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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2000 Aug 29;355(1400):1013–1019. doi: 10.1098/rstb.2000.0638

Is human T-cell lymphotropic virus type I really silent?

B Asquith 1, E Hanon 1, G P Taylor 1, C R Bangham 1
PMCID: PMC1692812  PMID: 11186302

Abstract

The role of the cellular immune response to human T-cell lymphotropic virus type I (HTLV-I) is not fully understood. The low level of HTLV-I protein expression in peripheral blood lymphocytes has led to the widely held belief that HTLV-I is transcriptionally silent in vivo. However, most HTLV-I-infected individuals mount a strong and persistently activated cytotoxic T-lymphocyte (CTL) response to the virus; this observation implies that there is abundant chronic transcription of HTLV-I genes. Here we show that HTLV-I Tax protein expression rises quickly in freshly isolated peripheral blood lymphocytes, but that expressing cells are rapidly killed by CTLs. Mathematical analysis of these results indicates that the CTL response is extremely efficient and that the half-life of a Tax-expressing cell is less than a day. We propose that HTLV-I protein expression in circulating lymphocytes is undetectable by current techniques because of the efficiency of the CTL-mediated immune surveillance in vivo.

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Selected References

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  1. Ameisen J. C., Capron A. Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis. Immunol Today. 1991 Apr;12(4):102–105. doi: 10.1016/0167-5699(91)90092-8. [DOI] [PubMed] [Google Scholar]
  2. Biddison W. E., Kubota R., Kawanishi T., Taub D. D., Cruikshank W. W., Center D. M., Connor E. W., Utz U., Jacobson S. Human T cell leukemia virus type I (HTLV-I)-specific CD8+ CTL clones from patients with HTLV-I-associated neurologic disease secrete proinflammatory cytokines, chemokines, and matrix metalloproteinase. J Immunol. 1997 Aug 15;159(4):2018–2025. [PubMed] [Google Scholar]
  3. Bieganowska K., Höllsberg P., Buckle G. J., Lim D. G., Greten T. F., Schneck J., Altman J. D., Jacobson S., Ledis S. L., Hanchard B. Direct analysis of viral-specific CD8+ T cells with soluble HLA-A2/Tax11-19 tetramer complexes in patients with human T cell lymphotropic virus-associated myelopathy. J Immunol. 1999 Feb 1;162(3):1765–1771. [PubMed] [Google Scholar]
  4. Cho I., Sugimoto M., Mita S., Tokunaga M., Imamura F., Ando M. In vivo proviral burden and viral RNA expression in T cell subsets of patients with human T lymphotropic virus type-1-associated myelopathy/tropical spastic paraparesis. Am J Trop Med Hyg. 1995 Oct;53(4):412–418. doi: 10.4269/ajtmh.1995.53.412. [DOI] [PubMed] [Google Scholar]
  5. Copeland K. F., Haaksma A. G., Goudsmit J., Krammer P. H., Heeney J. L. Inhibition of apoptosis in T cells expressing human T cell leukemia virus type I Tax. AIDS Res Hum Retroviruses. 1994 Oct;10(10):1259–1268. doi: 10.1089/aid.1994.10.1259. [DOI] [PubMed] [Google Scholar]
  6. Daenke S., Parker C. E., Niewiesk S., Newsom-Davis J., Nightingale S., Bangham C. R. Spastic paraparesis in a patient carrying defective human T cell leukemia virus type I (HTLV-I) provirus sequences but lacking a humoral or cytotoxic T cell response to HTLV-I. J Infect Dis. 1994 Apr;169(4):941–943. doi: 10.1093/infdis/169.4.941. [DOI] [PubMed] [Google Scholar]
  7. Douek D. C., McFarland R. D., Keiser P. H., Gage E. A., Massey J. M., Haynes B. F., Polis M. A., Haase A. T., Feinberg M. B., Sullivan J. L. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998 Dec 17;396(6712):690–695. doi: 10.1038/25374. [DOI] [PubMed] [Google Scholar]
