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BioDrugs

, Volume 10, Issue 3, pp 215–225 | Cite as

Use of Interleukin-2 in Immunotherapy of Human Immunodeficiency Virus Infection

Review Article Immunology-Based Agent

Abstract

Interleukin-2 (IL-2) is a cytokine produced by activated T cells. Its stimulatory activity allows T cells, B cells and natural killer cells to proliferate and to release cytokines and antibodies which protect the host against invading organisms. IL-2 plays a critical role in the prevention of apoptosis of HIV-infected cells, and the addition of IL-2 to a culture medium will increase the survival of T cells and will upregulate IL-2 receptor function.

Clinical studies of the administration of exogenous IL-2 to HIV-infected patients have demonstrated that it can be given in well tolerated doses and that it can increase and sustain the number of CD4+ cells while only transiently affecting viral proliferation, especially when given to patients with CD4+ counts >200 cells/mm3.

Further investigations are required to determine the optimal use of exogenous IL-2 in HIV-infected patients. There may also be an important role for IL-2 as an adjunct to gene therapy and preventive vaccines against HIV infection.

Keywords

Human Immunodeficiency Virus Natural Killer Cell Adis International Limited Human Immunodeficiency Virus Type Human Immunodeficiency Virus Infection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Marincola FM. Interleukin-2. Biol Ther Updates 1994; 4: 1–16Google Scholar
  2. 2.
    Seder RA, Grabstein KH, Berzofsky JA, et al. Cytokine interactions in human deficiency virus-infected individuals: roles of interleukin (IL)-2, IL-12, and IL-15. J Exp Med 1995 Oct; 182(4): 1067–77PubMedCrossRefGoogle Scholar
  3. 3.
    Adachi Y, Oyaizu N, Than S, et al. IL-2 rescues in vitro lymphocyte apoptosis in patients with HIV infection: correlation with its ability to block culture-induced down modulation of Bcl-2. J Immunol 1996 Nov; 157(9): 4184–93PubMedGoogle Scholar
  4. 4.
    Kaplan G, Cohn ZA, Smith KA. Rational immunotherapy with interleukin-2. Biotechnology 1992 Feb; 10: 157–62PubMedCrossRefGoogle Scholar
  5. 5.
    Kinter A, Fauci AS. Interleukin-2 and human deficiency virus infection: pathogenic mechanisms and potential for immunologic enhancement. Immunol Res 1996; 15(1): 1–5PubMedCrossRefGoogle Scholar
  6. 6.
    Butera, ST. Cytokine involvement in viral permissiveness and the progression of HIV disease. J Cell Biochem 1993; 53: 336–42PubMedCrossRefGoogle Scholar
  7. 7.
    Jacobson EI, Pilaro F, Smith KA. Rational interleukin-2 therapy for HIV-positive individuals: daily low doses enhance immune function without toxicity. Proc Natl Acad Sci USA 1996 Sep; 93(19): 10405–10PubMedCrossRefGoogle Scholar
  8. 8.
    Weissman D, Daucher J, Barker T, et al. Cytokine regulation of HIV replication induced by dendritic cell-CD4-positive T cell interactions. AIDS Res Hum Retroviruses 1996; 12(9): 759–67PubMedCrossRefGoogle Scholar
  9. 9.
    Levine BL, Mosca JD, Riley JL, et al. Antiviral effect and ex vivo CD4+ T cell proliferation in HIV-positive patients as a result of CD28 costimulation. Science 1996 Nov; 272: 1939–43PubMedCrossRefGoogle Scholar
  10. 10.
    Smith KA. Interleukin-2: inception, impact, and implications. Science 1988; 240: 1169–76PubMedCrossRefGoogle Scholar
  11. 11.
    Flores I, Casaseca T, Martinez AC, et al. Phosphatidic acid degeneration through interleukin-2 (IL-2)-induced alpha diacylglycerol kinase activation is an essential step in IL-2 lymphocyte proliferation. J Biol Chem 1996 Apr; 271(17): 10334–40PubMedCrossRefGoogle Scholar
  12. 12.
    Brenner BG, Gryllis C, Wainberg MA. Role of antibody-dependent cellular toxicity and lymphokine-activated killer cells in AIDS and related diseases. J Leukoc Biol 1991 Dec; 50(6): 628–40PubMedGoogle Scholar
  13. 13.
    Puri PK, Leland P, Aggarwal BB. Constitutive expression of human deficiency virus type 1 tat gene inhibits interleukin-2 and interleukin-2 receptor expression in a human CD4+ T lymphoid (H9) cell line. AIDS Res Hum Retroviruses 1995 Jan; 11(1): 31–40PubMedCrossRefGoogle Scholar
  14. 14.
    Honda M, Kitamura K, Matsuda K, et al. Soluble IL-2 receptor in AIDS. J Immunol 1989Jun; 142(12): 4248–55PubMedGoogle Scholar
  15. 15.
    Tsunetsugu-Yokota Y, Honda M. Effect of cytokines on HIV release and IL-2 receptor alpha expression in monocytic cell lines. J Acquir Immun Defic Syndr Hum Retrovirol 1990 Aug; 3(5): 511–6Google Scholar
  16. 16.
    Secreti I, Spear GT. Complement activation by HIV-1 infected target cells enhances IL-2 stimulated but not unstimulated ADCC activity mediated by peripheral blood mononuclear cells. Clin Immunol Immunopathol 1996 Jan; 78(1): 78–82Google Scholar
  17. 17.
    Lin SJ, Roberts RL, Ank BJ, et al. Human immunodeficiency virus (HIV) type-1 gp120-specific cell-mediated toxicity (CMC) and natural killer (NK) activity in HIV-infected (HIV+) subjects: enhancement with interleukin-2 (IL-2), IL-12, and IL-15. Clin Immunol Immunopathol 1997 Feb; 82(2): 163–73PubMedCrossRefGoogle Scholar
  18. 18.
    Westendorp MO, Li-Weber M, Frank RW, et al. Human immunodeficiency virus type 1 Tat upregulates interleukin-2 secretion in activated T cells. J Virol 1994 Jul; 68(7): 4177–85PubMedGoogle Scholar
  19. 19.
    Lederman MM. Host-directed and immune-based therapies for human immunodeficiency virus infection. Ann Intern Med 1995; 122: 218–22PubMedGoogle Scholar
  20. 20.
    Winkelstein A, Kingsley LA, Weaver LD, et al. Defective T cell colony formation and IL-2 receptor expression in HIV-infected homosexuals: relationship between functional abnormalities and CD4 cell numbers. J Acquir Immune Defic Syndr 1989; 2(4): 353–8PubMedGoogle Scholar
  21. 21.
    Winkelstein A, Kingsley LA, Klein RS, et al. Defective T-cell colony formation and IL-2 receptor expression at all stages of HIV infection. Clin Exp Immunol 1988 Mar; 71(3): 417–22PubMedGoogle Scholar
  22. 22.
    Clerici M, Hakim FT, Venzon DJ, et al. Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus sero-positive individuals. J Clin Invest 1993 Mar; 91(3): 759–65PubMedCrossRefGoogle Scholar
  23. 23.
    Clerici M, Balotta C, Meroni L, et al. Type 1 cytokine production and low prevalence of viral isolation correlate with long-term nonprogression in HIV infection. AIDS Res Hum Retroviruses 1996 Jul; 12(11): 1053–61PubMedCrossRefGoogle Scholar
  24. 24.
    Bost KL, Hahn BH, Saag MS, et al. Individuals infected with HIV possess antibodies against IL-2. Immunology 1988 Dec; 65(4): 611–5PubMedGoogle Scholar
  25. 25.
    Scott-Alzara D, Vuillier M, Marasescu M, et al. Serum levels of IL-2, IL-1α, TNF-α and soluble receptor of IL-2 in HIV-1-infected patients. AIDS Res Hum Retroviruses 1991 Apr; 7(4): 381–6CrossRefGoogle Scholar
  26. 26.
    Poli G, Fauci A. The effect of cytokines and pharmacologic agents on chronic HIV-infection. AIDS Res Hum Retroviruses 1992 Feb; 8(2): 191–7PubMedCrossRefGoogle Scholar
  27. 27.
    Rubin LA, Kurman CC, Fritz ME, et al. Soluble interleukin-2 receptors are released from activated human lymphoid cells in vitro. J Immunol 1985; 135: 3172–7PubMedGoogle Scholar
  28. 28.
    Rubin LA, Jay G, Nelson D. The released interleukin 2 receptor binds interleukin 2 efficiently. J Immunol 1986; 137: 3841–4PubMedGoogle Scholar
  29. 29.
    Cohen JJ. Apoptosis. Immunol Today 1993; 14(3): 126–30PubMedCrossRefGoogle Scholar
  30. 30.
    Radrizzani M, Accorneo P, Amidei A, et al. IL-12 inhibits apoptosis induced in a human Th1 clone by gp120/CD4 cross-linking and CD4/TCR activation or by IL-2 deprivation. Cell Immunol 1995 Mar; 161(1): 14–21PubMedCrossRefGoogle Scholar
  31. 31.
    Meyaard L, Otto SA, Jonker RR, et al. Programmed cell death. Science 1992; 257: 217–9PubMedCrossRefGoogle Scholar
  32. 32.
    Salmon M, Pilling D, Borthwick NJ, et al. The progressive differentiation of primed T cells is associated with an increasing susceptibility to apoptosis. Eur J Immunol 1994; 24: 892–9PubMedCrossRefGoogle Scholar
  33. 33.
    Miyawawaki T, Uehara R, Nibu T, et al. Differential expression of apoptosis-related Fas antigen on lymphocytes subpopulation in human peripheral blood. J Immunol 1992; 149: 3753Google Scholar
  34. 34.
    Pandolfi F, Pierdominici M, Oliva A, et al. Apoptosis-related mortality in vitro of mononuclear cells from patients with HIV infection correlates with disease severity and progression. J Acquir Immun Defic Syndr Hum Retrovirol 1995 Aug; 9(5): 450–8Google Scholar
  35. 35.
    Clerici M, Sarin A, Berzofsky JA, et al. Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and affected by lymphotoxin. AIDS 1996; 10(6): 603–11PubMedCrossRefGoogle Scholar
  36. 36.
    Clerici M, Balotta C, Salvaggio A, et al. Human immunodeficiency virus (HIV) phenotype and interleukin-2/interleukin-10 ratio are associated markers of protection and progression in HIV infection. Blood 1996 Jul; 88(2): 574–9PubMedGoogle Scholar
  37. 37.
    Mor F, Cohen IR. IL-2 rescues antigen-specific T cells from radiation or dexamethasone-induced apoptosis. J Immunol 1996; 156: 515–22PubMedGoogle Scholar
  38. 38.
    Kovacs JA, Baseler M, Dewar RJ, et al. Increases in CD4 lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection. N Engl J Med 1995; 332: 567–75PubMedCrossRefGoogle Scholar
  39. 39.
    Kovacs JA, Vogel S, Albert JM, et al. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N Engl J Med 1996 Oct; 335(18): 1350–6PubMedCrossRefGoogle Scholar
  40. 40.
    Kinter AL, Bende SM, Hardy EC, et al. Interleukin-2 induces CD8+ cell-mediated suppression of human immunodeficiency virus replication in CD4+ cells and this effect overrides its ability to stimulate virus expression. Proc Natl Acad Sci 1995 Nov; 92(24): 10985–9CrossRefGoogle Scholar
  41. 41.
    Teppler H, Kaplan G, Smith K, et al. Efficacy of the low doses of the polyethylene glycol derivative of interleukin-2 in modulating the immune response of patients with immunodeficiency virus type-1 infection. J Infect Dis 1993 Feb; 167(2): 291–8PubMedCrossRefGoogle Scholar
  42. 42.
    Wood R, Montoya JG, Kundu SK, et al. Safety and efficacy of polyethylene glycol-modified interleukin-2 and zidovudine in human deficiency virus type 1 infection: a phase I/II study. J Infect Dis 1993 Mar; 167(3): 519–25PubMedCrossRefGoogle Scholar
  43. 43.
    Barker E, Mackewicz CE, Levy JA. Effects of TH1 and TH2 cytokines on CD8+ cell response against human immunodeficiency virus: implications for long-term survival. Proc Natl Acad Sci USA 1995 Nov; 92: 11135–9PubMedCrossRefGoogle Scholar
  44. 44.
    Vyarkarman A, Matear PM, Martin SJ, et al. Th1 cells specific for HIV-1 gag p24 are less efficient than Th0 cells in supporting HIV replication, and inhibit virus replication in Th0 cells. Immunology 1995 Sep; 86(1): 85–96Google Scholar
  45. 45.
    Chehimi J, Ma X, Chouaib S, et al. Differential production of interleukin-10 during human immunodeficiency virus infection. AIDS Res Hum Retroviruses 1996; 12(12): 1141PubMedCrossRefGoogle Scholar
  46. 46.
    Hagiwara E, Sacks T, Leitman-Klinman SF, et al. Effect of HIV infection on the frequency of cytokine-secreting cells in human peripheral blood. AIDS Res Hum Retroviruses 1996 Jan; 12(2): 127–33PubMedCrossRefGoogle Scholar
  47. 47.
    Naif HM, Chang J, Ho-Shon M, et al. Inhibition of human immunodeficiency virus in differentiating monocytes by interleukin-10 occurs in parallel with inhibition of cellular RNA expression. AIDS Res Hum Retroviruses 1996; 12(13): 1237–45PubMedCrossRefGoogle Scholar
  48. 48.
    Koostra NA, Wout AB, Huisman HG, et al. Interference of interleukin-10 with human immunodeficiency virus type 1 replication in primary monocyte-derived macrophages. J Virol 1994 Nov; 68(11): 6967–75Google Scholar
  49. 49.
    Saville MW, Taga K, Foli A, et al. Interleukin-10 suppresses human immunodeficiency virus-1 replication in vitro in cells of the monocyte-macrophage lineage. Blood 1994 Jun; 83(12): 3591–9PubMedGoogle Scholar
  50. 50.
    Fan J, Bass HZ, Fahey JL. Elevated IFN-gamma and decreased IL-2 gene expression are associated with HIV infection. J Immunol 1993 Nov; 151(9): 5031–40PubMedGoogle Scholar
  51. 51.
    Sneller MC. Consensus symposium on combined antiretroviral therapy; overview of interferon and IL-2 combinations for the treatment of HIV infection. Antiviral Res 1996 Jan; 29(1): 105–9PubMedCrossRefGoogle Scholar
  52. 52.
    Kinter AL, Poli G, Fox L, et al. HIV replication in IL-2-stimulated peripheral blood mononuclear cells is driven in an autocrine/paracrine manner by endogenous cytokines. J Immunol 1995 Mar; 154(5): 2248–59Google Scholar
  53. 53.
    Bernstein ZP, Porter MM, Gould M, et al. 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; 86(9): 3287–94PubMedGoogle Scholar
  54. 54.
    Davey RT, Chaitt DG, Piscitelli SC, et al. Subcutaneous administration of interleukin-2 in human immunodeficiency virus type-1-infected persons. J Infect Dis 1997; 175: 781–9PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  1. 1.Department of MedicineUCLA Center for Clinical AIDS Research and EducationLos AngelesUSA

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