Current HIV/AIDS Reports

, Volume 5, Issue 1, pp 27–32 | Cite as

New players in cytokine control of HIV infection

  • Massimo Alfano
  • Andrea Crotti
  • Elisa Vicenzi
  • Guido PoliEmail author


Cytokines are involved early in the pathogenesis of HIV infection and disease progression as a component of immunologic dysregulation and immunodeficiency and as determinants controlling virus replication. Several steps, before and after retroviral integration into host DNA in T cells and macrophages, are affected by cytokines whereas CCR5 and CXCR4 binding chemokines can interfere with viral entry. A growing number of potential players—including the γ-common interleukin (IL)-7, IL-15, and IL-21 together with IL-17, IL-18, IL-19, IL-20, IL-23, and IL-27—are discussed in terms of their perturbation in HIV infection and of their effects on virus replication. Thus, an increasing intersection of HIV infection and the cytokine network represents a crucial determinant of virus replication and immunologic dysregulation and will likely play a key role in the development of effective strategies of HIV prevention and immunologic reconstitution.


Natural Killer Cell Long Terminal Repeat Lipodystrophy Immunologic Dysregulation 
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 and Recommended Reading

  1. 1.
    Alfano M, Poli G: Role of cytokines and chemokines in the regulation of innate immunity and HIV infection. Mol Immunol 2005, 42:161–82.PubMedCrossRefGoogle Scholar
  2. 2.
    Meanwell NA, Kadow JF: Maraviroc, a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS. Curr Opin Investig Drugs 2007, 8:669–681.PubMedGoogle Scholar
  3. 3.
    Selliah N, Zhang M, DeSimone D, et al.: The gammacytokine regulated transcription factor, STAT5, increases HIV-1 production in primary CD4 T cells. Virology 2006, 344:283–291.PubMedCrossRefGoogle Scholar
  4. 4.
    Crotti A, Lusic M, Lupo R, et al.: Naturally occurring C-terminally truncated STAT5 is a negative regulator of human immunodeficiency virus-type 1 expression. Blood 2007, 109:5380–5389.PubMedCrossRefGoogle Scholar
  5. 5.
    Schmitt N, Nugeyre MT, Scott-Algara D, et al.: Differential susceptibility of human thymic dendritic cell subsets to X4 and R5 HIV-1 infection. AIDS 2006, 20:533–542.PubMedCrossRefGoogle Scholar
  6. 6.
    Managlia EZ, Landay A, Al-Harthi L: Interleukin-7 induces HIV replication in primary naive T cells through a nuclear factor of activated T cell (NFAT)-dependent pathway. Virology 2006, 350:443–452.PubMedCrossRefGoogle Scholar
  7. 7.
    Wang FX, Xu Y, Sullivan J, et al.: IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART. J Clin Invest 2005, 115:128–137.PubMedCrossRefGoogle Scholar
  8. 8.
    Vassena L, Proschan M, Fauci AS, Lusso P: Interleukin 7 reduces the levels of spontaneous apoptosis in CD4+ and CD8+ T cells from HIV-1-infected individuals. Proc Natl Acad Sci U S A 2007, 104:2355–2360.PubMedCrossRefGoogle Scholar
  9. 9.
    Audige A, Schlaepfer E, Joller H, Speck RF: Uncoupled anti-HIV and immune-enhancing effects when combining IFN-alpha and IL-7. J Immunol 2005, 175:3724–3736.PubMedGoogle Scholar
  10. 10.
    Song H, Nakayama EE, Shioda T: Effects of human interleukin 7 on HIV-1 replication in monocyte-derived human macrophages. AIDS 2006, 20:937–939.PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang M, Drenkow J, Lankford CS, et al.: HIV regulation of the IL-7R: a viral mechanism for enhancing HIV-1 replication in human macrophages in vitro. J Leukoc Biol 2006, 79:1328–1338.PubMedCrossRefGoogle Scholar
  12. 12.
    Lum JJ, Schnepple DJ, Nie Z, et al.: Differential effects of interleukin-7 and interleukin-15 on NK cell anti-human immunodeficiency virus activity. J Virol 2004, 78:6033–6042.PubMedCrossRefGoogle Scholar
  13. 13.
    Kopka J, Mecikovsky D, Aulicino PC, et al.: High IL-7 plasma levels may induce and predict the emergence of HIV-1 virulent strains in pediatric infection. J Clin Virol 2005, 33:237–242.PubMedGoogle Scholar
  14. 14.
    Lin YL, Portales P, Segondy M, et al.: CXCR4 overexpression during the course of HIV-1 infection correlates with the emergence of X4 strains. J Acquir Immune Defic Syndr 2005, 39:530–536.PubMedGoogle Scholar