  8. Gessain A., Louie A., Gout O., Gallo R. C., Franchini G. Human T-cell leukemia-lymphoma virus type I (HTLV-I) expression in fresh peripheral blood mononuclear cells from patients with tropical spastic paraparesis/HTLV-I-associated myelopathy. J Virol. 1991 Mar;65(3):1628–1633. doi: 10.1128/jvi.65.3.1628-1633.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gessain A., Saal F., Giron M. L., Lasneret J., Lagaye S., Gout O., De Thé G., Sigaux F., Peries J. Cell surface phenotype and human T lymphotropic virus type 1 antigen expression in 12 T cell lines derived from peripheral blood and cerebrospinal fluid of West Indian, Guyanese and African patients with tropical spastic paraparesis. J Gen Virol. 1990 Feb;71(Pt 2):333–341. doi: 10.1099/0022-1317-71-2-333. [DOI] [PubMed] [Google Scholar]
  10. Hanon E., Hall S., Taylor G. P., Saito M., Davis R., Tanaka Y., Usuku K., Osame M., Weber J. N., Bangham C. R. Abundant tax protein expression in CD4+ T cells infected with human T-cell lymphotropic virus type I (HTLV-I) is prevented by cytotoxic T lymphocytes. Blood. 2000 Feb 15;95(4):1386–1392. [PubMed] [Google Scholar]
  11. Hellerstein M., Hanley M. B., Cesar D., Siler S., Papageorgopoulos C., Wieder E., Schmidt D., Hoh R., Neese R., Macallan D. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med. 1999 Jan;5(1):83–89. doi: 10.1038/4772. [DOI] [PubMed] [Google Scholar]
  12. Jacobson S., Gupta A., Mattson D., Mingioli E., McFarlin D. E. Immunological studies in tropical spastic paraparesis. Ann Neurol. 1990 Feb;27(2):149–156. doi: 10.1002/ana.410270209. [DOI] [PubMed] [Google Scholar]
  13. Jeffery K. J., Usuku K., Hall S. E., Matsumoto W., Taylor G. P., Procter J., Bunce M., Ogg G. S., Welsh K. I., Weber J. N. HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3848–3853. doi: 10.1073/pnas.96.7.3848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kataoka T., Shinohara N., Takayama H., Takaku K., Kondo S., Yonehara S., Nagai K. Concanamycin A, a powerful tool for characterization and estimation of contribution of perforin- and Fas-based lytic pathways in cell-mediated cytotoxicity. J Immunol. 1996 May 15;156(10):3678–3686. [PubMed] [Google Scholar]
  15. Kinoshita T., Shimoyama M., Tobinai K., Ito M., Ito S., Ikeda S., Tajima K., Shimotohno K., Sugimura T. 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 Jul;86(14):5620–5624. doi: 10.1073/pnas.86.14.5620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kira J., Nakamura M., Sawada T., Koyanagi Y., Ohori N., Itoyama Y., Yamamoto N., Sakaki Y., Goto I. Antibody titers to HTLV-I-p40tax protein and gag-env hybrid protein in HTLV-I-associated myelopathy/tropical spastic paraparesis: correlation with increased HTLV-I proviral DNA load. J Neurol Sci. 1992 Jan;107(1):98–104. doi: 10.1016/0022-510x(92)90215-7. [DOI] [PubMed] [Google Scholar]
  17. Koyanagi Y., Itoyama Y., Nakamura N., Takamatsu K., Kira J., Iwamasa T., Goto I., Yamamoto N. In vivo infection of human T-cell leukemia virus type I in non-T cells. Virology. 1993 Sep;196(1):25–33. doi: 10.1006/viro.1993.1451. [DOI] [PubMed] [Google Scholar]
  18. Lane H. C., Depper J. M., Greene W. C., Whalen G., Waldmann T. A., Fauci A. S. Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. Evidence for a selective defect in soluble antigen recognition. N Engl J Med. 1985 Jul 11;313(2):79–84. doi: 10.1056/NEJM198507113130204. [DOI] [PubMed] [Google Scholar]
  19. Marsh B. J. Infectious complications of human T cell leukemia/lymphoma virus type I infection. Clin Infect Dis. 1996 Jul;23(1):138–145. doi: 10.1093/clinids/23.1.138. [DOI] [PubMed] [Google Scholar]
  20. Miedema F., Petit A. J., Terpstra F. G., Schattenkerk J. K., de Wolf F., Al B. J., Roos M., Lange J. M., Danner S. A., Goudsmit J. Immunological abnormalities in human immunodeficiency virus (HIV)-infected asymptomatic homosexual men. HIV affects the immune system before CD4+ T helper cell depletion occurs. J Clin Invest. 1988 Dec;82(6):1908–1914. doi: 10.1172/JCI113809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Moritoyo T., Izumo S., Moritoyo H., Tanaka Y., Kiyomatsu Y., Nagai M., Usuku K., Sorimachi M., Osame M. Detection of human T-lymphotropic virus type I p40tax protein in cerebrospinal fluid cells from patients with human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis. J Neurovirol. 1999 Jun;5(3):241–248. doi: 10.3109/13550289909015810. [DOI] [PubMed] [Google Scholar]
