Skip to main content
PMC home page
Clinical and Diagnostic Laboratory Immunology logoLink to Clinical and Diagnostic Laboratory Immunology
. 1997 Nov;4(6):736–741. doi: 10.1128/cdli.4.6.736-741.1997

CD4+-T-cell counts, spontaneous apoptosis, and Fas expression in peripheral blood mononuclear cells obtained from human immunodeficiency virus type 1-infected subjects.

A H Patki 1, D L Georges 1, M M Lederman 1
PMCID: PMC170651  PMID: 9384300

Abstract

We examined the relationships among CD4+-T-cell counts, spontaneous apoptosis, and Fas expression among peripheral blood mononuclear cells obtained from human immunodeficiency virus type 1 (HIV-1)-infected patients. After 2 days of incubation, propidium iodide DNA staining and flow cytometry revealed that peripheral blood mononuclear cells from subjects with the lowest CD4+-cell numbers (0 to 99/microl; n = 20) showed the highest frequency of apoptosis: 22.4% +/- 2.7% (mean +/- standard error) versus 13.8% +/- 1.2% and 12.7% +/- 1.4% among peripheral blood mononuclear cells obtained from patients with 100 to 499 CD4+ cells/microl (n = 19) and >500 CD4+ cells/microl (n = 17), respectively. Each of these means differed significantly from the mean frequency of apoptosis (6.3% +/- 0.7%) of peripheral blood mononuclear cells obtained from HIV-1-seronegative controls (P < 0.001, Student's t test). After incubation, the percentage of peripheral blood mononuclear cells expressing Fas antigen was increased for the HIV-1-infected subjects, and this was most evident for patients with more advanced disease. Among patients with fewer than 100 CD4+ cells/microl, 64.4% +/- 5.4% of peripheral blood mononuclear cells were Fas+, as opposed to 25.8% +/- 3.0% and 14.5% +/- 1.7% Fas+ cells among patients with more than 100 CD4+ cells/microl and healthy controls, respectively (P < 0.05 for each group comparison). Interestingly, in all populations, most apoptotic cells did not express Fas. Thus, apoptosis and Fas expression are increased in incubated peripheral blood mononuclear cells obtained from HIV-1-infected patients and these phenomena are enhanced as disease progresses.

Full Text

The Full Text of this article is available as a PDF (195.3 KB).

