Skip to main content
PMC home page
Clinical and Diagnostic Laboratory Immunology logoLink to Clinical and Diagnostic Laboratory Immunology
. 1996 Sep;3(5):547–553. doi: 10.1128/cdli.3.5.547-553.1996

Differential effects of interleukin-12, interleukin-15, and interleukin-2 on human immunodeficiency virus type 1 replication in vitro.

M Bayard-McNeeley 1, H Doo 1, S He 1, A Hafner 1, W D Johnson Jr 1, J L Ho 1
PMCID: PMC170404  PMID: 8877133

Abstract

Cytokines may have clinical utility as therapeutic agents for human immunodeficiency virus type 1 (HIV-1) infection and as an adjuvant for vaccines. The effect of interleukin-12 (IL-12) and IL-15 on in vitro HIV-1 replication was investigated. IL-12 and IL-15 at doses up to 10 ng/ml had little effect on basal HIV-1 p24 antigen production by chronically HIV-infected T (ACH-2) and monocytic (U1) cell lines. For ACH-2 cells stimulated with phorbol 12-myristate 13-acetate (PMA; 50 ng/ml), IL-12 and IL-15 significantly increased p24 antigen production by 20 and 30%, respectively (n = 6). In contrast, IL-12 and IL-15 (10 ng/ml) treatment of PMA-stimulated U1 cells decreased p24 antigen production by 16 and 15%, respectively (n = 6). We next studied the effect of IL-12 and IL-15 on HIV-infected peripheral blood mononuclear cells (PBMCs). In 10 HIV-seropositive patients' PBMCs cocultured with mitogen-activated HIV-seronegative donor cells, two patterns of p24 antigen production were observed in response to IL-2: low (p24 antigen production < 10(3) pg/ml; n = 8) and high (p24 antigen production > 10(3) pg/ml; n = 2) response. For the low-response pattern, IL-12 and IL-15 increased viral replication by 97-fold and 100-fold, respectively (P = 0.05 and 0.004, respectively). For the high-response pattern, both IL-12 and IL-15 suppressed HIV replication. The effect of IL-2, IL-12, and IL-15 on acute in vitro infection by HIV-1JRCSF was also examined. IL-12 did not increase p24 antigen production above basal levels while IL-2 and IL-15 significantly enhanced p24 antigen production (by approximately 2-fold). In conclusion, IL-12 and IL-15 may have differential effects on latent and acute HIV infection, and their ability to enhance HIV production may depend on cell activation. Thus, the use of these cytokines may be dictated by the clinical state of the patient.

Full Text

The Full Text of this article is available as a PDF (254.2 KB).

