Journal of Clinical Immunology

, Volume 25, Issue 2, pp 134–141 | Cite as

Reduced Type 1 and Type 2 Cytokines in Antiviral Memory T Helper Function Among Women Coinfected with HIV and HCV

  • Maria C. VillacresEmail author
  • Oana Literat
  • Marina Degiacomo
  • Wenbo Du
  • Corinna La Rosa
  • Don J. Diamond
  • Andrea Kovacs


Bias in cytokine responses has been proposed as a contributing mechanism to pathogenesis in persistent HIV or hepatitis C virus (HCV) infections. We investigated whether coinfection with HCV modifies the profile of antigen-specific cytokine secretion in women persistently infected with HIV compared to women with single HIV or HCV infection. The T helper response to HIV, HCV and cytomegalovirus (CMV) as a positive viral control was dominated by type 1 cytokines (interleukin- [IL] 2, interferon- [IFN] γ and tumor necrosis factor- [TNF] α), with IFN-γ as the most abundantly secreted. IL-4, IL-5 and IL-10 were low in healthy controls and patients. Robust CMV-specific responses contrasted with curtailed HCV-specific responses in HCV-infected women. The overall anti-viral profile was dominated by Th1 cytokines even in coinfected women but both type 1 and type 2 responses were reduced in HIV-infected women and more extensively in women with HCV/HIV coinfection.


