A functional CD8 cell assay reveals individual variation in CD8 cell antiviral efficacy and explains differences in human T-lymphotropic virus type 1 proviral load Free

Abstract

The CD8 lymphocyte response is a main component of host immunity, yet it is difficult to quantify its contribution to the control of persistent viruses. Consequently, it remains controversial as to whether CD8 cells have a biologically significant impact on viral burden and disease progression in infections such as human immunodeficiency virus-1 and human T-lymphotropic virus type I (HTLV-I). Experiments to ascertain the impact of CD8 cells on viral burden based on CD8 cell frequency or specificity alone give inconsistent results. Here, an alternative approach was developed that directly quantifies the impact of CD8 lymphocytes on HTLV-I proviral burden by measuring the rate at which HTLV-I-infected CD4 cells were cleared by autologous CD8 cells . It was demonstrated that CD8 cells reduced the lifespan of infected CD4 cells to 1 day, considerably shorter than the 30 day lifespan of uninfected cells . Furthermore, it was shown that HTLV-I-infected individuals vary considerably in the rate at which their CD8 cells clear infected cells, and that this was a significant predictor of their HTLV-I proviral load. Forty to 50 % of between-individual variation in HTLV-I proviral load was explained by variation in the rate at which CD8 cells cleared infected cells. This novel approach demonstrates that CD8 cells are a major determinant of HTLV-I proviral load. This assay is applicable to quantifying the CD8 cell response to other viruses and malignancies and may be of particular importance in assessing vaccines.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.80766-0
2005-05-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/86/5/vir861515.html?itemId=/content/journal/jgv/10.1099/vir.0.80766-0&mimeType=html&fmt=ahah

References

  1. Asquith B., Bangham C. R. 2000; The role of cytotoxic T lymphocytes in human T-cell lymphotropic virus type 1 infection. J Theor Biol 207:65–79 [CrossRef]
    [Google Scholar]
  2. Bangham C. R. 2000; The immune response to HTLV-I. Curr Opin Immunol 12:397–402 [CrossRef]
    [Google Scholar]
  3. Betts M. R., Ambrozak D. R., Douek D. C., Bonhoeffer S., Brenchley J. M., Casazza J. P., Koup R. A., Picker L. J. 2001; Analysis of total human immunodeficiency virus (HIV)-specific CD4+ and CD8+ T-cell responses: relationship to viral load in untreated HIV infection. J Virol 75:11983–11991 [CrossRef]
    [Google Scholar]
  4. Biddison W. E., Kubota R., Kawanishi T., Taub D. D., Cruikshank W. W., Center D. M., Connor E. W., Utz U., Jacobson S. 1997; 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 159:2018–2025
    [Google Scholar]
  5. Bieganowska K., Hollsberg P., Buckle G. J. 11 other authors 1999; 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 162:1765–1771
    [Google Scholar]
  6. Bland J. M., Altman D. G. 1986; Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1:307–310
    [Google Scholar]
  7. Daenke S., Kermode A. G., Hall S. E., Taylor G., Weber J., Nightingale S., Bangham C. R. 1996; High activated and memory cytotoxic T-cell responses to HTLV-1 in healthy carriers and patients with tropical spastic paraparesis. Virology 217:139–146 [CrossRef]
    [Google Scholar]
  8. Debacq C., Asquith B., Kerkhofs P., Portetelle D., Burny A., Kettmann R., Willems L. 2002; Increased cell proliferation, but not reduced cell death, induces lymphocytosis in bovine leukemia virus-infected sheep. Proc Natl Acad Sci U S A 99:10048–10053 [CrossRef]
    [Google Scholar]
  9. Goon P. K., Biancardi A., Fast N. 8 other authors 2004; Human T cell lymphotropic virus (HTLV) type-1-specific CD8+ T cells: frequency and immunodominance hierarchy. J Infect Dis 189:2294–2298 [CrossRef]
    [Google Scholar]