  15. 15.
    Rodriguez AR, Arulanandam BP, Hodara VL, et al.: Influence of interleukin-15 on CD8+ natural killer cells in human immunodeficiency virus type 1-infected chimpanzees. J Gen Virol 2007, 88:641–651.PubMedCrossRefGoogle Scholar
  16. 16.
    Bolesta E, Kowalczyk A, Wierzbicki A, et al.: Increased level and longevity of protective immune responses induced by DNA vaccine expressing the HIV-1 Env glycoprotein when combined with IL-21 and IL-15 gene delivery. J Immunol 2006, 177:177–191.PubMedGoogle Scholar
  17. 17.
    Zeng R, Spolski R, Finkelstein SE, et al.: Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med 2005; 201:139–48.PubMedCrossRefGoogle Scholar
  18. 18.
    White L, Krishnan S, Strbo N, et al.: Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV). Blood 2007, 109:3873–3880.PubMedCrossRefGoogle Scholar
  19. 19.
    Mueller YM, Petrovas C, Bojczuk PM, et al.: Interleukin-15 increases effector memory CD8+ T cells and NK cells in simian immunodeficiency virus-infected macaques. J Virol 2005, 79:4877–4885.PubMedCrossRefGoogle Scholar
  20. 20.
    Chong SY, Egan MA, Kutzler MA, et al.: Comparative ability of plasmid IL-12 and IL-15 to enhance cellular and humoral immune responses elicited by a SIVgag plasmid DNA vaccine and alter disease progression following SHIV(89.6P) challenge in rhesus macaques. Vaccine 2007, 25:4967–4982.PubMedCrossRefGoogle Scholar
  21. 21.
    Hryniewicz A, Price DA, Moniuszko M, et al.: Interleukin-15 but not interleukin-7 abrogates vaccine-induced decrease in virus level in simian immunodeficiency virus mac251-infected macaques. J Immunol 2007, 178:3492–3504.PubMedGoogle Scholar
  22. 22.
    Forcina G, d’Ettorre G, Mastroianni CM, et al.: Interleukin-15 modulates interferon-gamma and beta-chemokine production in patients with HIV infection: implications for immune-based therapy. Cytokine 2004, 25:283–290.PubMedCrossRefGoogle Scholar
  23. 23.
    Biancotto A, Grivel JC, Iglehart SJ, et al.: Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1. Blood 2007, 109:4272–2479.PubMedCrossRefGoogle Scholar
  24. 24.
    Mueller YM, Bojczuk PM, Halstead ES, et al.: IL-15 enhances survival and function of HIV-specific CD8+ T cells. Blood 2003, 101:1024–1029.PubMedCrossRefGoogle Scholar
  25. 25.
    Mastroianni CM, d’Ettorre G, Forcina G, et al.: Interleukin-15 enhances neutrophil functional activity in patients with human immunodeficiency virus infection. Blood 2000, 96:1979–1984.PubMedGoogle Scholar
  26. 26.
    Stopak KS, Chiu YL, Kropp J, et al.: Distinct patterns of cytokine regulation of APOBEC3G expression and activity in primary lymphocytes, macrophages, and dendritic cells. J Biol Chem 2007, 282:3539–3546.PubMedCrossRefGoogle Scholar
  27. 27.
    Bettelli E, Korn T, Kuchroo VK: Th17: the third member of the effector T cell trilogy. Curr Opin Immunol 2007, [Epub ahead of print].Google Scholar
  28. 28.
    Ye P, Rodriguez FH, Kanaly S, et al.: Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 2001, 194:519–527.PubMedCrossRefGoogle Scholar
  29. 29.
    Maek ANW, Buranapraditkun S, Klaewsongkram J, Ruxrungtham K: Increased interleukin-17 production both in helper T cell subset Th17 and CD4-negative T cells in human immunodeficiency virus infection. Viral Immunol 2007, 20:66–75.CrossRefGoogle Scholar
  30. 30.
    Bradney CP, Sempowski GD, Liao HX, et al.: Cytokines as adjuvants for the induction of anti-human immunodeficiency virus peptide immunoglobulin G (IgG) and IgA antibodies in serum and mucosal secretions after nasal immunization. J Virol 2002, 76:517–524.PubMedCrossRefGoogle Scholar
  31. 31.
    Billaut-Mulot O, Idziorek T, Loyens M, et al.: Modulation of cellular and humoral immune responses to a multiepitopic HIV-1 DNA vaccine by interleukin-18 DNA immunization/viral protein boost. Vaccine 2001, 19:2803–2811.PubMedCrossRefGoogle Scholar
  32. 32.
    Sailer CA, Pott GB, Dinarello CA, et al.: Whole-blood interleukin-18 level during early HIV-1 infection is associated with reduced CXCR4 coreceptor expression and interferon-gamma levels. J Infect Dis 2007, 195:734–738.PubMedCrossRefGoogle Scholar
  33. 33.
