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. 1995 Apr;69(4):2649–2653. doi: 10.1128/jvi.69.4.2649-2653.1995

Naturally occurring variants of human T-cell leukemia virus type I Tax protein impair its recognition by cytotoxic T lymphocytes and the transactivation function of Tax.

S Niewiesk 1, S Daenke 1, C E Parker 1, G Taylor 1, J Weber 1, S Nightingale 1, C R Bangham 1
PMCID: PMC188948  PMID: 7533860

Abstract

There is a high degree of intraisolate sequence heterogeneity in the tax gene of human T-cell leukemia virus type I (HTLV-I), although the sequence variation between patients is small compared with that of human immunodeficiency virus type 1. In the present study, we investigated whether naturally occurring amino acid substitutions changed the properties of the Tax protein in two respects: first, recognition of the protein by cytotoxic T lymphocytes (CTL), and second, the ability of the Tax protein to transactivate various promoters. We found that (i) all of the observed amino acid substitutions that occur in known CTL epitopes abolished the recognition of the synthetic peptide representing the respective epitope; (ii) these substitutions occurred significantly more frequently in subjects carrying HLA-A2; and (iii) most of the amino acid substitutions severely reduced the ability of Tax protein to transactivate three promoters: the HTLV-I long terminal repeat, the c-fos promoter, and the interleukin-2 receptor alpha chain promoter.

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Selected References

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  1. Aebischer T., Moskophidis D., Rohrer U. H., Zinkernagel R. M., Hengartner H. In vitro selection of lymphocytic choriomeningitis virus escape mutants by cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11047–11051. doi: 10.1073/pnas.88.24.11047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bangham C. R., Daenke S., Phillips R. E., Cruickshank J. K., Bell J. I. Enzymatic amplification of exogenous and endogenous retroviral sequences from DNA of patients with tropical spastic paraparesis. EMBO J. 1988 Dec 20;7(13):4179–4184. doi: 10.1002/j.1460-2075.1988.tb03314.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berneman Z. N., Gartenhaus R. B., Reitz M. S., Jr, Klotman M. E., Gallo R. C. cDNA sequencing confirms HTLV-I expression in adult T-cell leukemia/lymphoma and different sequence variations in vivo and in vitro. Leukemia. 1992;6 (Suppl 3):67S–71S. [PubMed] [Google Scholar]
  4. Bosselut R., Duvall J. F., Gégonne A., Bailly M., Hémar A., Brady J., Ghysdael J. The product of the c-ets-1 proto-oncogene and the related Ets2 protein act as transcriptional activators of the long terminal repeat of human T cell leukemia virus HTLV-1. EMBO J. 1990 Oct;9(10):3137–3144. doi: 10.1002/j.1460-2075.1990.tb07511.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Clavel F., Hoggan M. D., Willey R. L., Strebel K., Martin M. A., Repaske R. Genetic recombination of human immunodeficiency virus. J Virol. 1989 Mar;63(3):1455–1459. doi: 10.1128/jvi.63.3.1455-1459.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dai L. C., West K., Littaua R., Takahashi K., Ennis F. A. Mutation of human immunodeficiency virus type 1 at amino acid 585 on gp41 results in loss of killing by CD8+ A24-restricted cytotoxic T lymphocytes. J Virol. 1992 May;66(5):3151–3154. doi: 10.1128/jvi.66.5.3151-3154.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ehrlich G. D., Andrews J., Sherman M. P., Greenberg S. J., Poiesz B. J. DNA sequence analysis of the gene encoding the HTLV-I p21e transmembrane protein reveals inter- and intraisolate genetic heterogeneity. Virology. 1992 Feb;186(2):619–627. doi: 10.1016/0042-6822(92)90028-n. [DOI] [PubMed] [Google Scholar]
  8. Evavold B. D., Sloan-Lancaster J., Allen P. M. Tickling the TCR: selective T-cell functions stimulated by altered peptide ligands. Immunol Today. 1993 Dec;14(12):602–609. doi: 10.1016/0167-5699(93)90200-5. [DOI] [PubMed] [Google Scholar]
  9. Gessain A., Barin F., Vernant J. C., Gout O., Maurs L., Calender A., de Thé G. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985 Aug 24;2(8452):407–410. doi: 10.1016/s0140-6736(85)92734-5. [DOI] [PubMed] [Google Scholar]
  10. Gessain A., Gallo R. C., Franchini G. Low degree of human T-cell leukemia/lymphoma virus type I genetic drift in vivo as a means of monitoring viral transmission and movement of ancient human populations. J Virol. 1992 Apr;66(4):2288–2295. doi: 10.1128/jvi.66.4.2288-2295.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Hinuma Y., Nagata K., Hanaoka M., Nakai M., Matsumoto T., Kinoshita K. I., Shirakawa S., Miyoshi I. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6476–6480. doi: 10.1073/pnas.78.10.6476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Holland J. J., De La Torre J. C., Steinhauer D. A. RNA virus populations as quasispecies. Curr Top Microbiol Immunol. 1992;176:1–20. doi: 10.1007/978-3-642-77011-1_1. [DOI] [PubMed] [Google Scholar]
  14. Jacobson S., Shida H., McFarlin D. E., Fauci A. S., Koenig S. Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease. Nature. 1990 Nov 15;348(6298):245–248. doi: 10.1038/348245a0. [DOI] [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. Klenerman P., Rowland-Jones S., McAdam S., Edwards J., Daenke S., Lalloo D., Köppe B., Rosenberg W., Boyd D., Edwards A. Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature. 1994 Jun 2;369(6479):403–407. doi: 10.1038/369403a0. [DOI] [PubMed] [Google Scholar]
  17. Li Y., Hui H., Burgess C. J., Price R. W., Sharp P. M., Hahn B. H., Shaw G. M. Complete nucleotide sequence, genome organization, and biological properties of human immunodeficiency virus type 1 in vivo: evidence for limited defectiveness and complementation. J Virol. 1992 Nov;66(11):6587–6600. doi: 10.1128/jvi.66.11.6587-6600.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lichtensteiger C. A., Cheevers W. P., Davis W. C. CD8+ cytotoxic T lymphocytes against antigenic variants of caprine arthritis-encephalitis virus. J Gen Virol. 1993 Oct;74(Pt 10):2111–2116. doi: 10.1099/0022-1317-74-10-2111. [DOI] [PubMed] [Google Scholar]
  19. Meyerhans A., Cheynier R., Albert J., Seth M., Kwok S., Sninsky J., Morfeldt-Månson L., Asjö B., Wain-Hobson S. Temporal fluctuations in HIV quasispecies in vivo are not reflected by sequential HIV isolations. Cell. 1989 Sep 8;58(5):901–910. doi: 10.1016/0092-8674(89)90942-2. [DOI] [PubMed] [Google Scholar]
  20. Muchardt C., Seeler J. S., Nirula A., Gong S., Gaynor R. Transcription factor AP-2 activates gene expression of HTLV-I. EMBO J. 1992 Jul;11(7):2573–2581. doi: 10.1002/j.1460-2075.1992.tb05322.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Osame M., Usuku K., Izumo S., Ijichi N., Amitani H., Igata A., Matsumoto M., Tara M. HTLV-I associated myelopathy, a new clinical entity. Lancet. 1986 May 3;1(8488):1031–1032. doi: 10.1016/s0140-6736(86)91298-5. [DOI] [PubMed] [Google Scholar]
  23. Parker C. E., Daenke S., Nightingale S., Bangham C. R. Activated, HTLV-1-specific cytotoxic T-lymphocytes are found in healthy seropositives as well as in patients with tropical spastic paraparesis. Virology. 1992 Jun;188(2):628–636. doi: 10.1016/0042-6822(92)90517-s. [DOI] [PubMed] [Google Scholar]
  24. Parker C. E., Nightingale S., Taylor G. P., Weber J., Bangham C. R. Circulating anti-Tax cytotoxic T lymphocytes from human T-cell leukemia virus type I-infected people, with and without tropical spastic paraparesis, recognize multiple epitopes simultaneously. J Virol. 1994 May;68(5):2860–2868. doi: 10.1128/jvi.68.5.2860-2868.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Phillips R. E., Rowland-Jones S., Nixon D. F., Gotch F. M., Edwards J. P., Ogunlesi A. O., Elvin J. G., Rothbard J. A., Bangham C. R., Rizza C. R. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature. 1991 Dec 12;354(6353):453–459. doi: 10.1038/354453a0. [DOI] [PubMed] [Google Scholar]
  26. Pircher H., Moskophidis D., Rohrer U., Bürki K., Hengartner H., Zinkernagel R. M. Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature. 1990 Aug 16;346(6285):629–633. doi: 10.1038/346629a0. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Semmes O. J., Jeang K. T. Mutational analysis of human T-cell leukemia virus type I Tax: regions necessary for function determined with 47 mutant proteins. J Virol. 1992 Dec;66(12):7183–7192. doi: 10.1128/jvi.66.12.7183-7192.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Siekevitz M., Feinberg M. B., Holbrook N., Wong-Staal F., Greene W. C. Activation of interleukin 2 and interleukin 2 receptor (Tac) promoter expression by the trans-activator (tat) gene product of human T-cell leukemia virus, type I. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5389–5393. doi: 10.1073/pnas.84.15.5389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Smith M. R., Greene W. C. Identification of HTLV-I tax trans-activator mutants exhibiting novel transcriptional phenotypes. Genes Dev. 1990 Nov;4(11):1875–1885. doi: 10.1101/gad.4.11.1875. [DOI] [PubMed] [Google Scholar]
  31. Sodroski J. G., Rosen C. A., Haseltine W. A. Trans-acting transcriptional activation of the long terminal repeat of human T lymphotropic viruses in infected cells. Science. 1984 Jul 27;225(4660):381–385. doi: 10.1126/science.6330891. [DOI] [PubMed] [Google Scholar]
  32. Takebe Y., Seiki M., Fujisawa J., Hoy P., Yokota K., Arai K., Yoshida M., Arai N. SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1988 Jan;8(1):466–472. doi: 10.1128/mcb.8.1.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Townsend A., Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol. 1989;7:601–624. doi: 10.1146/annurev.iy.07.040189.003125. [DOI] [PubMed] [Google Scholar]
  34. Treisman R. Transient accumulation of c-fos RNA following serum stimulation requires a conserved 5' element and c-fos 3' sequences. Cell. 1985 Oct;42(3):889–902. doi: 10.1016/0092-8674(85)90285-5. [DOI] [PubMed] [Google Scholar]
  35. White H. D., Robbins M. D., Green W. R. Mechanism of escape of endogenous murine leukemia virus emv-14 from recognition by anti-AKR/Gross virus cytolytic T lymphocytes. J Virol. 1990 Jun;64(6):2608–2619. doi: 10.1128/jvi.64.6.2608-2619.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]

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