  10. Greten T. F., Slansky J. E., Kubota R., Soldan S. S., Jaffee E. M., Leist T. P., Pardoll D. M., Jacobson S., Schneck J. P. 1998; Direct visualization of antigen-specific T cells: HTLV-1 Tax11-19- specific CD8+ T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients. Proc Natl Acad Sci U S A 95:7568–7573 [CrossRef]
    [Google Scholar]
  11. Hanon E., Hall S., Taylor G. P. 7 other authors 2000a; 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 95:1386–1392
    [Google Scholar]
  12. Hanon E., Stinchcombe J. C., Saito M., Asquith B. E., Taylor G. P., Tanaka Y., Weber J. N., Griffiths G. M., Bangham C. R. 2000b; Fratricide among CD8+ T lymphocytes naturally infected with human T cell lymphotropic virus type I. Immunity 13:657–664 [CrossRef]
    [Google Scholar]
  13. Hoger T. A., Jacobson S., Kawanishi T., Kato T., Nishioka K., Yamamoto K. 1997; Accumulation of human T lymphotropic virus (HTLV)-I-specific T cell clones in HTLV-I-associated myelopathy/tropical spastic paraparesis patients. J Immunol 159:2042–2048
    [Google Scholar]
  14. Howell D. C. 1992 Statistical Methods for Psychology , 3rd edn. Belmont: Duxbury Press;
    [Google Scholar]
  15. Jacobson S. 2002; Immunopathogenesis of human T cell lymphotropic virus type I-associated neurologic disease. J Infect Dis 186:S187–S192 [CrossRef]
    [Google Scholar]
  16. Jeffery K. J., Usuku K., Hall S. E. 14 other authors 1999; 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 96:3848–3853 [CrossRef]
    [Google Scholar]
  17. Jeffery K. J., Siddiqui A. A., Bunce M. 8 other authors 2000; The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection. J Immunol 165:7278–7284 [CrossRef]
    [Google Scholar]
  18. Kataoka T., Shinohara N., Takayama H., Takaku K., Kondo S., Yonehara S., Nagai K. 1996; Concanamycin A, a powerful tool for characterization and estimation of contribution of perforin- and Fas-based lytic pathways in cell-mediated cytotoxicity. J Immunol 156:3678–3686
    [Google Scholar]
  19. Kubota R., Kawanishi T., Matsubara H., Manns A., Jacobson S. 2000; HTLV-I specific IFN- γ + CD8+ lymphocytes correlate with the proviral load in peripheral blood of infected individuals. J Neuroimmunol 102:208–215 [CrossRef]
    [Google Scholar]
  20. Kwok S., Ehrlich G., Poiesz B., Kalish R., Sninsky J. J. 1988; Enzymatic amplification of HTLV-I viral sequences from peripheral blood mononuclear cells and infected tissues. Blood 72:1117–1123
    [Google Scholar]
  21. Lee B., Tanaka Y., Tozawa H. 1989; Monoclonal antibody defining tax protein of human T-cell leukemia virus type-I. Tohoku J Exp Med 157:1–11 [CrossRef]
    [Google Scholar]
  22. Macallan D. C., Asquith B., Irvine A. J. 7 other authors 2003; Measurement and modeling of human T cell kinetics. Eur J Immunol 33:2316–2326 [CrossRef]
    [Google Scholar]
  23. Matsuzaki T., Nakagawa M., Nagai M. 7 other authors 2001; HTLV-I proviral load correlates with progression of motor disability in HAM/TSP: analysis of 239 HAM/TSP patients including 64 patients followed up for 10 years. J Neurovirol 7:228–234 [CrossRef]
    [Google Scholar]
  24. Mohri H., Bonhoeffer S., Monard S., Perelson A. S., Ho D. D. 1998; Rapid turnover of T lymphocytes in SIV-infected rhesus macaques. Science 279:1223–1227 [CrossRef]
    [Google Scholar]
  25. Nagai M., Osame M. 2003; Human T-cell lymphotropic virus type I and neurological diseases. J Neurovirol 9:228–235 [CrossRef]
    [Google Scholar]
  26. Nagai M., Usuku K., Matsumoto W. 8 other authors 1998; 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 4:586–593 [CrossRef]
    [Google Scholar]
  27. Niewiesk S., Daenke S., Parker C. E., Taylor G., Weber J., Nightingale S., Bangham C. R. 1994; 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 68:6778–6781
    [Google Scholar]
  28. Ogg G. S., Jin X., Bonhoeffer S. 12 other authors 1998; Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279:2103–2106 [CrossRef]