  22. Nagai M., Usuku K., Matsumoto W., Kodama D., Takenouchi N., Moritoyo T., Hashiguchi S., Ichinose M., Bangham C. R., Izumo S. 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 Dec;4(6):586–593. doi: 10.3109/13550289809114225. [DOI] [PubMed] [Google Scholar]
  23. Niewiesk S., Bangham C. R. Evolution in a chronic RNA virus infection: selection on HTLV-I tax protein differs between healthy carriers and patients with tropical spastic paraparesis. J Mol Evol. 1996 Apr;42(4):452–458. doi: 10.1007/BF02498639. [DOI] [PubMed] [Google Scholar]
  24. Niewiesk S., Daenke S., Parker C. E., Taylor G., Weber J., Nightingale S., Bangham C. R. The transactivator gene of human T-cell leukemia virus type I is more variable within and between healthy carriers than patients with tropical spastic paraparesis. J Virol. 1994 Oct;68(10):6778–6781. doi: 10.1128/jvi.68.10.6778-6781.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nowak M. A., Bangham C. R. Population dynamics of immune responses to persistent viruses. Science. 1996 Apr 5;272(5258):74–79. doi: 10.1126/science.272.5258.74. [DOI] [PubMed] [Google Scholar]
  26. Pedroza Martins L., Chenciner N., Wain-Hobson S. Complex intrapatient sequence variation in the V1 and V2 hypervariable regions of the HIV-1 gp 120 envelope sequence. Virology. 1992 Dec;191(2):837–845. doi: 10.1016/0042-6822(92)90259-r. [DOI] [PubMed] [Google Scholar]
  27. Pinching A. J. Factors affecting the natural history of human immunodeficiency virus infection. Immunodefic Rev. 1988;1(1):23–38. [PubMed] [Google Scholar]
  28. Poiesz B. J., Ruscetti F. W., Gazdar A. F., Bunn P. A., Minna J. D., Gallo R. C. 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 U S A. 1980 Dec;77(12):7415–7419. doi: 10.1073/pnas.77.12.7415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Richardson J. H., Edwards A. J., Cruickshank J. K., Rudge P., Dalgleish A. G. In vivo cellular tropism of human T-cell leukemia virus type 1. J Virol. 1990 Nov;64(11):5682–5687. doi: 10.1128/jvi.64.11.5682-5687.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Richardson J. H., Höllsberg P., Windhagen A., Child L. A., Hafler D. A., Lever A. M. Variable immortalizing potential and frequent virus latency in blood-derived T-cell clones infected with human T-cell leukemia virus type I. Blood. 1997 May 1;89(9):3303–3314. [PubMed] [Google Scholar]
  31. Taylor G. P., Hall S. E., Navarrete S., Michie C. A., Davis R., Witkover A. D., Rossor M., Nowak M. A., Rudge P., Matutes E. Effect of lamivudine on human T-cell leukemia virus type 1 (HTLV-1) DNA copy number, T-cell phenotype, and anti-tax cytotoxic T-cell frequency in patients with HTLV-1-associated myelopathy. J Virol. 1999 Dec;73(12):10289–10295. doi: 10.1128/jvi.73.12.10289-10295.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tochikura T., Iwahashi M., Matsumoto T., Koyanagi Y., Hinuma Y., Yamamoto N. Effect of human serum anti-HTLV antibodies on viral antigen induction in vitro cultured peripheral lymphocytes from adult T-cell leukemia patients and healthy virus carriers. Int J Cancer. 1985 Jul 15;36(1):1–7. doi: 10.1002/ijc.2910360102. [DOI] [PubMed] [Google Scholar]
  33. Wattel E., Cavrois M., Gessain A., Wain-Hobson S. Clonal expansion of infected cells: a way of life for HTLV-I. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;13 (Suppl 1):S92–S99. doi: 10.1097/00042560-199600001-00016. [DOI] [PubMed] [Google Scholar]
  34. Wodarz D., Nowak M. A., Bangham C. R. The dynamics of HTLV-I and the CTL response. Immunol Today. 1999 May;20(5):220–227. doi: 10.1016/s0167-5699(99)01446-2. [DOI] [PubMed] [Google Scholar]
  35. Wucherpfennig K. W., Höllsberg P., Richardson J. H., Benjamin D., Hafler D. A. T-cell activation by autologous human T-cell leukemia virus type I-infected T-cell clones. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2110–2114. doi: 10.1073/pnas.89.6.2110. [DOI] [PMC free article] [PubMed] [Google Scholar]

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