T helper cells cytokines infectious diseases hepatitis C virus HIV 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL: Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357, 1986Google Scholar
  2. 2.
    Altfeld M, Addo MM, Kreuzer KA, Rockstroh JK, Dumoulin FL, Schliefer K, et al.: TH1 to TH2 shift of cytokines in peripheral blood of HIV-infected patients is detectable by reverse transcriptase polymerase chain reaction but not by enzyme-linked immunosorbent assay under nonstimulated conditions. J Acquir Immune Defic Syndr 23:287–294, 2000Google Scholar
  3. 3.
    Oxenius A, Price DA, Easterbrook PJ, O’Callaghan CA, Kelleher AD, Whelan JA, et al.: Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc Natl Acad Sci USA 97:3382–3387, 2000Google Scholar
  4. 4.
    Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, et al.: Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278:1447–1450, 1997Google Scholar
  5. 5.
    Kalams SA, Buchbinder SP, Rosenberg ES, Billingsley JM, Colbert DS, Jones NG, et al.: Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection. J Virol 73:6715–6720, 1999Google Scholar
  6. 6.
    Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, et al.: Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 191:1499–1512, 2000Google Scholar
  7. 7.
    Gerlach JT, Diepolder HM, Jung MC, Gruener NH, Schraut WW, Zachoval R, et al.: Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology 117:933–941, 1999Google Scholar
  8. 8.
    Botarelli P, Brunetto MR, Minutello MA, Calvo P, Unutmaz D, Weiner AJ, et al.: T-lymphocyte response to hepatitis C virus in different clinical courses of infection. Gastroenterology 104:580–587, 1993Google Scholar
  9. 9.
    Hoffmann RM, Diepolder HM, Zachoval R, Zwiebel FM, Jung MC, Scholz S, et al.: Mapping of immunodominant CD4+ T lymphocyte epitopes of hepatitis C virus antigens and their relevance during the course of chronic infection. Hepatology 21:632–638, 1995Google Scholar
  10. 10.
    McCune JM: The dynamics of CD4+ T-cell depletion in HIV disease. Nature 410:974–979, 2001Google Scholar
  11. 11.
    Pitcher CJ, Quittner C, Peterson DM, Connors M, Koup RA, Maino VC, et al.: HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat Med 5:518–525, 1999Google Scholar
  12. 12.
    Giorgi JV, Fahey JL, Smith DC, Hultin LE, Cheng HL, Mitsuyasu RT, et al.: Early effects of HIV on CD4 lymphocytes in vivo. J Immunol 138:3725–3730, 1987Google Scholar
  13. 13.
    Miedema F, Petit AJ, Terpstra FG, Schattenkerk JK, de Wolf F, Al BJ, et al.: Immunological abnormalities in human immunodeficiency virus (HIV)- infected asymptomatic homosexual men. HIV affects the immune system before CD4+ T helper cell depletion occurs. J. Clin. Invest 82:1908–1914, 1988Google Scholar
  14. 14.
    Clerici M, Stocks NI, Zajac RA, Boswell RN, Lucey DR, Via CS, Shearer GM: 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 84:1892–1899, 1989Google Scholar
  15. 15.
    Clerici M, Hakim FT, Venzon DJ, Blatt S, Hendrix CW, Wynn TA, Shearer GM: Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. J Clin Invest 91:759–765, 1993Google Scholar
  16. 16.
    Fan J, Bass HZ, Fahey JL: Elevated IFN-gamma and decreased IL-2 gene expression are associated with HIV infection. J Immunol 151:5031–5040, 1993Google Scholar
  17. 17.
    Graziosi C, Gantt KR, Vaccarezza M, Demarest JF, Daucher M, Saag MS, et al.: Kinetics of cytokine expression during primary human immunodeficiency virus type 1 infection. Proc Natl Acad Sci USA 93:4386–4391, 1996Google Scholar
  18. 18.
    Greub G, Ledergerber B, Battegay M, Grob P, Perrin L, Furrer H, et al., and the Swiss HIV Cohort Study: Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet 356:1800–1805, 2000Google Scholar
  19. 19.
    Daar ES, Lynn H, Donfield S, Gomperts E, O’Brien SJ, Hilgartner MW et al.: Hepatitis C virus load is associated with human immunodeficiency virus type 1 disease progression in hemophiliacs. J Infect Dis 183:589–595, 2001Google Scholar
  20. 20.
    Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, et al.: Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: A meta-analysis. Clin Infect Dis 33:562–569, 2001Google Scholar
  21. 21.
    Ragni MV, Belle SH: Impact of human immunodeficiency virus infection on progression to end-stage liver disease in individuals with hemophilia and hepatitis C virus infection. J Infect Dis 183:1112–1115, 2001Google Scholar
  22. 22.
    Soto B, Sanchez-Quijano A, Rodrigo L, del Olmo JA, Garcia-Bengoechea M, Hernandez-Quero J, et al.: Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis. J Hepatol 26:1–5, 1997Google Scholar
  23. 23.
    Lauer GM, Nguyen TN, Day CL, Robbins GK, Flynn T, McGowan K, et al.: Human immunodeficiency virus type 1-hepatitis C virus coinfection: intraindividual comparison of cellular immune responses against two persistent viruses. J Virol 76:2817–2826, 2002Google Scholar
  24. 24.
    Barkan SE, Melnick SL, Preston-Martin S, Weber K, Kalish LA, Miotti P, et al.: The women’s interagency HIV study. WIHS Collaborative Study Group. Epidemiology 9:117–25, 1998Google Scholar
  25. 25.
    Cook EB, Stahl JL, Lowe L, Chen R, Morgan E, Wilson J, et al.: Simultaneous measurement of six cytokines in a single sample of human tears using microparticle-based flow cytometry: allergics vs. non- allergics. J Immunol Methods 254:109–118, 2001Google Scholar