Selected References

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

  1. Anderson D. M., Kumaki S., Ahdieh M., Bertles J., Tometsko M., Loomis A., Giri J., Copeland N. G., Gilbert D. J., Jenkins N. A. Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL15RA and IL2RA genes. J Biol Chem. 1995 Dec 15;270(50):29862–29869. doi: 10.1074/jbc.270.50.29862. [DOI] [PubMed] [Google Scholar]
  2. Armitage R. J., Macduff B. M., Eisenman J., Paxton R., Grabstein K. H. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J Immunol. 1995 Jan 15;154(2):483–490. [PubMed] [Google Scholar]
  3. Aste-Amezaga M., D'Andrea A., Kubin M., Trinchieri G. Cooperation of natural killer cell stimulatory factor/interleukin-12 with other stimuli in the induction of cytokines and cytotoxic cell-associated molecules in human T and NK cells. Cell Immunol. 1994 Jul;156(2):480–492. doi: 10.1006/cimm.1994.1192. [DOI] [PubMed] [Google Scholar]
  4. Bamford R. N., Grant A. J., Burton J. D., Peters C., Kurys G., Goldman C. K., Brennan J., Roessler E., Waldmann T. A. The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4940–4944. doi: 10.1073/pnas.91.11.4940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bernstein Z. P., Porter M. M., Gould M., Lipman B., Bluman E. M., Stewart C. C., Hewitt R. G., Fyfe G., Poiesz B., Caligiuri M. A. Prolonged administration of low-dose interleukin-2 in human immunodeficiency virus-associated malignancy results in selective expansion of innate immune effectors without significant clinical toxicity. Blood. 1995 Nov 1;86(9):3287–3294. [PubMed] [Google Scholar]
  6. Cao Y., Qin L., Zhang L., Safrit J., Ho D. D. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med. 1995 Jan 26;332(4):201–208. doi: 10.1056/NEJM199501263320401. [DOI] [PubMed] [Google Scholar]
  7. Carson W. E., Giri J. G., Lindemann M. J., Linett M. L., Ahdieh M., Paxton R., Anderson D., Eisenmann J., Grabstein K., Caligiuri M. A. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med. 1994 Oct 1;180(4):1395–1403. doi: 10.1084/jem.180.4.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carson W. E., Ross M. E., Baiocchi R. A., Marien M. J., Boiani N., Grabstein K., Caligiuri M. A. Endogenous production of interleukin 15 by activated human monocytes is critical for optimal production of interferon-gamma by natural killer cells in vitro. J Clin Invest. 1995 Dec;96(6):2578–2582. doi: 10.1172/JCI118321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cassatella M. A., Meda L., Gasperini S., D'Andrea A., Ma X., Trinchieri G. Interleukin-12 production by human polymorphonuclear leukocytes. Eur J Immunol. 1995 Jan;25(1):1–5. doi: 10.1002/eji.1830250102. [DOI] [PubMed] [Google Scholar]
  10. Chehimi J., Starr S. E., Frank I., D'Andrea A., Ma X., MacGregor R. R., Sennelier J., Trinchieri G. Impaired interleukin 12 production in human immunodeficiency virus-infected patients. J Exp Med. 1994 Apr 1;179(4):1361–1366. doi: 10.1084/jem.179.4.1361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chehimi J., Valiante N. M., D'Andrea A., Rengaraju M., Rosado Z., Kobayashi M., Perussia B., Wolf S. F., Starr S. E., Trinchieri G. Enhancing effect of natural killer cell stimulatory factor (NKSF/interleukin-12) on cell-mediated cytotoxicity against tumor-derived and virus-infected cells. Eur J Immunol. 1993 Aug;23(8):1826–1830. doi: 10.1002/eji.1830230814. [DOI] [PubMed] [Google Scholar]
  12. Clerici M., Lucey D. R., Berzofsky J. A., Pinto L. A., Wynn T. A., Blatt S. P., Dolan M. J., Hendrix C. W., Wolf S. F., Shearer G. M. Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro. Science. 1993 Dec 10;262(5140):1721–1724. doi: 10.1126/science.7903123. [DOI] [PubMed] [Google Scholar]
  13. Clerici M., Shearer G. M. A TH1-->TH2 switch is a critical step in the etiology of HIV infection. Immunol Today. 1993 Mar;14(3):107–111. doi: 10.1016/0167-5699(93)90208-3. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Collier A. C., Coombs R. W., Schoenfeld D. A., Bassett R. L., Timpone J., Baruch A., Jones M., Facey K., Whitacre C., McAuliffe V. J. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N Engl J Med. 1996 Apr 18;334(16):1011–1017. doi: 10.1056/NEJM199604183341602. [DOI] [PubMed] [Google Scholar]
  16. Coombs R. W. HIV-1 burden as a marker of disease progression and clinical response to therapy in AIDS. Clin Lab Med. 1994 Jun;14(2):301–311. [PubMed] [Google Scholar]
