Immunologic Research

, Volume 38, Issue 1–3, pp 373–386 | Cite as

Role of common gamma chain utilizing cytokines for immune reconstitution in HIV infection

Article

Abstract

Many cytokines that utilize the common gamma (Cγ) chain signaling pathway, viz Interleukin (IL)-2, IL-15, and IL-7 are known to be important for inducing T cell maturation, proliferation, or survival. Untreated chronic HIV infection is associated with profound quantitative and qualitative deficiency of CD4 T cells, which is partially reversed following highly active antiretroviral therapy (HAART). A subset of patients, however, fail to recover CD4 T cells despite virologic suppression. The role of Cγ chain cytokines in influencing immune reconstitution following potent antiretroviral therapy is discussed. Maturation markers (naïve, central memory, effector memory, and effector), cytokine receptors IL-2Rβ, Cγ chain, IL-7Rα, IL-15Rα, and cytokine-induced proliferative responses of T cells in a cohort of HIV-infected pediatric patients and adults classified on the basis of immunologic and virologic response to antiretroviral therapy were examined. The studies indicated that patients had increased percentages of effector memory CD8+ T cells in comparison to healthy volunteers. While patients with partially controlled viremia and poor CD4 T cell reconstitution manifested poor proliferative responses to anti-CD3 or HIV gag antigen stimulation, proliferative responses to Cγ chain utilizing cytokines IL-2, IL-7, and IL-15 were robust. Another Cγ chain utilizing cytokine, IL-21 had no influence on cellular proliferation but enhanced perforin expression in effector CD8 T cells. Thus, cytokine receptor deficiencies may contribute to immune deficiency in HIV-infected patients, and Cγ chain cytokines may play an important role in vivo in immune homeostasis in lymphopenic patients by maintaining the memory subsets of T cells in patients with CD4 T cell deficiency.

