Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1994 Mar;93(3):982–988. doi: 10.1172/JCI117105

Programmed death of T cells in human immunodeficiency virus infection. No correlation with progression to disease.

L Meyaard 1, S A Otto 1, I P Keet 1, M T Roos 1, F Miedema 1
PMCID: PMC294014  PMID: 8132784

Abstract

Programmed death of T cells has been proposed as one of the mechanisms by which HIV affects immune functions in stages of infection where the number of infected cells is low. Indeed, in HIV-infected individuals both CD4+ and CD8+ T cells are primed for programmed cell death, which can be enhanced by polyclonal stimulation. Here, we investigated programmed death of T cells in all stages of HIV infection, including acute infection. In individuals with primary infection the number of T cells dying due to apoptosis was much higher than in the asymptomatic phase of infection and paralleled increased numbers of CD8+ cells. In asymptomatic HIV-infected individuals, cells were dying in increased percentages compared with noninfected controls, although at much lower numbers than during acute infection. Death of T cells was not quantitatively correlated with CD4+ T cell numbers or appearance of more cytopathic, syncytium-inducing HIV variants. Analysis of the phenotype of cells undergoing apoptosis revealed that cell death was not confined to a specific T cell subset nor correlated with expression of certain T cell activation markers. Our results imply that the extent of programmed cell death of T cells in HIV infection does not correlate with progression to disease.