  17. D'Andrea A., Rengaraju M., Valiante N. M., Chehimi J., Kubin M., Aste M., Chan S. H., Kobayashi M., Young D., Nickbarg E. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med. 1992 Nov 1;176(5):1387–1398. doi: 10.1084/jem.176.5.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Desai B. B., Quinn P. M., Wolitzky A. G., Mongini P. K., Chizzonite R., Gately M. K. IL-12 receptor. II. Distribution and regulation of receptor expression. J Immunol. 1992 May 15;148(10):3125–3132. [PubMed] [Google Scholar]
  19. Dewar R. L., Highbarger H. C., Sarmiento M. D., Todd J. A., Vasudevachari M. B., Davey R. T., Jr, Kovacs J. A., Salzman N. P., Lane H. C., Urdea M. S. Application of branched DNA signal amplification to monitor human immunodeficiency virus type 1 burden in human plasma. J Infect Dis. 1994 Nov;170(5):1172–1179. doi: 10.1093/infdis/170.5.1172. [DOI] [PubMed] [Google Scholar]
  20. Foli A., Saville M. W., Baseler M. W., Yarchoan R. Effects of the Th1 and Th2 stimulatory cytokines interleukin-12 and interleukin-4 on human immunodeficiency virus replication. Blood. 1995 Apr 15;85(8):2114–2123. [PubMed] [Google Scholar]
  21. Folks T. M., Justement J., Kinter A., Schnittman S., Orenstein J., Poli G., Fauci A. S. Characterization of a promonocyte clone chronically infected with HIV and inducible by 13-phorbol-12-myristate acetate. J Immunol. 1988 Feb 15;140(4):1117–1122. [PubMed] [Google Scholar]
  22. Folks T., Benn S., Rabson A., Theodore T., Hoggan M. D., Martin M., Lightfoote M., Sell K. Characterization of a continuous T-cell line susceptible to the cytopathic effects of the acquired immunodeficiency syndrome (AIDS)-associated retrovirus. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4539–4543. doi: 10.1073/pnas.82.13.4539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Giri J. G., Ahdieh M., Eisenman J., Shanebeck K., Grabstein K., Kumaki S., Namen A., Park L. S., Cosman D., Anderson D. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994 Jun 15;13(12):2822–2830. doi: 10.1002/j.1460-2075.1994.tb06576.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Giri J. G., Anderson D. M., Kumaki S., Park L. S., Grabstein K. H., Cosman D. IL-15, a novel T cell growth factor that shares activities and receptor components with IL-2. J Leukoc Biol. 1995 May;57(5):763–766. doi: 10.1002/jlb.57.5.763. [DOI] [PubMed] [Google Scholar]
  25. Grabstein K. H., Eisenman J., Shanebeck K., Rauch C., Srinivasan S., Fung V., Beers C., Richardson J., Schoenborn M. A., Ahdieh M. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994 May 13;264(5161):965–968. doi: 10.1126/science.8178155. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Johnston J. A., Bacon C. M., Finbloom D. S., Rees R. C., Kaplan D., Shibuya K., Ortaldo J. R., Gupta S., Chen Y. Q., Giri J. D. Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8705–8709. doi: 10.1073/pnas.92.19.8705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kim P. K., He S., HO J. L. Rapid culture and quantitation of human immunodeficiency virus type 1 from patient cells without the use of mitogen-stimulated donor cells. Clin Diagn Lab Immunol. 1994 Nov;1(6):660–666. doi: 10.1128/cdli.1.6.660-666.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Klein M. R., van Baalen C. A., Holwerda A. M., Kerkhof Garde S. R., Bende R. J., Keet I. P., Eeftinck-Schattenkerk J. K., Osterhaus A. D., Schuitemaker H., Miedema F. Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics. J Exp Med. 1995 Apr 1;181(4):1365–1372. doi: 10.1084/jem.181.4.1365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kornbluth R. S., Oh P. S., Munis J. R., Cleveland P. H., Richman D. D. The role of interferons in the control of HIV replication in macrophages. Clin Immunol Immunopathol. 1990 Feb;54(2):200–219. doi: 10.1016/0090-1229(90)90082-2. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Krauss A. H., Nieves A. L., Spada C. S., Woodward D. F. Determination of leukotriene effects on human neutrophil chemotaxis in vitro by differential assessment of cell motility and polarity. J Leukoc Biol. 1994 Feb;55(2):201–208. doi: 10.1002/jlb.55.2.201. [DOI] [PubMed] [Google Scholar]
