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. 1990 Jun;87(12):4818–4822. doi: 10.1073/pnas.87.12.4818

CD8+ T lymphocytes of patients with AIDS maintain normal broad cytolytic function despite the loss of human immunodeficiency virus-specific cytotoxicity.

G Pantaleo 1, A De Maria 1, S Koenig 1, L Butini 1, B Moss 1, M Baseler 1, H C Lane 1, A S Fauci 1
PMCID: PMC54209  PMID: 2112749

Abstract

In this study, we have investigated the potential mechanisms responsible for the loss of human immunodeficiency virus type 1 (HIV-1)-specific cytolytic activity in the advanced stages of HIV-1 infection. We have demonstrated that HIV-1-specific cytotoxic T lymphocytes are predominantly contained within the CD8+DR+ subset. Furthermore, we have shown by a redirected killing assay that there is a dichotomy between HIV-1-specific cytolytic activity and broad cytolytic potential since the cytolytic machinery of CD8+DR+ cells is still functioning even in patients with AIDS who have lost their HIV-1-specific cytolytic activity. In addition, by comparative analysis of these two types of cytolytic activity over time we have demonstrated a progressive loss of HIV-1-specific cytolytic activity in the advanced stages of the disease, whereas the cytolytic potential remained unchanged regardless of the clinical stage. As previously shown in patients with AIDS, even in asymptomatic HIV-1-seropositive patients, CD8+DR+ cells from the same patient, compared to CD8+DR- lymphocytes, showed a substantial reduction in their ability to proliferate in vitro in response to different stimuli, such as mitogens (phytohemagglutinin and phorbol 12-myristate 13-acetate) and monoclonal antibodies directed against CD3, CD2, and CD28 molecules, and displayed a defective clonogenic potential. Thus, on the basis of these results we propose that the loss of HIV-1-specific cytolytic activity in HIV-1-infected individuals may result at least in part from a progressive decrease in the pool of HIV-1-specific cytotoxic T lymphocytes belonging to the CD8+DR+ subset whose ability to expand has been impaired.

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Selected References

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

  1. Carney W. P., Iacoviello V., Hirsch M. S. Functional properties of T lymphocytes and their subsets in cytomegalovirus mononucleosis. J Immunol. 1983 Jan;130(1):390–393. [PubMed] [Google Scholar]
  2. Chakrabarti S., Brechling K., Moss B. Vaccinia virus expression vector: coexpression of beta-galactosidase provides visual screening of recombinant virus plaques. Mol Cell Biol. 1985 Dec;5(12):3403–3409. doi: 10.1128/mcb.5.12.3403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Fauci A. S. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988 Feb 5;239(4840):617–622. doi: 10.1126/science.3277274. [DOI] [PubMed] [Google Scholar]
  4. Fleischer B. Lysis of bystander target cells after triggering of human cytotoxic T lymphocytes. Eur J Immunol. 1986 Aug;16(8):1021–1024. doi: 10.1002/eji.1830160826. [DOI] [PubMed] [Google Scholar]
  5. Hahn B. H., Shaw G. M., Taylor M. E., Redfield R. R., Markham P. D., Salahuddin S. Z., Wong-Staal F., Gallo R. C., Parks E. S., Parks W. P. Genetic variation in HTLV-III/LAV over time in patients with AIDS or at risk for AIDS. Science. 1986 Jun 20;232(4757):1548–1553. doi: 10.1126/science.3012778. [DOI] [PubMed] [Google Scholar]
  6. Hoffenbach A., Langlade-Demoyen P., Dadaglio G., Vilmer E., Michel F., Mayaud C., Autran B., Plata F. Unusually high frequencies of HIV-specific cytotoxic T lymphocytes in humans. J Immunol. 1989 Jan 15;142(2):452–462. [PubMed] [Google Scholar]
  7. James S. P., Neckers L. M., Graeff A. S., Cossman J., Balch C. M., Strober W. Suppression of immunoglobulin synthesis by lymphocyte subpopulations in patients with Crohn's disease. Gastroenterology. 1984 Jun;86(6):1510–1518. [PubMed] [Google Scholar]
  8. Joly P., Guillon J. M., Mayaud C., Plata F., Theodorou I., Denis M., Debre P., Autran B. Cell-mediated suppression of HIV-specific cytotoxic T lymphocytes. J Immunol. 1989 Oct 1;143(7):2193–2201. [PubMed] [Google Scholar]
  9. Koenig S., Earl P., Powell D., Pantaleo G., Merli S., Moss B., Fauci A. S. Group-specific, major histocompatibility complex class I-restricted cytotoxic responses to human immunodeficiency virus 1 (HIV-1) envelope proteins by cloned peripheral blood T cells from an HIV-1-infected individual. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8638–8642. doi: 10.1073/pnas.85.22.8638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Linker-Israeli M., Gray J. D., Quismorio F. P., Jr, Horwitz D. A. Characterization of lymphocytes that suppress IL-2 production in systemic lupus erythematosus. Clin Exp Immunol. 1988 Aug;73(2):236–241. [PMC free article] [PubMed] [Google Scholar]
  11. Lum L. G. The kinetics of immune reconstitution after human marrow transplantation. Blood. 1987 Feb;69(2):369–380. [PubMed] [Google Scholar]
  12. Moretta A., Pantaleo G., Moretta L., Cerottini J. C., Mingari M. C. Direct demonstration of the clonogenic potential of every human peripheral blood T cell. Clonal analysis of HLA-DR expression and cytolytic activity. J Exp Med. 1983 Feb 1;157(2):743–754. doi: 10.1084/jem.157.2.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Moretta A., Pantaleo G., Moretta L., Mingari M. C., Cerottini J. C. Quantitative assessment of the pool size and subset distribution of cytolytic T lymphocytes within human resting or alloactivated peripheral blood T cell populations. J Exp Med. 1983 Aug 1;158(2):571–585. doi: 10.1084/jem.158.2.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Pitzalis C., Kingsley G., Lanchbury J. S., Murphy J., Panayi G. S. Expression of HLA-DR, DQ and DP antigens and interleukin-2 receptor on synovial fluid T lymphocyte subsets in rheumatoid arthritis: evidence for "frustrated" activation. J Rheumatol. 1987 Aug;14(4):662–666. [PubMed] [Google Scholar]
  17. 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]
  18. Rook A. H., Manischewitz J. F., Frederick W. R., Epstein J. S., Jackson L., Gelmann E., Steis R., Masur H., Quinnan G. V., Jr Deficient, HLA-restricted, cytomegalovirus-specific cytotoxic T cells and natural killer cells in patients with the acquired immunodeficiency syndrome. J Infect Dis. 1985 Sep;152(3):627–630. doi: 10.1093/infdis/152.3.627. [DOI] [PubMed] [Google Scholar]
  19. Sethi K. K., Näher H., Stroehmann I. Phenotypic heterogeneity of cerebrospinal fluid-derived HIV-specific and HLA-restricted cytotoxic T-cell clones. Nature. 1988 Sep 8;335(6186):178–181. doi: 10.1038/335178a0. [DOI] [PubMed] [Google Scholar]
  20. Shearer G. M., Bernstein D. C., Tung K. S., Via C. S., Redfield R., Salahuddin S. Z., Gallo R. C. A model for the selective loss of major histocompatibility complex self-restricted T cell immune responses during the development of acquired immune deficiency syndrome (AIDS). J Immunol. 1986 Oct 15;137(8):2514–2521. [PubMed] [Google Scholar]
  21. Takahashi H., Cohen J., Hosmalin A., Cease K. B., Houghten R., Cornette J. L., DeLisi C., Moss B., Germain R. N., Berzofsky J. A. An immunodominant epitope of the human immunodeficiency virus envelope glycoprotein gp160 recognized by class I major histocompatibility complex molecule-restricted murine cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1988 May;85(9):3105–3109. doi: 10.1073/pnas.85.9.3105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Taswell C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol. 1981 Apr;126(4):1614–1619. [PubMed] [Google Scholar]
  23. Tomkinson B. E., Wagner D. K., Nelson D. L., Sullivan J. L. Activated lymphocytes during acute Epstein-Barr virus infection. J Immunol. 1987 Dec 1;139(11):3802–3807. [PubMed] [Google Scholar]
  24. 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]
  25. 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]
  26. Zarling J. M., Morton W., Moran P. A., McClure J., Kosowski S. G., Hu S. L. T-cell responses to human AIDS virus in macaques immunized with recombinant vaccinia viruses. 1986 Sep 25-Oct 1Nature. 323(6086):344–346. doi: 10.1038/323344a0. [DOI] [PubMed] [Google Scholar]

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