Full text

PDF
982

Images in this article

Selected References

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

  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. Banda N. K., Bernier J., Kurahara D. K., Kurrle R., Haigwood N., Sekaly R. P., Finkel T. H. Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med. 1992 Oct 1;176(4):1099–1106. doi: 10.1084/jem.176.4.1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Clerici M., Stocks N. I., Zajac R. A., Boswell R. N., Lucey D. R., Via C. S., Shearer G. M. Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging. J Clin Invest. 1989 Dec;84(6):1892–1899. doi: 10.1172/JCI114376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gendelman H. E., Ehrlich G. D., Baca L. M., Conley S., Ribas J., Kalter D. C., Meltzer M. S., Poiesz B. J., Nara P. The inability of human immunodeficiency virus to infect chimpanzee monocytes can be overcome by serial viral passage in vivo. J Virol. 1991 Jul;65(7):3853–3863. doi: 10.1128/jvi.65.7.3853-3863.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gougeon M. L., Garcia S., Heeney J., Tschopp R., Lecoeur H., Guetard D., Rame V., Dauguet C., Montagnier L. Programmed cell death in AIDS-related HIV and SIV infections. AIDS Res Hum Retroviruses. 1993 Jun;9(6):553–563. doi: 10.1089/aid.1993.9.553. [DOI] [PubMed] [Google Scholar]
  6. Groux H., Torpier G., Monté D., Mouton Y., Capron A., Ameisen J. C. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med. 1992 Feb 1;175(2):331–340. doi: 10.1084/jem.175.2.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gruters R. A., Terpstra F. G., De Jong R., Van Noesel C. J., Van Lier R. A., Miedema F. Selective loss of T cell functions in different stages of HIV infection. Early loss of anti-CD3-induced T cell proliferation followed by decreased anti-CD3-induced cytotoxic T lymphocyte generation in AIDS-related complex and AIDS. Eur J Immunol. 1990 May;20(5):1039–1044. doi: 10.1002/eji.1830200514. [DOI] [PubMed] [Google Scholar]
  8. Kawabe Y., Ochi A. Programmed cell death and extrathymic reduction of Vbeta8+ CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B. Nature. 1991 Jan 17;349(6306):245–248. doi: 10.1038/349245a0. [DOI] [PubMed] [Google Scholar]
  9. Koot M., Keet I. P., Vos A. H., de Goede R. E., Roos M. T., Coutinho R. A., Miedema F., Schellekens P. T., Tersmette M. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med. 1993 May 1;118(9):681–688. doi: 10.7326/0003-4819-118-9-199305010-00004. [DOI] [PubMed] [Google Scholar]
  10. Meyaard L., Otto S. A., Jonker R. R., Mijnster M. J., Keet R. P., Miedema F. Programmed death of T cells in HIV-1 infection. Science. 1992 Jul 10;257(5067):217–219. doi: 10.1126/science.1352911. [DOI] [PubMed] [Google Scholar]
  11. Meyaard L., Schuitemaker H., Miedema F. T-cell dysfunction in HIV infection: anergy due to defective antigen-presenting cell function? Immunol Today. 1993 Apr;14(4):161–164. doi: 10.1016/0167-5699(93)90279-T. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Miyawaki T., Uehara T., Nibu R., Tsuji T., Yachie A., Yonehara S., Taniguchi N. Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol. 1992 Dec 1;149(11):3753–3758. [PubMed] [Google Scholar]
  14. Moss D. J., Bishop C. J., Burrows S. R., Ryan J. M. T lymphocytes in infectious mononucleosis. I. T cell death in vitro. Clin Exp Immunol. 1985 Apr;60(1):61–69. [PMC free article] [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. Prince H. E., Jensen E. R. HIV-related alterations in CD8 cell subsets defined by in vitro survival characteristics. Cell Immunol. 1991 May;134(2):276–286. doi: 10.1016/0008-8749(91)90302-r. [DOI] [PubMed] [Google Scholar]
  17. Razvi E. S., Welsh R. M. Programmed cell death of T lymphocytes during acute viral infection: a mechanism for virus-induced immune deficiency. J Virol. 1993 Oct;67(10):5754–5765. doi: 10.1128/jvi.67.10.5754-5765.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Roos M. T., Lange J. M., de Goede R. E., Coutinho R. A., Schellekens P. T., Miedema F., Tersmette M. Viral phenotype and immune response in primary human immunodeficiency virus type 1 infection. J Infect Dis. 1992 Mar;165(3):427–432. doi: 10.1093/infdis/165.3.427. [DOI] [PubMed] [Google Scholar]
  19. Russell J. H., White C. L., Loh D. Y., Meleedy-Rey P. Receptor-stimulated death pathway is opened by antigen in mature T cells. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2151–2155. doi: 10.1073/pnas.88.6.2151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Salazar-Gonzalez J. F., Moody D. J., Giorgi J. V., Martinez-Maza O., Mitsuyasu R. T., Fahey J. L. Reduced ecto-5'-nucleotidase activity and enhanced OKT10 and HLA-DR expression on CD8 (T suppressor/cytotoxic) lymphocytes in the acquired immune deficiency syndrome: evidence of CD8 cell immaturity. J Immunol. 1985 Sep;135(3):1778–1785. [PubMed] [Google Scholar]
  21. Schellekens P. T., Roos M. T., De Wolf F., Lange J. M., Miedema F. Low T-cell responsiveness to activation via CD3/TCR is a prognostic marker for acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus-1 (HIV-1)-infected men. J Clin Immunol. 1990 Mar;10(2):121–127. doi: 10.1007/BF00918194. [DOI] [PubMed] [Google Scholar]
  22. Schnittman S. M., Psallidopoulos M. C., Lane H. C., Thompson L., Baseler M., Massari F., Fox C. H., Salzman N. P., Fauci A. S. The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science. 1989 Jul 21;245(4915):305–308. doi: 10.1126/science.2665081. [DOI] [PubMed] [Google Scholar]
  23. Schuitemaker H., Koot M., Kootstra N. A., Dercksen M. W., de Goede R. E., van Steenwijk R. P., Lange J. M., Schattenkerk J. K., Miedema F., Tersmette M. Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J Virol. 1992 Mar;66(3):1354–1360. doi: 10.1128/jvi.66.3.1354-1360.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sellins K. S., Cohen J. J. Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes. J Immunol. 1987 Nov 15;139(10):3199–3206. [PubMed] [Google Scholar]
  25. Stites D. P., Moss A. R., Bacchetti P., Osmond D., McHugh T. M., Wang Y. J., Hebert S., Colfer B. Lymphocyte subset analysis to predict progression to AIDS in a cohort of homosexual men in San Francisco. Clin Immunol Immunopathol. 1989 Jul;52(1):96–103. doi: 10.1016/0090-1229(89)90196-7. [DOI] [PubMed] [Google Scholar]
  26. Terai C., Kornbluth R. S., Pauza C. D., Richman D. D., Carson D. A. Apoptosis as a mechanism of cell death in cultured T lymphoblasts acutely infected with HIV-1. J Clin Invest. 1991 May;87(5):1710–1715. doi: 10.1172/JCI115188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Uehara T., Miyawaki T., Ohta K., Tamaru Y., Yokoi T., Nakamura S., Taniguchi N. Apoptotic cell death of primed CD45RO+ T lymphocytes in Epstein-Barr virus-induced infectious mononucleosis. Blood. 1992 Jul 15;80(2):452–458. [PubMed] [Google Scholar]
  28. Wang R., Murphy K. M., Loh D. Y., Weaver C., Russell J. H. Differential activation of antigen-stimulated suicide and cytokine production pathways in CD4+ T cells is regulated by the antigen-presenting cell. J Immunol. 1993 May 1;150(9):3832–3842. [PubMed] [Google Scholar]
  29. Watanabe M., Ringler D. J., Fultz P. N., MacKey J. J., Boyson J. E., Levine C. G., Letvin N. L. A chimpanzee-passaged human immunodeficiency virus isolate is cytopathic for chimpanzee cells but does not induce disease. J Virol. 1991 Jun;65(6):3344–3348. doi: 10.1128/jvi.65.6.3344-3348.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wesselborg S., Janssen O., Kabelitz D. Induction of activation-driven death (apoptosis) in activated but not resting peripheral blood T cells. J Immunol. 1993 May 15;150(10):4338–4345. [PubMed] [Google Scholar]
  31. de Jong R., Brouwer M., Miedema F., van Lier R. A. Human CD8+ T lymphocytes can be divided into CD45RA+ and CD45RO+ cells with different requirements for activation and differentiation. J Immunol. 1991 Apr 1;146(7):2088–2094. [PubMed] [Google Scholar]
  32. de Wolf F., Lange J. M., Houweling J. T., Coutinho R. A., Schellekens P. T., van der Noordaa J., Goudsmit J. Numbers of CD4+ cells and the levels of core antigens of and antibodies to the human immunodeficiency virus as predictors of AIDS among seropositive homosexual men. J Infect Dis. 1988 Sep;158(3):615–622. doi: 10.1093/infdis/158.3.615. [DOI] [PubMed] [Google Scholar]
  33. van Lier R. A., Boot J. H., Verhoeven A. J., de Groot E. R., Brouwer M., Aarden L. A. Functional studies with anti-CD3 heavy chain isotype switch-variant monoclonal antibodies. Accessory cell-independent induction of interleukin 2 responsiveness in T cells by epsilon-anti-CD3. J Immunol. 1987 Nov 1;139(9):2873–2879. [PubMed] [Google Scholar]
  34. van Noesel C. J., Gruters R. A., Terpstra F. G., Schellekens P. T., van Lier R. A., Miedema F. Functional and phenotypic evidence for a selective loss of memory T cells in asymptomatic human immunodeficiency virus-infected men. J Clin Invest. 1990 Jul;86(1):293–299. doi: 10.1172/JCI114698. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES