura M. Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. Oncogene 2001; 20:2055-2067.

 

165. Kehn K, Fuente Cde L, Strouss K, Berro R, Jiang H, Brady J,

 

 

et al

. The HTLV-I Tax oncoprotein targets the retinoblastoma protein for proteasomal degradation. Oncogene 2005; 24:525-540.

166. Ohtani K IR, Arai M, Huang Y, Matsumura Y, Nakamura M. Cell type-specific E2F activation and cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. Biol Chem 2000; 275:11154-1163.

 

167. Lemasson I TS, Sardet C, Devaux C, Mesnard JM. Activation of E2F-mediated transcription by human T-cell leukemia virus type I Tax protein in a p16(INK4A)-negative T-cell line. Biol Chem 1998;

 

 

 

 

194

 

 

273:23598-23604.

168. Kitajima M, Korogi Y, Shigematsu Y, Liang L, Matsuoka M, Yamamoto T,

et al

. Central nervous system lesions in adult T-cell leukaemia: MRI and pathology. Neuroradiology 2002 ;44:559-567.

169. Ohtani K, Iwanaga R, Arai M, Huang Y, Matsumura Y, Nakamura M. Cell type-specific E2F activation and cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. J Biol Chem 2000; 275:11154-11163.

 

170. Martino A, Holmes JHt, Lord JD, Moon JJ, Nelson BH. Stat5 and Sp1 regulate transcription of the cyclin D2 gene in response to IL-2. J Immunol 2001; 166:1723-1729.

 

171. Fung MM, Chu YL, Fink JL, Wallace A, McGuire KL. IL-2- and STAT5- regulated cytokine gene expression in cells expressing the Tax protein of HTLV-I. Oncogene 2005; 24:4624-4633.

 

172. Santiago F, Clark E, Chong S, Molina C, Mozafari F, Mahieux R,

 

 

et al

. Transcriptional up-regulation of the cyclin D2 gene and acquisition of new cyclin-dependent kinase partners in human T-cell leukemia virus type 1-infected cells. J Virol 1999c;73:9917-9927.

173. Huang H H-LJ, Chen H, Ben-Sasson SZ, Paul WE. IL-4 and IL-13 production in differentiated T helper type 2 cells is not IL-4 dependent. Immunology 1997; 159:3731-3738.

 

174. Van PL YK, Jin DY, Dapolito G, Kurimasa A, Jeang KT. Genetic evidence of a role for ATM in functional interaction between human T-cell leukemia virus type 1 Tax and p53.

 

. Virology 2001;75:396-407.

 

175. Haller K, Wu Y, Derow E, Schmitt I, Jeang KT, Grassmann R. Physical interaction of human T-cell leukemia virus type 1 Tax with cyclin-dependent kinase 4 stimulates the phosphorylation of retinoblastoma protein. Mol Cell Biol 2002; 22:3327-3338.

 

176. Kehn K, Deng L, de la Fuente C, Strouss K, Wu K, Maddukuri A,

 

 

et al

. The role of cyclin D2 and p21/waf1 in human T-cell leukemia virus type 1 infected cells. Retrovirology 2004;1:6.

177. Akagi T OH, Shimotohno K. Expression of cell-cycle regulatory genes in HTLV-I infected T-cell lines: possible involvement of Tax1 in the altered expression of cyclin D2, p18Ink4 and p21Waf1/Cip1/ Sdi1. Oncogene 1996; 12:1645-1652.

 

178. Cereseto A, Diella F, Mulloy JC, Cara A, Michieli P, Grassmann R,

 

 

et al

. p53 functional impairment and high p21waf1/cip1 expression in human T-cell lymphotropic/leukemia virus type I-transformed T cells. Blood 1996; 88:1551-1560.

179. Akagi T OH, Tsuchida N, Shimotohno K. Aberrant expression and function of p53 in T-cells immortalized by HTLV-I Tax1. FEBS Lett 1997; 406:263-266.

 

180. Uittenbogaard MN, Giebler HA, Reisman D, Nyborg JK. Transcriptional repression of p53 by human T-cell leukemia virus type I Tax protein. J Biol Chem 1995; 270:28503-28506.

 

181.Pise-Masison CA, Radonovich M, Sakaguchi K, Appella E, Brady JN. Phosphorylation of p53: a novel pathway for p53 inactivation in human T-cell lymphotropic virus type 1-transformed cells. J Virol 1998; 72:6348-6355.

 

182. Hollsberg P. Mechanisms of T-cell activation by human T-cell lymphotropic virus type I. Microbiol Mol Biol Rev 1999; 63:308-333.

 

183. Yssel H, de Waal Malefyt R, Duc Dodon MD, Blanchard D, Gazzolo L, de Vries JE,

 

 

et al

. Human T cell leukemia/lymphoma virus type I infection of a CD4+ proliferative/cytotoxic T cell clone progresses in at least two distinct phases based on changes in function and phenotype of the infected cells. J Immunol 1989; 142:2279-2289.

184. Cross SL FM, Wolf JB, Holbrook NJ, Wong-Staal F, Leonard WJ. Regulation of the human interleukin-2 receptor alpha chain promoter: activation of a nonfunctional promoter by the transactivator gene of HTLV-I. Cell 1987; 49:47-56.

 

185. Maruyama M, Shibuya H, Harada H, Hatakeyama M, Seiki M, Fujita T,

 

 

et al

. Evidence for aberrant activation of the interleukin-2 autocrine loop by HTLV-I-encoded p40x and T3/Ti complex triggering. Cell 1987; 48:343-350.

186. Ruben S, Poteat H, Tan TH, Kawakami K, Roeder R, Haseltine W,

 

 

et al

. Cellular transcription factors and regulation of IL-2 receptor gene expression by HTLV-I tax gene product. Science 1988; 241:89-92.

187. Migone N, Padovan S, Zappador C, Giachino C, Bottaro M, Matullo G,

 

 

et al

. Restriction of the T-cell receptor V delta gene repertoire is due to preferential rearrangement and is independent of antigen selection. Immunogenetics 1995; 42:323-332.

188. Xu X, Chong AS. Cross-linking of CD45 on NK cells stimulates p56lck-mediated tyrosine phosphorylation and IFN-gamma production. J Immunol 1995; 155:5241-5248.

 

189. Niitsu Y, Urushizaki Y, Koshida Y, Terui K, Mahara K, Kohgo Y,

 

 

et al

. Expression of TGF-beta gene in adult T cell leukemia. Blood 1988; 71:263-266.

190. Kim SJ, Kehrl JH, Burton J, Tendler CL, Jeang KT, Danielpour D,

 

 

et al

. Transactivation of the transforming growth factor beta 1 (TGF-beta 1) gene by human T lymphotropic virus type 1 tax: a potential mechanism for the increased production of TGF-beta 1 in adult T cell leukemia. J Exp Med 1990; 172:121-129.

191. Hollsberg P, Ausubel LJ, Hafler DA. Human T cell lymphotropic virus type I-induced T cell activation. Resistance to TGF-beta 1-induced suppression. J Immunol 1994; 153:566-753.

 

192. Mesnard JM, Devaux C. Multiple control levels of cell proliferation by human T-cell leukemia virus type 1 Tax protein. Virology 1999; 257:277-284.

 

193. Neuveut C, Jeang KT. HTLV-I Tax and cell cycle progression. Prog Cell Cycle Res 2000; 4:157-162.

 

194. Hatta Y, Koeffler HP. Role of tumor suppressor genes in the development of adult T cell leukemia/lymphoma (ATLL). Leukemia 2002; 16:1069-1085.

 

195. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD,

 

 

et al

. Mutations of mitotic checkpoint genes in human cancers. Nature 1998; 392:300-303.

196. Tighe A, Johnson VL, Albertella M, Taylor SS. Aneuploid colon cancer cells have a robust spindle checkpoint. EMBO Rep 2001; 2:609-614.