  26. 26.
    Oliver KG, Kettman JR, Fulton RJ: Multiplexed analysis of human cytokines by use of the FlowMetrix system. Clin Chem 44:2057–2060, 1998Google Scholar
  27. 27.
    Sester M, Sester U, Gartner B, Kubuschok B, Girndt M, Meyerhans A, et al.: Sustained high frequencies of specific CD4 T cells restricted to a single persistent virus. J Virol 76:3748–3755, 2002Google Scholar
  28. 28.
    Bitmansour AD, Waldrop SL, Pitcher CJ, Khatamzas E, Kern F, Maino VC, et al.: Clonotypic structure of the human CD4+ memory T cell response to cytomegalovirus. J Immunol 167:1151–1163, 2001Google Scholar
  29. 29.
    Alp NJ, Allport TD, van Zanten J, Rodgers B, Sissons JG, Borysiewicz LK: Fine specificity of cellular immune responses in humans to human cytomegalovirus immediate-early 1 protein. J Virol 65:4812–4820, 1991Google Scholar
  30. 30.
    Villacres MC, Lacey SF, La Rosa C, Krishnan R, Auge C, Longmate J, et al.: Human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy maintain activated CD8+ T cell subsets as a strong adaptive immune response to cytomegalovirus. J Infect Dis 184:256–267, 2001CrossRefPubMedGoogle Scholar
  31. 31.
    Weinberg A, Wohl DA, Barrett RJ, van der Horst C: Inconsistent reconstitution of cytomegalovirus-specific cell-mediated immunity in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy. J Infect Dis 184:707–712, 2001Google Scholar
  32. 32.
    Komanduri KV, Viswanathan MN, Wieder ED, Schmidt DK, Bredt BM, Jacobson MA, et al.: Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nat Med 4:953–956, 1998Google Scholar
  33. 33.
    Chang KM, Thimme R, Melpolder JJ, Oldach D, Pemberton J, Moorhead-Loudis J, et al.: Differential CD4(+) and CD8(+) T-cell responsiveness in hepatitis C virus infection. Hepatology 33:267–276, 2001Google Scholar
  34. 34.
    Zhu N, Ware CF, Lai MM: Hepatitis C virus core protein enhances FADD-mediated apoptosis and suppresses TRADD signaling of tumor necrosis factor receptor. Virology 283:178–187, 2001Google Scholar
  35. 35.
    Zhu N, Khoshnan A, Schneider R, Matsumoto M, Dennert G, Ware C et al.: Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. J Virol 72:3691–3697, 1998PubMedGoogle Scholar
  36. 36.
    Laskus T, Radkowski M, Piasek A, Nowicki M, Horban A, Cianciara J et al.: Hepatitis C virus in lymphoid cells of patients coinfected with human immunodeficiency virus type 1: Evidence of active replication in monocytes/macrophages and lymphocytes. J Infect Dis 181:442–448, 2000Google Scholar
  37. 37.
    Laskus T, Radkowski M, Wang LF, Vargas H, Rakela J: The presence of active hepatitis C virus replication in lymphoid tissue in patients coinfected with human immunodeficiency virus type 1. J Infect Dis 178:1189–1192, 1998Google Scholar
  38. 38.
    Sansonno D, Iacobelli AR, Cornacchiulo V, Iodice G, Dammacco F: Detection of hepatitis C virus (HCV) proteins by immunofluorescence and HCV RNA genomic sequences by non-isotopic in situ hybridization in bone marrow and peripheral blood mononuclear cells of chronically HCV- infected patients. Clin Exp Immunol 103:414–421, 1996Google Scholar
  39. 39.
    Watson MW, Jaksic A, Price P, Cheng W, McInerney M, French MA et al.: Interferon-gamma Response by Peripheral Blood Mononuclear Cells to Hepatitis C Virus Core Antigen Is Reduced in Patients with Liver Fibrosis. J Infect Dis 188:1533–1536, 2003Google Scholar
  40. 40.
    Anthony DD, Post AB, Valdez H, Peterson DL, Murphy M, Heeger PS: ELISPOT analysis of hepatitis C virus protein-specific IFN-gamma-producing peripheral blood lymphocytes in infected humans with and without cirrhosis. Clin Immunol 99:232–240, 2001Google Scholar
  41. 41.
    Valdez H, Anthony D, Farukhi F, Patki A, Salkowitz J, Heeger P et al.: Immune responses to hepatitis C and non-heoatitis C antigens in hepatitis C virus infected and HIV-1 coinfected patients. AIDS 14:2239–2246, 2000Google Scholar
  42. 42.
    Gallimore A, Glithero A, Godkin A, Tissot AC, Pluckthun A, Elliott T, et al.: Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J Exp Med 187:1383–1393, 1998Google Scholar
  43. 43.
    Oxenius A, Zinkernagel RM, Hengartner H: Comparison of activation versus induction of unresponsiveness of virus- specific CD4+ and CD8+ T cells upon acute versus persistent viral infection. Immunity 9:449–457, 1998Google Scholar
  44. 44.
    Fuchs D, Forsman A, Hagberg L, Larsson M, Norkrans G, Reibnegger G et al.: Immune activation and decreased tryptophan in patients with HIV-1 infection. J Interferon Res 10(6):599–560 1990Google Scholar
  45. 45.
    Fallarino F, Grohmann U, Vacca C, Orabona C, Spreca A, Fioretti MC et al.: T cell apoptosis by kynurenines. Avd Exp Med Biol 527:183–190, 2003Google Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Maria C. Villacres
    • 1
    • 3
    Email author
  • Oana Literat
    • 1
  • Marina Degiacomo
    • 1
  • Wenbo Du
    • 1
  • Corinna La Rosa
    • 2
  • Don J. Diamond
    • 2
  • Andrea Kovacs
    • 1
  1. 1.Maternal, Child and Adolescent Center for Infectious Diseases and Virology, Keck School of MedicineUniversity of Southern CaliforniaLos Angeles
  2. 2.Laboratory of Vaccine ResearchBeckman Research Institute of the City of HopeDuarte
  3. 3.Department of Pediatrics, Keck School of MedicineUniversity of Southern CaliforniaLos Angeles

Personalised recommendations