  33. Lee T. H., Sheppard H. W., Reis M., Dondero D., Osmond D., Busch M. P. Circulating HIV-1-infected cell burden from seroconversion to AIDS: importance of postseroconversion viral load on disease course. J Acquir Immune Defic Syndr. 1994 Apr;7(4):381–388. [PubMed] [Google Scholar]
  34. Lewko W. M., Smith T. L., Bowman D. J., Good R. W., Oldham R. K. Interleukin-15 and the growth of tumor derived activated T-cells. Cancer Biother. 1995 Spring;10(1):13–20. doi: 10.1089/cbr.1995.10.13. [DOI] [PubMed] [Google Scholar]
  35. Maggi E., Mazzetti M., Ravina A., Annunziato F., de Carli M., Piccinni M. P., Manetti R., Carbonari M., Pesce A. M., del Prete G. Ability of HIV to promote a TH1 to TH0 shift and to replicate preferentially in TH2 and TH0 cells. Science. 1994 Jul 8;265(5169):244–248. doi: 10.1126/science.8023142. [DOI] [PubMed] [Google Scholar]
  36. Manetti R., Gerosa F., Giudizi M. G., Biagiotti R., Parronchi P., Piccinni M. P., Sampognaro S., Maggi E., Romagnani S., Trinchieri G. Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones. J Exp Med. 1994 Apr 1;179(4):1273–1283. doi: 10.1084/jem.179.4.1273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Miedema F., Klein M. R. AIDS pathogenesis: a finite immune response to blame? Science. 1996 Apr 26;272(5261):505–506. doi: 10.1126/science.272.5261.505. [DOI] [PubMed] [Google Scholar]
  38. Munger W., DeJoy S. Q., Jeyaseelan R., Sr, Torley L. W., Grabstein K. H., Eisenmann J., Paxton R., Cox T., Wick M. M., Kerwar S. S. Studies evaluating the antitumor activity and toxicity of interleukin-15, a new T cell growth factor: comparison with interleukin-2. Cell Immunol. 1995 Oct 15;165(2):289–293. doi: 10.1006/cimm.1995.1216. [DOI] [PubMed] [Google Scholar]
  39. Pantaleo G., Graziosi C., Fauci A. S. New concepts in the immunopathogenesis of human immunodeficiency virus infection. N Engl J Med. 1993 Feb 4;328(5):327–335. doi: 10.1056/NEJM199302043280508. [DOI] [PubMed] [Google Scholar]
  40. Poli G., Fauci A. S. The effect of cytokines and pharmacologic agents on chronic HIV infection. AIDS Res Hum Retroviruses. 1992 Feb;8(2):191–197. doi: 10.1089/aid.1992.8.191. [DOI] [PubMed] [Google Scholar]
  41. Quinn L. S., Haugk K. L., Grabstein K. H. Interleukin-15: a novel anabolic cytokine for skeletal muscle. Endocrinology. 1995 Aug;136(8):3669–3672. doi: 10.1210/endo.136.8.7628408. [DOI] [PubMed] [Google Scholar]
  42. Radrizzani M., Accornero P., Amidei A., Aiello A., Delia D., Kurrle R., Colombo M. P. IL-12 inhibits apoptosis induced in a human Th1 clone by gp120/CD4 cross-linking and CD3/TCR activation or by IL-2 deprivation. Cell Immunol. 1995 Mar;161(1):14–21. doi: 10.1006/cimm.1995.1003. [DOI] [PubMed] [Google Scholar]
  43. Romagnani S. Induction of TH1 and TH2 responses: a key role for the 'natural' immune response? Immunol Today. 1992 Oct;13(10):379–381. doi: 10.1016/0167-5699(92)90083-J. [DOI] [PubMed] [Google Scholar]
  44. Seder R. A., Grabstein K. H., Berzofsky J. A., McDyer J. F. Cytokine interactions in human immunodeficiency virus-infected individuals: roles of interleukin (IL)-2, IL-12, and IL-15. J Exp Med. 1995 Oct 1;182(4):1067–1077. doi: 10.1084/jem.182.4.1067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Sirianni M. C., Ansotegui I. J., Aiuti F., Wigzell H. Natural killer cell stimulatory factor (NKSF)/IL-12 and cytolytic activities of PBL/NK cells from human immunodeficiency virus type-1 infected patients. Scand J Immunol. 1994 Jul;40(1):83–86. doi: 10.1111/j.1365-3083.1994.tb03437.x. [DOI] [PubMed] [Google Scholar]
  46. Street N. E., Schumacher J. H., Fong T. A., Bass H., Fiorentino D. F., Leverah J. A., Mosmann T. R. Heterogeneity of mouse helper T cells. Evidence from bulk cultures and limiting dilution cloning for precursors of Th1 and Th2 cells. J Immunol. 1990 Mar 1;144(5):1629–1639. [PubMed] [Google Scholar]
  47. Trinchieri G., Wysocka M., D'Andrea A., Rengaraju M., Aste-Amezaga M., Kubin M., Valiante N. M., Chehimi J. Natural killer cell stimulatory factor (NKSF) or interleukin-12 is a key regulator of immune response and inflammation. Prog Growth Factor Res. 1992;4(4):355–368. doi: 10.1016/0955-2235(92)90016-b. [DOI] [PubMed] [Google Scholar]
  48. 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]
  49. Wilkinson P. C., Liew F. Y. Chemoattraction of human blood T lymphocytes by interleukin-15. J Exp Med. 1995 Mar 1;181(3):1255–1259. doi: 10.1084/jem.181.3.1255. [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