Selected References

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

  1. Alderson M. R., Tough T. W., Davis-Smith T., Braddy S., Falk B., Schooley K. A., Goodwin R. G., Smith C. A., Ramsdell F., Lynch D. H. Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med. 1995 Jan 1;181(1):71–77. doi: 10.1084/jem.181.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Badley A. D., McElhinny J. A., Leibson P. J., Lynch D. H., Alderson M. R., Paya C. V. Upregulation of Fas ligand expression by human immunodeficiency virus in human macrophages mediates apoptosis of uninfected T lymphocytes. J Virol. 1996 Jan;70(1):199–206. doi: 10.1128/jvi.70.1.199-206.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boudet F., Lecoeur H., Gougeon M. L. Apoptosis associated with ex vivo down-regulation of Bcl-2 and up-regulation of Fas in potential cytotoxic CD8+ T lymphocytes during HIV infection. J Immunol. 1996 Mar 15;156(6):2282–2293. [PubMed] [Google Scholar]
  5. Brunner T., Mogil R. J., LaFace D., Yoo N. J., Mahboubi A., Echeverri F., Martin S. J., Force W. R., Lynch D. H., Ware C. F. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature. 1995 Feb 2;373(6513):441–444. doi: 10.1038/373441a0. [DOI] [PubMed] [Google Scholar]
  6. Buhl R., Jaffe H. A., Holroyd K. J., Wells F. B., Mastrangeli A., Saltini C., Cantin A. M., Crystal R. G. Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet. 1989 Dec 2;2(8675):1294–1298. doi: 10.1016/s0140-6736(89)91909-0. [DOI] [PubMed] [Google Scholar]
  7. Buttke T. M., Sandstrom P. A. Oxidative stress as a mediator of apoptosis. Immunol Today. 1994 Jan;15(1):7–10. doi: 10.1016/0167-5699(94)90018-3. [DOI] [PubMed] [Google Scholar]
  8. Cheng J., Zhou T., Liu C., Shapiro J. P., Brauer M. J., Kiefer M. C., Barr P. J., Mountz J. D. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science. 1994 Mar 25;263(5154):1759–1762. doi: 10.1126/science.7510905. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Debatin K. M., Fahrig-Faissner A., Enenkel-Stoodt S., Kreuz W., Benner A., Krammer P. H. High expression of APO-1 (CD95) on T lymphocytes from human immunodeficiency virus-1-infected children. Blood. 1994 May 15;83(10):3101–3103. [PubMed] [Google Scholar]
  11. Dhein J., Walczak H., Bäumler C., Debatin K. M., Krammer P. H. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) Nature. 1995 Feb 2;373(6513):438–441. doi: 10.1038/373438a0. [DOI] [PubMed] [Google Scholar]
  12. Estaquier J., Tanaka M., Suda T., Nagata S., Golstein P., Ameisen J. C. Fas-mediated apoptosis of CD4+ and CD8+ T cells from human immunodeficiency virus-infected persons: differential in vitro preventive effect of cytokines and protease antagonists. Blood. 1996 Jun 15;87(12):4959–4966. [PubMed] [Google Scholar]
  13. 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]
  14. Gougeon M. L., Lecoeur H., Dulioust A., Enouf M. G., Crouvoiser M., Goujard C., Debord T., Montagnier L. Programmed cell death in peripheral lymphocytes from HIV-infected persons: increased susceptibility to apoptosis of CD4 and CD8 T cells correlates with lymphocyte activation and with disease progression. J Immunol. 1996 May 1;156(9):3509–3520. [PubMed] [Google Scholar]
  15. 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]
  16. Ho D. D., Neumann A. U., Perelson A. S., Chen W., Leonard J. M., Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 Jan 12;373(6510):123–126. doi: 10.1038/373123a0. [DOI] [PubMed] [Google Scholar]
  17. Ju S. T., Panka D. J., Cui H., Ettinger R., el-Khatib M., Sherr D. H., Stanger B. Z., Marshak-Rothstein A. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature. 1995 Feb 2;373(6513):444–448. doi: 10.1038/373444a0. [DOI] [PubMed] [Google Scholar]
  18. Katsikis P. D., Wunderlich E. S., Smith C. A., Herzenberg L. A., Herzenberg L. A. Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. J Exp Med. 1995 Jun 1;181(6):2029–2036. doi: 10.1084/jem.181.6.2029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lewis D. E., Tang D. S., Adu-Oppong A., Schober W., Rodgers J. R. Anergy and apoptosis in CD8+ T cells from HIV-infected persons. J Immunol. 1994 Jul 1;153(1):412–420. [PubMed] [Google Scholar]
  20. McCloskey T. W., Oyaizu N., Coronesi M., Pahwa S. Use of a flow cytometric assay to quantitate apoptosis in human lymphocytes. Clin Immunol Immunopathol. 1994 Apr;71(1):14–18. doi: 10.1006/clin.1994.1045. [DOI] [PubMed] [Google Scholar]
  21. McCloskey T. W., Oyaizu N., Kaplan M., Pahwa S. Expression of the Fas antigen in patients infected with human immunodeficiency virus. Cytometry. 1995 Jun 15;22(2):111–114. doi: 10.1002/cyto.990220206. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Meyaard L., Otto S. A., Keet I. P., Roos M. T., Miedema F. Programmed death of T cells in human immunodeficiency virus infection. No correlation with progression to disease. J Clin Invest. 1994 Mar;93(3):982–988. doi: 10.1172/JCI117105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Muro-Cacho C. A., Pantaleo G., Fauci A. S. Analysis of apoptosis in lymph nodes of HIV-infected persons. Intensity of apoptosis correlates with the general state of activation of the lymphoid tissue and not with stage of disease or viral burden. J Immunol. 1995 May 15;154(10):5555–5566. [PubMed] [Google Scholar]
  26. Nicoletti I., Migliorati G., Pagliacci M. C., Grignani F., Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 1991 Jun 3;139(2):271–279. doi: 10.1016/0022-1759(91)90198-o. [DOI] [PubMed] [Google Scholar]
  27. Oyaizu N., McCloskey T. W., Than S., Hu R., Kalyanaraman V. S., Pahwa S. Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor-alpha secretion. Blood. 1994 Oct 15;84(8):2622–2631. [PubMed] [Google Scholar]
  28. Patki A. H., Lederman M. M. Detection of apoptotic cells by selective precipitation of [3H]thymidine-labelled DNA. Clin Diagn Lab Immunol. 1996 Jan;3(1):1–4. doi: 10.1128/cdli.3.1.1-4.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Patki A. H., Lederman M. M. HIV-1 Tat protein and its inhibitor Ro 24-7429 inhibit lymphocyte proliferation and induce apoptosis in peripheral blood mononuclear cells from healthy donors. Cell Immunol. 1996 Apr 10;169(1):40–46. doi: 10.1006/cimm.1996.0088. [DOI] [PubMed] [Google Scholar]
  30. Purvis S. F., Jacobberger J. W., Sramkoski R. M., Patki A. H., Lederman M. M. HIV type 1 Tat protein induces apoptosis and death in Jurkat cells. AIDS Res Hum Retroviruses. 1995 Apr;11(4):443–450. doi: 10.1089/aid.1995.11.443. [DOI] [PubMed] [Google Scholar]
  31. Schimenti K. J., Jacobberger J. W. Fixation of mammalian cells for flow cytometric evaluation of DNA content and nuclear immunofluorescence. Cytometry. 1992;13(1):48–59. doi: 10.1002/cyto.990130109. [DOI] [PubMed] [Google Scholar]
  32. Shinohara S., Sawada T., Nishioka Y., Tohma S., Kisaki T., Inoue T., Ando K., Ikeda M., Fujii H., Ito K. Differential expression of Fas antigen and Bcl-2 protein on CD4+ T cells, CD8+ T cells, and monocytes. Cell Immunol. 1995 Jul;163(2):303–308. doi: 10.1006/cimm.1995.1130. [DOI] [PubMed] [Google Scholar]
  33. Silvestris F., Cafforio P., Frassanito M. A., Tucci M., Romito A., Nagata S., Dammacco F. Overexpression of Fas antigen on T cells in advanced HIV-1 infection: differential ligation constantly induces apoptosis. AIDS. 1996 Feb;10(2):131–141. doi: 10.1097/00002030-199602000-00002. [DOI] [PubMed] [Google Scholar]
  34. Wei X., Ghosh S. K., Taylor M. E., Johnson V. A., Emini E. A., Deutsch P., Lifson J. D., Bonhoeffer S., Nowak M. A., Hahn B. H. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995 Jan 12;373(6510):117–122. doi: 10.1038/373117a0. [DOI] [PubMed] [Google Scholar]
  35. Westendorp M. O., Frank R., Ochsenbauer C., Stricker K., Dhein J., Walczak H., Debatin K. M., Krammer P. H. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature. 1995 Jun 8;375(6531):497–500. doi: 10.1038/375497a0. [DOI] [PubMed] [Google Scholar]
  36. 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 Clinical and Diagnostic Laboratory Immunology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES