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An HTLV-I Transgenic Mouse Model: Role of the Tax Gene in Pathogenesis in Multiple Organ Systems

  • M. I. Nerenberg
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 160)

Abstract

The human T-lymphotropic virus type I (HTLV-I) has been associated with a lymphoproliferative disease called adult T-cell leukemia/lymphoma (ATLL) (Poiesz et al. 1980; Yoshida et al. 1982; Hinuma et al. 1981; Kalyanaraman et al. 1982) and a neurodegenerative disease called tropical spastic paraparesis (TSP) (Gessain et al. 1985; Rodgers-Johnson et al. 1985; Bartholomew et al. 1986) or HTLV-I-associated myelopathy (HAM) (Osame et al. 1986a). These diseases appear to share few common clinical features. ATLL has a prolonged latency, but once established is frequently rapidly fatal (Broder et al. 1984). The disturbance consists of a monoclonal expansion of mature peripheral T cells each of which contains copies of retroviral sequences (Poiesz et al. 1980; Miyoshi et al. 1980; Yamamoto et al. 1981; Popovic et al. 1983; Chen et al. 1983; Yoshida et al. 1984). Death results from consequences of uncontrolled cellular proliferation and dysfunction. In contrast, the associated neurologic disease usually shows a shorter latency period and a slowly progressive course (Roman 1988; Osame et al. 1986a). Though variable degrees of HTLV-I-infected lymphocytic infiltration into the CNS may be seen in this disease, the cellular target for viral infection within the nervous system remains unclear (Jacobson et al. 1988). To study potential mechanisms of these disparate HTLV-I-induced diseases, we created a transgenic mouse model in which the tax gene (trans-activator of transcription) was introduced under control of the HTLV-I viral long-terminal repeat (LTR) promoter.

Keywords

Tropical Spastic Paraparesis Cell Leukemia Virus Type Monoclonal Expansion Uncontrolled Cellular Proliferation Chloramphenicol Acetyl Transferase Reporter 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Bartholomew CF, Cleghaorn F, Charles W, Ratan P, Roberts L, Maharaj K, Janke N, Daisley H, Hanchard B, Blattner W (1986) HTLV-I and tropical spastic paraparesis. Lancet II: 99–100CrossRefGoogle Scholar
  2. Broder S, Jaffe ES, Blattner W, Gallo RC, Wong-Staal F, Waldman TA, DeVita VT (1984) T cell lymphoproliferative syndrome associated with human T cell leukemia/lymphoma virus. Ann Intern Me 100: 543–557Google Scholar
  3. Cann AJ, Rosenblatt JD, Wachsman W, Shaw NP, Chen ISY (1985) Identification of the gene responsible for human T cell leukemia virus transcriptional regulation. Nature 318: 571–574PubMedCrossRefGoogle Scholar
  4. Chan JY, Slamon DJ, Nimer SD, Golde DW, Gasson JC (1986) Regulation of expression of human granulocyte/macrophage colony-stimulating factor. Proc Natl Acad Sci USA 83: 8669–8673PubMedCrossRefGoogle Scholar
  5. Chen IS, Quan SG, Golde DW (1983) Human T cell leukemia virus type II transforms normal human lymphocytes. Proc Natl Acad Sci USA 80: 7006–7009PubMedCrossRefGoogle Scholar
  6. Erlandson RA (1985) Peripheral nerve sheath tumors. Ultrastruct Pathol 9: 113–122PubMedCrossRefGoogle Scholar
  7. Gessain A, Vernant JC, Maurs L, Bann F, Gout O, Calender A, DeThe G (1985) Antibodies to human T lymphotropic virus type I in patients with tropical spastic paraparesis. Lancet ii: 407–409CrossRefGoogle Scholar
  8. Goh WC, Sodroski J, Rosen C, HaseltineWA (1985) Subcellular localization of the product of the long open reading frame of human T cell leukemia virus type I. Science 227: 1227–1228PubMedCrossRefGoogle Scholar
  9. Greene WC, Leonard WJ, Wano Y, Svetlik PB, Peffer NK, Sodroski JG, Rosen CA, Goh WC, Haseltine WC (1986) Trans-activator gene of HTLV-II induces IL-2 receptor and IL-2 cellular gene expression. Science 232: 877–880PubMedCrossRefGoogle Scholar
  10. Hinrichs SH, Nerenberg M, Reynolds RK, Khoury G, Jay G (1987) A transgenic mouse model for human neurofibromatosis. Science 237: 1340–1343PubMedCrossRefGoogle Scholar
  11. Hinuma Y, Nagata K, Hanaoka M, Nakai M, Matsumoto T, Kinoshita K-I, Shirakawa S, Miyoshi I (1981) Adult T cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci USA 78: 6476–6480PubMedCrossRefGoogle Scholar
  12. Hiramatsu K, Yoshikura H (1986) Frequent partial deletion of human adult T cell leukemia virus type I proviruses in experimental transmission: pattern and possible implication. J Virol 58: 508–512PubMedGoogle Scholar
  13. Ho D, Rota T, Hirsch M (1984) Infection of human endothelial cells by human T lymphotropic virus type I. Proc Natl Acad Sci USA 81: 7588–7590PubMedCrossRefGoogle Scholar
  14. Hoxie JA, Matthews DM, Cines DB (1984) Infection of human endothelial cells by human T cell leukemia virus type I. Proc Natl Acad Sci USA 81: 7591–7595PubMedCrossRefGoogle Scholar
  15. Jacobson S, Raine CS, Mingioli ES, McFarlin DE (1988) Isolation of an HTLV-I-like retrovirus from patients with tropical spastic paraparesis. Nature 331: 540–543PubMedCrossRefGoogle Scholar
  16. Kalyanaraman VS, Samgadharan MG, Nakao Y, Ito Y, Aoki T, Gallo RC (1982) Natural antibodies to the structural core protein (p24) of the human T cell leukemia (lymphoma) retrovirus found in sera of leukemia patients in Japan. Proc Natl Acad Sci USA 79: 1653–1657PubMedCrossRefGoogle Scholar
  17. Kiyokawa T, Seiki M, Iwashita S, Imagawa K, Shimizu F, Yoshida M (1985) p2T-I“ and p21X-11’ Proteins encoded by the pX sequence of human T cell leukemia virus type I. Proc Natl Acad Sci USA 82: 8359–8363PubMedCrossRefGoogle Scholar
  18. Maruyama M, Shibuya H, Harada H, Hatakeyama M, Seiki M, Fujita T, Inoue J, Yoshida M, Taniguchi T (1987) Evidence for aberrant activation of the interleukin-2 autocrine loop by HTLVI encoded p40 and T3/Ti complex triggering. Cell 48: 343–350PubMedCrossRefGoogle Scholar
  19. Miyoshi I, Kubonishi I, Yoshimoto S, Akagi T, Ohtsuki Y, Shiraishi Y, Nagata K, Hinuma Y (1981) Type C virus particles in a cord T cell line derived by co-cultivating normal human cord lymphocytes and human leukaemic T cells. Nature 294: 770–771PubMedCrossRefGoogle Scholar
  20. Mora CA, Garruto RM, Brown P, Guiroy D, Morgan OSC, Rodgers-Johnson P, Ceroni M, Yanagihara R, Goldfarb LG, Gibbs CJ, Gajdusek DC (1988) Seroprevalence of antibodies to HTLV-I in patients with chronic neurological disorders other than tropical spastic paraparesis. Ann Neurol 23 (Suppl): S192 - S195PubMedCrossRefGoogle Scholar
  21. Nagashima K, Yoshida M, Seiki M (1986) A single species of pX mRNA of human T cell leukemia virus type I encodes trans-activator p40x and two other phosphoproteins. J Virol 60: 394–399PubMedGoogle Scholar
  22. Nagy K, Clapham P, Cheingsong-Popov R, Weiss R (1983) Human T cell leukemia virus type I: induction of syncytia by patients sera. Int J Cancer 32: 321–328PubMedCrossRefGoogle Scholar
  23. Nerenberg MI, Hinrichs SH, Reynolds RK, Khoury G, Jay G (1987) The tatgene of human T lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice. Science 237: 1324–1329PubMedCrossRefGoogle Scholar
  24. Nerenberg MI, Wiley CA (1989) The HTLV-I tax protein induces tissue specific disorders of neoplasia and atrophy in transgenic mice. Am. J. Pathol., in press.Google Scholar
  25. Osame MK, Usuku K, Izumo S, Ijichi N, Amitani H, Igata A, Matsumoto M, Tara M (1986a) HTLVI associated myelopathy, a new clinical entity. Lancet is 1932–1033Google Scholar
  26. Osame M, Izumo S, Igata A, Matsumoto M, Matsumoto T, Sonoda S, Tara M, Shibata Y (1986b) Blood transfusion and HTLV-I associated myelopathy. Lancet II: 104–105CrossRefGoogle Scholar
  27. Poiesz BJ, Ruscetti FW, Gadzar AF, Bunn PA, Minna JD, Gallo RC (1980) Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T cell lymphoma. Proc Natl Acad Sci USA 77: 7415–7419PubMedCrossRefGoogle Scholar
  28. Poiesz BJ, Ruscetti FW, Reitz MS, Kalyanaraman VS, Gallo RC (1981) Isolation of a new type C retrovirus ( HTLV) in primary uncultured cells of a patient with Sezary T cell leukaemia. Nature 294: 268–271PubMedCrossRefGoogle Scholar
  29. Popovic M, Sarin PS, Robert-Guroff M, Kalyanaraman VS, Mann D, Minowada J, Gallo RC (1983) Isolation and transmission of human retrovirus (human T cell leukemia virus). Science 219: 856–859PubMedCrossRefGoogle Scholar
  30. Robert-Guroff M, Nakao Y, Notake K, Ito Y, Sliski A, Gallo RC (1982) Natural antibodies to human retrovirus HTLV in a cluster of Japanese patients with adult T cell leukemia. Science 215: 975–978PubMedCrossRefGoogle Scholar
  31. Rodgers-Johnson P, Morgan C, St O, Zaninovic V, Sarin P, Graham DS (1985) HTLV-1 and HTLVII antibodies and tropical spastic paraparesis. Lancet ii: 1247–1248CrossRefGoogle Scholar
  32. Roman GC (1988) The neuroepidemiology of tropical spastic paraparesis. Ann Neurol 23: 5113 - S120CrossRefGoogle Scholar
  33. Rosenblatt JD, Cann, AJ, Slamon DJ, Smalberg IS, Shaw NP, Fujii J, Wachsman W, Chen ISY (1988) HTLV-II transactivation is regulated by the overlapping tax/rex nonstructural genes. Science 240: 916–918PubMedCrossRefGoogle Scholar
  34. Slamon DL, Press MF, Souza CM, Murdock DC, Kline MJ, Golde DW, Gasson JC, Chen ISY (1985) Studies of the putative transforming protein of the type I human T cell leukemia virus. Science 228: 1427–1430PubMedCrossRefGoogle Scholar
  35. Weiss R (1982) In: Weiss R, Teich N, Varmus H, Coffin J (eds) RNA tumor viruses. Cold Spring Harbor Laboratory, New York, pp 1205–1281Google Scholar
  36. Yamamoto N, Okada M, Koyanagi Y, Kannagi M, Hinuma Y (1981) Transformation of human leukocytes by cocultivation with an adult T cell leukemia virus producer cell line. Science 217: 737–739CrossRefGoogle Scholar
  37. Yoshida B, Miyoshi I, Hinuma Y (1982) Isolation and characterization of retrovirus from cell lines of human adult T cell leukemia and its implication in the disease. Proc Natl Acad Sci USA 79: 2031–2035PubMedCrossRefGoogle Scholar
  38. Yoshida M, Seiki M, Yamaguchi K, Takatsuki K (1984) 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 USA 81: 2534–2537PubMedCrossRefGoogle Scholar
  39. Zack JA, Cann AJ, Lugo JP, Chen ISY (1988) HIV-production from infected peripheral T cells after HTLV-1 induced mitogenic stimulation. Science 240: 1029–1032CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1990

Authors and Affiliations

  • M. I. Nerenberg
    • 1
  1. 1.Department of ImmunologyScripps Clinic and Research FoundationLa JollaUSA

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