 

197. Baldwin RL, Friess H, Yokoyama M, Lopez ME, Kobrin MS, Buchler MW,

 

 

et al

. Attenuated ALK5 receptor expression in human pancreatic cancer: correlation with resistance to growth inhibition. Int J Cancer 1996; 67:283-288.

198. Mercurio F, DiDonato JA, Rosette C, Karin M. p105 and p98 precursor proteins play an active role in NF-kappa B-mediated signal transduction. Genes Dev 1993; 7:705-718.

 

199. Pomerantz JL, Baltimore D. Two pathways to NF-kappaB. Mol Cell 2002; 10:693-695.

 

200. Jang IK, Gu H. Negative regulation of TCR signaling and T-cell activation by selective protein degradation. Curr Opin Immunol 2003; 15:315-320.

 

201. Brown K, Park S, Kanno T, Franzoso G, Siebenlist U. Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha. Proc Natl Acad Sci U S A 1993; 90:2532-2536.

 

202. Sun L, Ganea D. Vasoactive intestinal peptide inhibits interleukin (IL)-2 and IL-4 production through different molecular mechanisms in T cells activated via the T cell receptor/CD3 complex. J Neuroimmunol 1993; 48:59-69.

 

203. Ballard DW, Bohnlein E, Lowenthal JW, Wano Y, Franza BR, Greene WC. HTLV-I tax induces cellular proteins that activate the kappa B element in the IL-2 receptor alpha gene. Science 1988; 241:1652-1655.

 

204. Leung K, Nabel GJ. HTLV-I transactivator induces interleukin-2 receptor expression through an NF-kappa B-like factor. Nature 1988; 333:776-778.

 

205. Arima N, Molitor JA, Smith MR, Kim JH, Daitoku Y, Greene WC. Human T-cell leukemia virus type I Tax induces expression of the Rel-related family of kappa B enhancer-binding proteins: evidence for a pretranslational component of regulation. J Virol 1991; 65:6892-6899.

 

206. Koga Y, Oh-Hori N, Sato H, Yamamoto N, Kimura G, Nomoto K. Absence of transcription of lck (lymphocyte specific protein tyrosine kinase) message in IL-2-independent, HTLV-I-transformed T cell lines. J Immunol 1989; 142:4493-4499.

 

207. Weil R, Levraud JP, Dodon MD, Bessia C, Hazan U, Kourilsky P,

 

 

et al

. Altered expression of tyrosine kinases of the Src and Syk families in human T-cell leukemia virus type 1-infected T-cell lines. J Virol 1999; 73:3709-3717.

208. Lanoix J, Lacoste J, Pepin N, Rice N, Hiscott J. Overproduction of NFKB2 (lyt-10) and c-Rel: a mechanism for HTLV-I Tax-mediated trans-activation via the NF-kappa B signalling pathway. Onco

 

 

 

 

195

 

 

gene 1994; 9:841-852.

209. Xiao G, Cvijic ME, Fong A, Harhaj EW, Uhlik MT, Waterfield M,

et al

. Retroviral oncoprotein Tax induces processing of NF-kappaB2/ p100 in T cells: evidence for the involvement of IKKalpha. EMBO J 2001; 20:6805-6815.

210. Hironaka N, Mochida K, Mori N, Maeda M, Yamamoto N, Yamaoka S. Tax-independent constitutive IkappaB kinase activation in adult T-cell leukemia cells. Neoplasia 2004; 6:266-278.

 

211. Murakami T, Hirai H, Suzuki T, Fujisawa J, Yoshida M. HTLV-I Tax enhances NF-kappa B2 expression and binds to the products p52 and p100, but does not suppress the inhibitory function of p100. Virology 1995; 206:1066-1074.

 

212. Suzuki T, Hirai H, Murakami T, Yoshida M. Tax protein of HTLV-I destabilizes the complexes of NF-kappa B and I kappa B-alpha and induces nuclear translocation of NF-kappa B for transcriptional activation. Oncogene 1995; 10:1199-1207.

 

213. Kanno T, Brown K, Franzoso G, Siebenlist U. Kinetic analysis of human T-cell leukemia virus type I Tax-mediated activation of NF-kappa B. Mol Cell Biol 1994; 14:6443-6451.

 

214. McKinsey TA, Brockman JA, Scherer DC, Al-Murrani SW, Green PL, Ballard DW. Inactivation of IkappaBbeta by the tax protein of human T-cell leukemia virus type 1: a potential mechanism for constitutive induction of NF-kappaB. Mol Cell Biol 1996; 16:2083- 92080.

 

215. Brockman JA, Scherer DC, McKinsey TA, Hall SM, Qi X, Lee WY,

 

 

et al

. Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation. Mol Cell Biol 1995; 15:2809-2818.

216. Traenckner EB, Pahl HL, Henkel T, Schmidt KN, Wilk S, Baeuerle PA. Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli. EMBO J 1995; 14:2876-2883.

 

217. Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F,

 

 

et al

. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 1998; 93:1231-1240.

218. O’Mahony AM, Montano M, Van Beneden K, Chen LF, Greene WC. Human T-cell lymphotropic virus type 1 tax induction of biologically Active NF-kappaB requires IkappaB kinase-1-mediated phosphorylation of RelA/p65. J Biol Chem 2004; 279:18137-1845.

 

219. Iwanaga Y, Tsukahara T, Ohashi T, Tanaka Y, Arai M, Nakamura M,

 

 

et al

. Human T-cell leukemia virus type 1 tax protein abrogates interleukin-2 dependence in a mouse T-cell line. J Virol 1999; 73:1271-1277.

220. Kinoshita T, Shimoyama M, Tobinai K, Ito M, Ito S, Ikeda S,

 

 

et al

. Detection of mRNA for the tax1/rex1 gene of human T-cell leukemia virus type I in fresh peripheral blood mononuclear cells of adult T-cell leukemia patients and viral carriers by using the polymerase chain reaction. Proc Natl Acad Sci U S A 1989; 86:5620-5624.

221. Furukawa Y, Okadome T, Tara M, Niina K, Izumo S, Osame M. Human T-cell lymphotropic virus type-I (HTLV-I)-associated myelopathy/tropical spastic paraparesis with acute type of adult T-cell leukemia. Intern Med 1995; 34:1130-1133.

 

222. Furukawa Y, Kubota R, Tara M, Izumo S, Osame M. Existence of escape mutant in HTLV-I tax during the development of adult T-cell leukemia. Blood 2001; 97:987-993.

 

223. Akagi T, Ono H, Sasaki T, Shimotohno K. Increased protein tyrosine-phosphorylation in primary T-cells transduced with Tax1 of human T-cell leukemia virus type I. FEBS Lett 1995 Jan; 358:34-38.

 

224. Evangelista A, Maroushek S, Minnigan H, Larson A, Retzel E, Haase A,

 

 

et al

. Nucleotide sequence analysis of a provirus derived from an individual with tropical spastic paraparesis. Microb Pathog 1990; 8:259-278.

225. Akari H, Kannagi M, Shinjo T, Harada S. Simple assay system for detecting human T cell leukemia virus type I-binding cells and its application in titrating binding inhibitory antibodies. Lab Invest 1993; 69:629-634.

 

226. Kchour G, Makhoul NJ, Mahmoudi M, Kooshyar MM, Shirdel A,

 

 

et al

. Zidovudine and interferon-alpha treatment induces a high response rate and reduces HTLV-I proviral load and VEGF plasma levels in patients with adult T-cell leukemia from North East Iran. Leuk Lymphoma 2007; 48:330-336.

227. Rafatpanah H, Rezaee A, Etemadi MM, Hosseini RF, Khorram B, Afsahr L,

 

 

et al

. The impact of interferon-alpha treatment on clinical and immunovirological aspects of HTLV-I-associated myelopathy in northeast of Iran. J Neuroimmunol 2012; 250:87-93.