Keywords

HIV infection Immune deficiency Immune reconstitution Immune hemeostasis 

References

  1. 1.
    Good RA. Cellular immunology in a historical perspective. Immunol Rev 2002;185:136–58.PubMedCrossRefGoogle Scholar
  2. 2.
    Leonard WJ, Noguchi M, Russell SM, McBride OW. The molecular basis of X-linked severe combined immunodeficiency: the role of the interleukin-2 receptor gamma chain as a common gamma chain, gamma c. Immunol Rev 1994;138:61–86.PubMedCrossRefGoogle Scholar
  3. 3.
    Puck JM, Pepper AE, Henthorn PS, et al. Mutation analysis of IL2RG in human X-linked severe combined immunodeficiency. Blood 1997;89:1968–77.PubMedGoogle Scholar
  4. 4.
    Chatila T, Castigli E, Pahwa R et al. Primary combined immunodeficiency resulting from defective transcription of multiple T-cell lymphokine genes. Proc Natl Acad Sci USA 1990;87:10033–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Pahwa R, Chatila T, Pahwa S, et al. Recombinant interleukin 2 therapy in severe combined immunodeficiency disease. Proc Natl Acad Sci U S A 1989;86:5069–73.PubMedCrossRefGoogle Scholar
  6. 6.
    Pahwa R, Paradise C, Good RA. Management of a novel immune deficiency with IL-2 therapy. Cancer Treat Rev 1989;16 Suppl A:143–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Picard C, Casanova JL. Inherited disorders of cytokines. Curr Opin Pediatr 2004;16:648–58.PubMedCrossRefGoogle Scholar
  8. 8.
    Giorgi JV, Detels R. T-cell subset alterations in HIV-infected homosexual men: NIAID Multicenter AIDS cohort study. Clin Immunol Immunopathol 1989;52:10–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Ho HN, Hultin LE, Mitsuyasu RT, et al. Circulating HIV-specific CD8+ cytotoxic T cells express CD38 and HLA-DR antigens. J Immunol 1993;150:3070–9.PubMedGoogle Scholar
  10. 10.
    Oyaizu N, McCloskey TW, Coronesi M, Chirmule N, Kalyanaraman VS, Pahwa S. Accelerated apoptosis in peripheral blood mononuclear cells (PBMCs) from human immunodeficiency virus type-1 infected patients and in CD4 cross-linked PBMCs from normal individuals. Blood 1993;82:3392–400.PubMedGoogle Scholar
  11. 11.
    Oyaizu N, McCloskey TW, Than S, Hu R, Pahwa S. Mechanism of apoptosis in peripheral blood mononuclear cells of HIV-infected patients. Adv Exp Med Biol 1995;374:101–14.PubMedGoogle Scholar
  12. 12.
    Oyaizu N, Pahwa S. Role of apoptosis in HIV disease pathogenesis. J Clin Immunol 1995;15:217–31.PubMedCrossRefGoogle Scholar
  13. 13.
    Wang X, Rasmussen T, Pahar B, et al. Massive infection and loss of CD4+ T cells occurs in the intestinal tract of neonatal rhesus macaques in acute SIV infection. Blood 2006.Google Scholar
  14. 14.
    Veazey RS, Lackner AA. HIV swiftly guts the immune system. Nat Med 2005;11:469–70.PubMedCrossRefGoogle Scholar
  15. 15.
    Brenchley JM, Price DA, Douek DC. HIV disease: fallout from a mucosal catastrophe? Nat Immunol 2006;7:235–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Fauci AS, Lane HC. The acquired immunodeficiency syndrome (AIDS): an update. Int Arch Allergy Appl Immunol 1985;77:81–8.PubMedGoogle Scholar
  17. 17.
    Oyaizu N, Chirmule N, Kalyanaraman VS, et al. Human immunodeficiency virus type 1 envelope glycoprotein gp120 produces immune defects in CD4+ T lymphocytes by inhibiting interleukin 2 mRNA. Proc Natl Acad Sci USA 1990;87:2379–83.PubMedCrossRefGoogle Scholar
  18. 18.
    Oyaizu N, Chirmule N, Ohnishi Y, Kalyanaraman VS, Pahwa S. Human immunodeficiency virus type 1 envelope glycoproteins gp120 and gp160 induce interleukin-6 production in CD4+ T-cell clones. J Virol 1991;65:6277–82.PubMedGoogle Scholar
  19. 19.
    Harari A, Petitpierre S, Vallelian F, Pantaleo G. Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1-infected subjects with progressive disease: changes after antiretroviral therapy. Blood 2004;103:966–72.PubMedCrossRefGoogle Scholar
  20. 20.
    Zimmerli SC, Harari A, Cellerai C, Vallelian F, Bart PA, Pantaleo G. HIV-1-specific IFN-gamma/IL-2-secreting CD8 T cells support CD4-independent proliferation of HIV-1-specific CD8 T cells. Proc Natl Acad Sci USA 2005;102:7239–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Essajee SM, Kim M, Gonzalez C, et al. Immunologic and virologic responses to HAART in severely immunocompromised HIV-1-infected children. Aids 1999;13:2523–32.PubMedCrossRefGoogle Scholar
  22. 22.
