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. 1995 Jun 20;92(13):5773–5777. doi: 10.1073/pnas.92.13.5773

Persistent high frequency of human immunodeficiency virus-specific cytotoxic T cells in peripheral blood of infected donors.

P A Moss 1, S L Rowland-Jones 1, P M Frodsham 1, S McAdam 1, P Giangrande 1, A J McMichael 1, J I Bell 1
PMCID: PMC41583  PMID: 7597028

Abstract

Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTLs) are thought to play a major role in the immune response to HIV infection. The HIV-specific CTL response is much stronger than previously documented in an infectious disease, yet estimates of CTL frequency derived from limiting-dilution analysis (LDA) are relatively low and comparable to other viral infections. Here we show that individual CTL clones specific for peptides from HIV gag and pol gene products are present at high levels in the peripheral blood of three infected patients and that individual CTL clones may represent between 0.2% and 1% of T cells. Previous LDA in one donor had shown a frequency of CTL precursors of 1/8000, suggesting that LDA may underestimate CTL effector frequency. In some donors individual CTL clones persisted in vivo for at least 5 years. In contrast, in one patient there was a switch in CTL usage suggesting that different populations of CTLs can be recruited during infection. These data imply strong stimulation of CTLs, potentially leading some clones to exhaustion.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Autran B., Mayaud C. M., Raphael M., Plata F., Denis M., Bourguin A., Guillon J. M., Debre P., Akoun G. Evidence for a cytotoxic T-lymphocyte alveolitis in human immunodeficiency virus-infected patients. AIDS. 1988 Jun;2(3):179–183. [PubMed] [Google Scholar]
  2. Bowness P., Moss P. A., Rowland-Jones S., Bell J. I., McMichael A. J. Conservation of T cell receptor usage by HLA B27-restricted influenza-specific cytotoxic T lymphocytes suggests a general pattern for antigen-specific major histocompatibility complex class I-restricted responses. Eur J Immunol. 1993 Jul;23(7):1417–1421. doi: 10.1002/eji.1830230702. [DOI] [PubMed] [Google Scholar]
  3. Carmichael A., Jin X., Sissons P., Borysiewicz L. Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein-Barr virus in late disease. J Exp Med. 1993 Feb 1;177(2):249–256. doi: 10.1084/jem.177.2.249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gotch F. M., Nixon D. F., Alp N., McMichael A. J., Borysiewicz L. K. High frequency of memory and effector gag specific cytotoxic T lymphocytes in HIV seropositive individuals. Int Immunol. 1990;2(8):707–712. doi: 10.1093/intimm/2.8.707. [DOI] [PubMed] [Google Scholar]
  5. Henwood J., Loveridge J., Bell J. I., Gaston J. S. Restricted T cell receptor expression by human T cell clones specific for mycobacterial 65-kDa heat-shock protein: selective in vivo expansion of T cells bearing defined receptors. Eur J Immunol. 1993 Jun;23(6):1256–1265. doi: 10.1002/eji.1830230610. [DOI] [PubMed] [Google Scholar]
  6. Kalams S. A., Johnson R. P., Trocha A. K., Dynan M. J., Ngo H. S., D'Aquila R. T., Kurnick J. T., Walker B. D. Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire. J Exp Med. 1994 Apr 1;179(4):1261–1271. doi: 10.1084/jem.179.4.1261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Koup R. A., Pikora C. A., Luzuriaga K., Brettler D. B., Day E. S., Mazzara G. P., Sullivan J. L. Limiting dilution analysis of cytotoxic T lymphocytes to human immunodeficiency virus gag antigens in infected persons: in vitro quantitation of effector cell populations with p17 and p24 specificities. J Exp Med. 1991 Dec 1;174(6):1593–1600. doi: 10.1084/jem.174.6.1593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Koup R. A., Sullivan J. L., Levine P. H., Brettler D., Mahr A., Mazzara G., McKenzie S., Panicali D. Detection of major histocompatibility complex class I-restricted, HIV-specific cytotoxic T lymphocytes in the blood of infected hemophiliacs. Blood. 1989 May 15;73(7):1909–1914. [PubMed] [Google Scholar]
  9. Loh E. Y., Elliott J. F., Cwirla S., Lanier L. L., Davis M. M. Polymerase chain reaction with single-sided specificity: analysis of T cell receptor delta chain. Science. 1989 Jan 13;243(4888):217–220. doi: 10.1126/science.2463672. [DOI] [PubMed] [Google Scholar]
  10. Moskophidis D., Lechner F., Pircher H., Zinkernagel R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993 Apr 22;362(6422):758–761. doi: 10.1038/362758a0. [DOI] [PubMed] [Google Scholar]
  11. Moss P. A., Moots R. J., Rosenberg W. M., Rowland-Jones S. J., Bodmer H. C., McMichael A. J., Bell J. I. Extensive conservation of alpha and beta chains of the human T-cell antigen receptor recognizing HLA-A2 and influenza A matrix peptide. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8987–8990. doi: 10.1073/pnas.88.20.8987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Moss P. A., Rosenberg W. M., Zintzaras E., Bell J. I. Characterization of the human T cell receptor alpha-chain repertoire and demonstration of a genetic influence on V alpha usage. Eur J Immunol. 1993 May;23(5):1153–1159. doi: 10.1002/eji.1830230526. [DOI] [PubMed] [Google Scholar]
  13. Nixon D. F., Townsend A. R., Elvin J. G., Rizza C. R., Gallwey J., McMichael A. J. HIV-1 gag-specific cytotoxic T lymphocytes defined with recombinant vaccinia virus and synthetic peptides. Nature. 1988 Dec 1;336(6198):484–487. doi: 10.1038/336484a0. [DOI] [PubMed] [Google Scholar]
  14. Pantaleo G., Koenig S., Baseler M., Lane H. C., Fauci A. S. Defective clonogenic potential of CD8+ T lymphocytes in patients with AIDS. Expansion in vivo of a nonclonogenic CD3+CD8+DR+CD25- T cell population. J Immunol. 1990 Mar 1;144(5):1696–1704. [PubMed] [Google Scholar]
  15. 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]
  16. Plata F., Autran B., Martins L. P., Wain-Hobson S., Raphaël M., Mayaud C., Denis M., Guillon J. M., Debré P. AIDS virus-specific cytotoxic T lymphocytes in lung disorders. Nature. 1987 Jul 23;328(6128):348–351. doi: 10.1038/328348a0. [DOI] [PubMed] [Google Scholar]
  17. Riviere Y., Tanneau-Salvadori F., Regnault A., Lopez O., Sansonetti P., Guy B., Kieny M. P., Fournel J. J., Montagnier L. Human immunodeficiency virus-specific cytotoxic responses of seropositive individuals: distinct types of effector cells mediate killing of targets expressing gag and env proteins. J Virol. 1989 May;63(5):2270–2277. doi: 10.1128/jvi.63.5.2270-2277.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rosenberg W. M., Moss P. A., Bell J. I. Variation in human T cell receptor V beta and J beta repertoire: analysis using anchor polymerase chain reaction. Eur J Immunol. 1992 Feb;22(2):541–549. doi: 10.1002/eji.1830220237. [DOI] [PubMed] [Google Scholar]
  19. Spits H., Ijssel H., Terhorst C., de Vries J. E. Establishment of human T lymphocyte clones highly cytotoxic for an EBV-transformed B cell line in serum-free medium: isolation of clones that differ in phenotype and specificity. J Immunol. 1982 Jan;128(1):95–99. [PubMed] [Google Scholar]
  20. Tsomides T. J., Walker B. D., Eisen H. N. An optimal viral peptide recognized by CD8+ T cells binds very tightly to the restricting class I major histocompatibility complex protein on intact cells but not to the purified class I protein. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11276–11280. doi: 10.1073/pnas.88.24.11276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Walker B. D., Chakrabarti S., Moss B., Paradis T. J., Flynn T., Durno A. G., Blumberg R. S., Kaplan J. C., Hirsch M. S., Schooley R. T. HIV-specific cytotoxic T lymphocytes in seropositive individuals. Nature. 1987 Jul 23;328(6128):345–348. doi: 10.1038/328345a0. [DOI] [PubMed] [Google Scholar]
  22. Walker B. D., Flexner C., Paradis T. J., Fuller T. C., Hirsch M. S., Schooley R. T., Moss B. HIV-1 reverse transcriptase is a target for cytotoxic T lymphocytes in infected individuals. Science. 1988 Apr 1;240(4848):64–66. doi: 10.1126/science.2451288. [DOI] [PubMed] [Google Scholar]
  23. Walker C. M., Moody D. J., Stites D. P., Levy J. A. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science. 1986 Dec 19;234(4783):1563–1566. doi: 10.1126/science.2431484. [DOI] [PubMed] [Google Scholar]
  24. Wedderburn L. R., O'Hehir R. E., Hewitt C. R., Lamb J. R., Owen M. J. In vivo clonal dominance and limited T-cell receptor usage in human CD4+ T-cell recognition of house dust mite allergens. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8214–8218. doi: 10.1073/pnas.90.17.8214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Wilson R. K., Lai E., Concannon P., Barth R. K., Hood L. E. Structure, organization and polymorphism of murine and human T-cell receptor alpha and beta chain gene families. Immunol Rev. 1988 Jan;101:149–172. doi: 10.1111/j.1600-065x.1988.tb00736.x. [DOI] [PubMed] [Google Scholar]
  26. von Boehmer H. Immunology. Tolerance by exhaustion. Nature. 1993 Apr 22;362(6422):696–696. doi: 10.1038/362696a0. [DOI] [PubMed] [Google Scholar]

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