    [Google Scholar]
  29. Osame M., Usuku K., Izumo S., Ijichi N., Amitani H., Igata A., Matsumoto M., Tara M. 1986; HTLV-I associated myelopathy, a new clinical entity. Lancet 1:1031–1032
    [Google Scholar]
  30. Oxenius A., Sewell A. K., Dawson S. J. 9 other authors 2002; Functional discrepancies in HIV-specific CD8+ T-lymphocyte populations are related to plasma virus load. J Clin Immunol 22:363–374 [CrossRef]
    [Google Scholar]
  31. Pantaleo G., Koup R. A. 2004; Correlates of immune protection in HIV-1 infection: what we know, what we don't know, what we should know. Nat Med 10:806–810 [CrossRef]
    [Google Scholar]
  32. Perelson A. S., Neumann A. U., Markowitz M., Leonard J. M., Ho D. D. 1996; HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271:1582–1586 [CrossRef]
    [Google Scholar]
  33. Richardson J. H., Hollsberg P., Windhagen A., Child L. A., Hafler D. A., Lever A. M. 1997; Variable immortalizing potential and frequent virus latency in blood-derived T-cell clones infected with human T-cell leukemia virus type I. Blood 89:3303–3314
    [Google Scholar]
  34. Rowland-Jones S. L., Pinheiro S., Kaul R. 9 other authors 2001; How important is the ‘quality’ of the cytotoxic T lymphocyte (CTL) response in protection against HIV infection?. Immunol Lett 79:15–20 [CrossRef]
    [Google Scholar]
  35. Seiki M., Hikikoshi A., Taniguchi T., Yoshida M. 1985; Expression of the pX gene of HTLV-I: general splicing mechanism in the HTLV family. Science 228:1532–1534 [CrossRef]
    [Google Scholar]
  36. Snyder J. E., Bowers W. J., Livingstone A. M., Lee F. E., Federoff H. J., Mosmann T. R. 2003; Measuring the frequency of mouse and human cytotoxic T cells by the Lysispot assay: independent regulation of cytokine secretion and short-term killing. Nat Med 9:231–235 [CrossRef]
    [Google Scholar]
  37. van Baalen C. A., Guillon C., van Baalen M., Verschuren E. J., Boers P. H., Osterhaus A. D., Gruters R. A. 2002; Impact of antigen expression kinetics on the effectiveness of HIV-specific cytotoxic T lymphocytes. Eur J Immunol 32:2644–2652 [CrossRef]
    [Google Scholar]
  38. Vine A. M., Heaps A. G., Kaftantzi L. 10 other authors; 2004; The role of CTLs in persistent viral infection: cytolytic gene expression in CD8+ lymphocytes distinguishes between individuals with a high or low proviral load of human T cell lymphotropic virus type 1. J Immunol 173:5121–5129 [CrossRef]
    [Google Scholar]
  39. Wodarz D., Hall S. E., Usuku K., Osame M., Ogg G. S., McMichael A. J., Nowak M. A., Bangham C. R. 2001; Cytotoxic T-cell abundance and virus load in human immunodeficiency virus type 1 and human T-cell leukaemia virus type 1. Proc R Soc Lond B Biol Sci 268:1215–1221 [CrossRef]
    [Google Scholar]
  40. Yamano Y., Cohen C. J., Takenouchi N., Yao K., Tomaru U., Li H. C., Reiter Y., Jacobson S. 2004; Increased expression of human T lymphocyte virus type I (HTLV-I) Tax11-19 peptide-human histocompatibility leukocyte antigen A*201 complexes on CD4+ CD25+ T cells detected by peptide-specific, major histocompatibility complex-restricted antibodies in patients with HTLV-I-associated neurologic disease. J Exp Med 199:1367–1377 [CrossRef]
    [Google Scholar]
  41. Yang O. O. 2003; Will we be able to ‘spot’ an effective HIV-1 vaccine?. Trends Immunol 24:67–72 [CrossRef]
    [Google Scholar]
  42. Yang O. O., Sarkis P. T., Trocha A., Kalams S. A., Johnson R. P., Walker B. D. 2003; Impacts of avidity and specificity on the antiviral efficiency of HIV-1-specific CTL. J Immunol 171:3718–3724 [CrossRef]
    [Google Scholar]
  43. Zhang D., Shankar P., Xu Z. 7 other authors 2003; Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic. Blood 101:226–235 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.80766-0
Loading
/content/journal/jgv/10.1099/vir.0.80766-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited Most Cited RSS feed