    Benveniste O, Flahault A, Rollot F, et al. Mechanisms involved in the low-level regeneration of CD4+ cells in HIV-1-infected patients receiving highly active antiretroviral therapy who have prolonged undetectable plasma viral loads. J Infect Dis 2005;191:1670–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Broussard SR, Staprans SI, White R, Whitehead EM, Feinberg MB, Allan JS. Simian immunodeficiency virus replicates to high levels in naturally infected African green monkeys without inducing immunologic or neurologic disease. J Virol 2001;75:2262–75.PubMedCrossRefGoogle Scholar
  24. 24.
    Dunham R, Pagliardini P, Gordon S, et al. The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus. Blood 2006;108:209–17.PubMedCrossRefGoogle Scholar
  25. 25.
    Silvestri G, Sodora DL, Koup RA, et al. Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity 2003;18:441–52.PubMedCrossRefGoogle Scholar
  26. 26.
    Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 2005;434:1093–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Geginat J, Lanzavecchia A, Sallusto F. Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood 2003;101:4260–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Surh CD, Boyman O, Purton JF, Sprent J. Homeostasis of memory T cells. Immunol Rev 2006;211:154–63.PubMedCrossRefGoogle Scholar
  29. 29.
    Zambricki E, Shigeoka A, Kishimoto H, et al. Signaling T-cell survival and death by IL-2 and IL-15. Am J Transplant 2005;5:2623–31.PubMedCrossRefGoogle Scholar
  30. 30.
    Schluns KS, Lefrancois L. Cytokine control of memory T-cell development and survival. Nat Rev Immunol 2003;3:269–79.PubMedCrossRefGoogle Scholar
  31. 31.
    Chitnis V, Pahwa R, Pahwa S. Determinants of HIV-specific CD8 T-cell responses in HIV-infected pediatric patients and enhancement of HIV-gag-specific responses with exogenous IL-15. Clin Immunol 2003;107:36–45.PubMedCrossRefGoogle Scholar
  32. 32.
    Pahwa R, McCloskey TW, Aroniadis OC, Strbo N, Krishnan S, Pahwa S. CD8+ T cells in HIV disease exhibit cytokine receptor perturbation and poor T cell receptor activation but are responsive to gamma-chain cytokine-driven proliferation. J Infect Dis 2006;193:879–87.PubMedCrossRefGoogle Scholar
  33. 33.
    Centers for Disease Control and Prevention Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR 1994;43:1–12.Google Scholar
  34. 34.
    Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999;401:708–12.PubMedCrossRefGoogle Scholar
  35. 35.
    Appay V, Dunbar PR, Callan M, et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 2002;8:379–85.PubMedCrossRefGoogle Scholar
  36. 36.
    Champagne P, Ogg GS, King AS, et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 2001;410:106–11.PubMedCrossRefGoogle Scholar
  37. 37.
    Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006;443:350–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Petrovas C, Casazza JP, Brenchley JM, et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 2006;203:2281–92.PubMedCrossRefGoogle Scholar
  39. 39.
    Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 2006;12:1198–202.PubMedCrossRefGoogle Scholar
  40. 40.
    Trimble LA, Lieberman J. Circulating CD8 T lymphocytes in human immunodeficiency virus-infected individuals have impaired function and downmodulate CD3 zeta, the signaling chain of the T-cell receptor complex. Blood 1998;91:585–94.PubMedGoogle Scholar
  41. 41.
    Montes M, Lewis DE, Sanchez C, et al. Foxp3+ regulatory T cells in antiretroviral-naive HIV patients. Aids 2006;20:1669–71.PubMedCrossRefGoogle Scholar
  42. 42.
    Boasso A, Vaccari M, Nilsson J, et al. Do regulatory T-cells play a role in AIDS pathogenesis? AIDS Rev 2006;8:141–7.PubMedGoogle Scholar
  43. 43.
    Adachi Y, Oyaizu N, Than S, McCloskey TW, Pahwa S. 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;157:4184–93.PubMedGoogle Scholar
  44. 44.
    Kovacs JA, Lempicki RA, Sidorov IA, et al. Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients. J Clin Invest 2005;115:2139–48.PubMedCrossRefGoogle Scholar
  45. 45.
    Mueller YM, Bojczuk PM, Halstead ES, et al. IL-15 enhances survival and function of HIV-specific CD8+ T cells. Blood 2003;101:1024–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Mueller YM, Makar V, Bojczuk PM, Witek J, Katsikis PD. IL-15 enhances the function and inhibits CD95/Fas-induced apoptosis of human CD4+ and CD8+ effector-memory T cells. Int Immunol 2003;15:49–58.PubMedCrossRefGoogle Scholar
  47. 47.
    McCloskey TW, Haridas V, Pahwa R, Pahwa S. Human immunodeficiency virus gag and pol-specific CD8 T cells in perinatal HIV infection. Cytometry 2001;46:265–70.PubMedCrossRefGoogle Scholar
  48. 48.
    Kovacs JA, Baseler M, Dewar RJ, et al. 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;332:567–75.PubMedCrossRefGoogle Scholar
  49. 49.
    Smith KA. Lowest dose interleukin-2 immunotherapy. Blood 1993;81:1414–23.PubMedGoogle Scholar
  50. 50.
    Taniguchi T, Matsui H, Fujita T, et al. Structure and expression of a cloned cDNA for human interleukin-2. 1983. Biotechnology 1992;24:304–9.PubMedGoogle Scholar
  51. 51.
    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;335:1350–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Levy Y, Capitant C, Houhou S, et al. Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial. ANRS 048 study group. Lancet 1999;353:1923–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Davey RT Jr, Chaitt DG, Piscitelli SC, et al. Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons. J Infect Dis 1997;175:781–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Sereti I, Imamichi H, Natarajan V, et al. In vivo expansion of CD4CD45RO-CD25 T cells expressing foxP3 in IL-2-treated HIV-infected patients. J Clin Invest 2005;115:1839–47.PubMedCrossRefGoogle Scholar
  55. 55.
    Zhang H, Chua KS, Guimond M, et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med 2005;11:1238–43.PubMedCrossRefGoogle Scholar
  56. 56.
    Kovanen PE, Leonard WJ. Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol Rev 2004;202:67–83.PubMedCrossRefGoogle Scholar
  57. 57.
    Haridas V, McCloskey TW, Pahwa R, Pahwa S. Discordant expression of perforin and granzyme A in total and HIV-specific CD8 T lymphocytes of HIV infected children and adolescents. Aids 2003;17:2313–22.PubMedCrossRefGoogle Scholar
  58. 58.
    Amicosante M, Poccia F, Gioia C, et al. Levels of interleukin-15 in plasma may predict a favorable outcome of structured treatment interruption in patients with chronic human immunodeficiency virus infection. J Infect Dis 2003;188:661–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Aspinall R, Henson S, Pido-Lopez J, Ngom PT. Interleukin-7: an interleukin for rejuvenating the immune system. Ann N Y Acad Sci 2004;1019:116–22.PubMedCrossRefGoogle Scholar
  60. 60.
    Schluns KS, Kieper WC, Jameson SC, Lefrancois L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol 2000;1:426–32.PubMedCrossRefGoogle Scholar
  61. 61.
    Beq S, Rannou MT, Fontanet A, Delfraissy JF, Theze J, Colle JH. HIV infection: pre-highly active antiretroviral therapy IL-7 plasma levels correlate with long-term CD4 cell count increase after treatment. Aids 2004;18:563–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Resino S, Galan I, Correa R, Pajuelo L, Bellon JM, Munoz-Fernandez MA. Homeostatic role of IL-7 in HIV-1 infected children on HAART: association with immunological and virological parameters. Acta Paediatr 2005;94:170–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Oh S, Berzofsky JA, Burke DS, Waldmann TA, Perera LP. Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity. Proc Natl Acad Sci USA 2003;100:3392–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Pahwa S, Muresan P, Sleasman J, Fenton T, Moye J, Deyeikis A, Wara D, Van Dyke R. Pediatric Aids Clinical Trials Group 402 Tcam. Phase I/II trial of intermittent subcutaneous [L-2 administration in pediatric patients with moderate immune suppression: Results of Pediatric AIDS Clinical Trials Study 402. J Allergy Clin Immunol 2007;119(6):1538–41.PubMedCrossRefGoogle Scholar
  65. 65.
    Serefi I, Aga E, Spritzler J, Landay A, Pahwa S, Fischi M, Asmuth D, Tenorio A, Buffet R, Lederman M and ACTG 5214 team: rhJL 7 in HIV-1-infected Subjects with CD4 T- cells Count > 1[x]cells/µL and Viral Load < 50,000 copies/mL: Results from a Randomized, Placebo-controlled, Double-blinded Study (ACTG5214); Abstract # 128, 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, February 25–28, 2007.Google Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Miller School of Medicine, Department of Microbiology and ImmunologyUniversity of MiamiMiamiUSA

Personalised recommendations