    Tornero C, Alberola J, Tamarit A, Navarro D: Effect of highly active anti-retroviral therapy and hepatitis C virus co-infection on serum levels of pro-inflammatory and immunoregulatory cytokines in human immunodeficiency virus-1-infected individuals. Clin Microbiol Infect 2006, 12:555–560.PubMedCrossRefGoogle Scholar
  34. 34.
    Wiercinska-Drapalo A, Jaroszewicz J, Flisiak R, Prokopowicz D: Plasma interleukin-18 is associated with viral load and disease progression in HIV-1-infected patients. Microbes Infect 2004, 6:1273–1277.PubMedCrossRefGoogle Scholar
  35. 35.
    Lindegaard B, Hansen AB, Pilegaard H, et al.: Adipose tissue expression of IL-18 and HIV-associated lipodystrophy. AIDS 2004, 18:1956–1958.PubMedCrossRefGoogle Scholar
  36. 36.
    Lindegaard B, Hansen AB, Gerstoft J, Pedersen BK: High plasma level of interleukin-18 in HIV-infected subjects with lipodystrophy. J Acquir Immune Defic Syndr 2004, 36:588–593.PubMedCrossRefGoogle Scholar
  37. 37.
    Falasca K, Manigrasso MR, Racciatti D, et al.: Associations between hypertriglyceridemia and serum ghrelin, adiponectin, and IL-18 levels in HIV-infected patients. Ann Clin Lab Sci 2006, 36:59–66.PubMedGoogle Scholar
  38. 38.
    von Giesen HJ, Jander S, Koller H, Arendt G: Serum and cerebrospinal fluid levels of interleukin-18 in human immunodeficiency virus type 1-associated central nervous system disease. J Neurovirol 2004, 10:383–386.CrossRefGoogle Scholar
  39. 39.
    Ahmad R, Sindhu ST, Toma E, et al.: Elevated levels of circulating interleukin-18 in human immunodeficiency virus-infected individuals: role of peripheral blood mononuclear cells and implications for AIDS pathogenesis. J Virol 2002, 76:12448–12456.PubMedCrossRefGoogle Scholar
  40. 40.
    Ahmad R, Iannello A, Samarani S, et al.: Contribution of platelet activation to plasma IL-18 concentrations in HIV-infected AIDS patients. AIDS 2006, 20:1907–1909.PubMedCrossRefGoogle Scholar
  41. 41.
    Pugliese A, Vidotto V, Beltramo T, Torre D: Regulation of interleukin-18 by THP-1 monocytoid cells stimulated with HIV-1 and Nef viral protein. Eur Cytokine Netw 2005, 16:186–190.PubMedGoogle Scholar
  42. 42.
    Shapiro L, Puren AJ, Barton HA, et al.: Interleukin 18 stimulates HIV type 1 in monocytic cells. Proc Natl Acad Sci U S A 1998, 95:12550–12555.PubMedCrossRefGoogle Scholar
  43. 43.
    Torre D, Pugliese A, Speranza F, et al.: Role of interleukin-18 in human immunodeficiency virus type 1 infection. J Infect Dis 2002, 185:998–999.PubMedCrossRefGoogle Scholar
  44. 44.
    Choi HJ, Dinarello CA, Shapiro L: Interleukin-18 inhibits human immunodeficiency virus type 1 production in peripheral blood mononuclear cells. J Infect Dis 2001, 184:560–568.PubMedCrossRefGoogle Scholar
  45. 45.
    Sabat R, Wallace E, Endesfelder S, Wolk K: IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases. Expert Opin Ther Targets 2007, 11:601–612.PubMedCrossRefGoogle Scholar
  46. 46.
    Bettaccini AA, Baj A, Accolla RS, et al.: Proliferative activity of extracellular HIV-1 Tat protein in human epithelial cells: expression profile of pathogenetically relevant genes. BMC Microbiol 2005, 5:20.PubMedCrossRefGoogle Scholar
  47. 47.
    Brandt K, Singh PB, Bulfone-Paus S, Ruckert R: Interleukin-21: a new modulator of immunity, infection, and cancer. Cytokine Growth Factor Rev 2007, 18:223–232.PubMedCrossRefGoogle Scholar
  48. 48.
    Kastelein RA, Hunter CA, Cua DJ: Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 2007, 25:221–242.PubMedCrossRefGoogle Scholar
  49. 49.
    Lapenta C, Santini SM, Spada M, et al.: IFN-alpha-conditioned dendritic cells are highly efficient in inducing cross-priming CD8(+) T cells against exogenous viral antigens. Eur J Immunol 2006, 36:2046–2060.PubMedCrossRefGoogle Scholar
  50. 50.
    Fakruddin JM, Lempicki RA, Gorelick RJ, et al.: Noninfectious papilloma virus-like particles inhibit HIV-1 replication: implications for immune control of HIV-1 infection by IL-27. Blood 2007, 109:1841–1849.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  • Massimo Alfano
  • Andrea Crotti
  • Elisa Vicenzi
  • Guido Poli
    • 1
    Email author
  1. 1.P2/P3 LaboratoriesDIBITMilanoItaly

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