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. 1995 Nov 21;92(24):10985–10989. doi: 10.1073/pnas.92.24.10985

Interleukin 2 induces CD8+ T cell-mediated suppression of human immunodeficiency virus replication in CD4+ T cells and this effect overrides its ability to stimulate virus expression.

A L Kinter 1, S M Bende 1, E C Hardy 1, R Jackson 1, A S Fauci 1
PMCID: PMC40555  PMID: 7479922

Abstract

The nonlytic suppression of human immunodeficiency virus (HIV) production from infected CD4+ T cells by CD8+ lymphocytes from HIV-infected individuals is one of the most potent host-mediated antiviral activities observed in vitro. We demonstrate that the pleiotropic cytokine interleukin 2 (IL-2), but not IL-12, is a potent inducer of the CD8+ HIV suppressor phenomenon. IL-2 induces HIV expression in peripheral blood or lymph node mononuclear cells from HIV-infected individuals in the absence of CD8+ T cells. However, IL-2 induces CD8+ T cells to suppress HIV expression when added back to these cultures, and this effect dramatically supersedes the ability to IL-2 to induce HIV expression. Five to 25 times fewer CD8+ cells were required to obtain comparable levels of inhibition of viral production if they were activated in the presence of IL-2 as compared with IL-12 or no exogenous cytokine. Furthermore, IL-2 appeared either to induce a qualitative increase in HIV suppressor cell activity or to increase the relative frequency of suppressor cells in the activated (CD25+) CD8+ populations. Analyses of proviral levels in peripheral blood mononuclear cells suggest that CD8+ T cell-mediated lysis of in vivo infected cells is not induced by IL-2. These results have implications for our understanding of the effects of impaired IL-2 production during HIV disease as well as the overall effects of IL-2-based immunotherapy on HIV replication in vivo.

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Selected References

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

  1. Chen C. H., Weinhold K. J., Bartlett J. A., Bolognesi D. P., Greenberg M. L. CD8+ T lymphocyte-mediated inhibition of HIV-1 long terminal repeat transcription: a novel antiviral mechanism. AIDS Res Hum Retroviruses. 1993 Nov;9(11):1079–1086. doi: 10.1089/aid.1993.9.1079. [DOI] [PubMed] [Google Scholar]
  2. Fauci A. S. Multifactorial nature of human immunodeficiency virus disease: implications for therapy. Science. 1993 Nov 12;262(5136):1011–1018. doi: 10.1126/science.8235617. [DOI] [PubMed] [Google Scholar]
  3. Grimm E. A., Owen-Schaub L. The IL-2 mediated amplification of cellular cytotoxicity. J Cell Biochem. 1991 Apr;45(4):335–339. doi: 10.1002/jcb.240450405. [DOI] [PubMed] [Google Scholar]
  4. Gómez A. M., Smaill F. M., Rosenthal K. L. Inhibition of HIV replication by CD8+ T cells correlates with CD4 counts and clinical stage of disease. Clin Exp Immunol. 1994 Jul;97(1):68–75. doi: 10.1111/j.1365-2249.1994.tb06581.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  6. Ivashkiv L. B. Cytokines and STATs: how can signals achieve specificity? Immunity. 1995 Jul;3(1):1–4. doi: 10.1016/1074-7613(95)90152-3. [DOI] [PubMed] [Google Scholar]
  7. Kannagi M., Chalifoux L. V., Lord C. I., Letvin N. L. Suppression of simian immunodeficiency virus replication in vitro by CD8+ lymphocytes. J Immunol. 1988 Apr 1;140(7):2237–2242. [PubMed] [Google Scholar]
  8. Kovacs J. A., Baseler M., Dewar R. J., Vogel S., Davey R. T., Jr, Falloon J., Polis M. A., Walker R. E., Stevens R., Salzman N. P. Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection. A preliminary study. N Engl J Med. 1995 Mar 2;332(9):567–575. doi: 10.1056/NEJM199503023320904. [DOI] [PubMed] [Google Scholar]
  9. Mackewicz C. E., Blackbourn D. J., Levy J. A. CD8+ T cells suppress human immunodeficiency virus replication by inhibiting viral transcription. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2308–2312. doi: 10.1073/pnas.92.6.2308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Mackewicz C. E., Ortega H. W., Levy J. A. CD8+ cell anti-HIV activity correlates with the clinical state of the infected individual. J Clin Invest. 1991 Apr;87(4):1462–1466. doi: 10.1172/JCI115153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Mackewicz C. E., Ortega H., Levy J. A. Effect of cytokines on HIV replication in CD4+ lymphocytes: lack of identity with the CD8+ cell antiviral factor. Cell Immunol. 1994 Feb;153(2):329–343. doi: 10.1006/cimm.1994.1032. [DOI] [PubMed] [Google Scholar]
  12. Mackewicz C., Levy J. A. CD8+ cell anti-HIV activity: nonlytic suppression of virus replication. AIDS Res Hum Retroviruses. 1992 Jun;8(6):1039–1050. doi: 10.1089/aid.1992.8.1039. [DOI] [PubMed] [Google Scholar]
  13. Mehrotra P. T., Wu D., Crim J. A., Mostowski H. S., Siegel J. P. Effects of IL-12 on the generation of cytotoxic activity in human CD8+ T lymphocytes. J Immunol. 1993 Sep 1;151(5):2444–2452. [PubMed] [Google Scholar]
  14. Mosmann T. R. Cytokine patterns during the progression to AIDS. Science. 1994 Jul 8;265(5169):193–194. doi: 10.1126/science.8023139. [DOI] [PubMed] [Google Scholar]
  15. Nakamura Y., Nishimura T., Tokuda Y., Kobayashi N., Watanabe K., Noto T., Mitomi T., Sugamura K., Habu S. Macrophage-T cell interaction is essential for the induction of p75 interleukin 2 (IL-2) receptor and IL-2 responsiveness in human CD4+ T cells. Jpn J Cancer Res. 1991 Mar;82(3):257–261. doi: 10.1111/j.1349-7006.1991.tb01839.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Pantaleo G., Graziosi C., Demarest J. F., Butini L., Montroni M., Fox C. H., Orenstein J. M., Kotler D. P., Fauci A. S. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355–358. doi: 10.1038/362355a0. [DOI] [PubMed] [Google Scholar]
  17. Perussia B., Chan S. H., D'Andrea A., Tsuji K., Santoli D., Pospisil M., Young D., Wolf S. F., Trinchieri G. Natural killer (NK) cell stimulatory factor or IL-12 has differential effects on the proliferation of TCR-alpha beta+, TCR-gamma delta+ T lymphocytes, and NK cells. J Immunol. 1992 Dec 1;149(11):3495–3502. [PubMed] [Google Scholar]
  18. Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994 Dec 15;84(12):4008–4027. [PubMed] [Google Scholar]
  19. Waldmann T. A. The IL-2/IL-2 receptor system: a target for rational immune intervention. Immunol Today. 1993 Jun;14(6):264–270. doi: 10.1016/0167-5699(93)90043-K. [DOI] [PubMed] [Google Scholar]
  20. Walker C. M., Levy J. A. A diffusible lymphokine produced by CD8+ T lymphocytes suppresses HIV replication. Immunology. 1989 Apr;66(4):628–630. [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. 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]
  23. Willey R. L., Smith D. H., Lasky L. A., Theodore T. S., Earl P. L., Moss B., Capon D. J., Martin M. A. In vitro mutagenesis identifies a region within the envelope gene of the human immunodeficiency virus that is critical for infectivity. J Virol. 1988 Jan;62(1):139–147. doi: 10.1128/jvi.62.1.139-147.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]

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