Current Hepatitis Reports

, Volume 10, Issue 3, pp 186–195 | Cite as

Hepatitis C Virus and Innate Immunity: Taking a Fresh Look into an Old Issue



The innate immune response represents the first line of defense against hepatitis C virus (HCV) infection. The response is an early, coordinated effort orchestrated by host interferon (IFN) production, natural killer cell activation, and dendritic cell maturation, which, when effective, primes a successful adaptive immune response, leading to resolution of infection. Numerous mechanisms allow subversion of innate immunity, often establishing chronicity and resistance to conventional antiviral therapy. Recent groundbreaking studies examining viral evasion of host defenses and genetic host determinants of response to IFN have advanced our understanding of the innate immune response to HCV. This has provided the framework for individualized treatment approaches and the development of novel therapeutics aimed at restoring innate immune signaling during chronic infection. The objective of this report is to review advances in our understanding of HCV and host innate immune defenses, and to highlight their clinical translation.


Hepatitis C Virus Innate immunity Interferon NK cell Dendritic cell Genome wide association study Single nucleotide polymorphism IL-28B Interferon lambda Protease inhibitor 



J.S. Crippin received grant funding from Merck for a hepatitis C treatment trial, and has received payment for development of educational presentations for Genentech and Vertex; A. Seetharam reported no potential conflicts of interest relevant to this article.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Kim WR. The burden of hepatitis C in the United States. Hepatology. 2002;36(Suppl):S30–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Deuffic-Burban S, Poynard T, Sulkowski MS, Wong JB. Estimating the future health burden of chronic hepatitis C and human immunodeficiency virus infections in the United States. J Viral Hepat. 2007;14:107–15.PubMedCrossRefGoogle Scholar
  3. 3.
    Afdahl NH. The natural history of hepatitis C. Semin Liver Dis. 2004;24 Suppl 2:3–8.CrossRefGoogle Scholar
  4. 4.
    Lindenbach BD, Rice CM: Flaviridae: The viruses and their replication. In Fields virology. Edited by Knipe D. et. al. Philadelphia: Lippincott Williams and Wilkins; 2001:991–1041.Google Scholar
  5. 5.
    Rehermann B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Invest. 2009;119:1745–54.PubMedCrossRefGoogle Scholar
  6. 6.
    Georgel P, Schuster C, Zeisel MB. et. al.: Virus–host interactions in hepatitis C virus infection: implications for molecular pathogenesis and antiviral strategies. Trends Mol Med. 2010;16:277–86.PubMedCrossRefGoogle Scholar
  7. 7.
    Dustin LB, Rice CM. Flying under the radar: the immunobiology of Hepatitis C. Annu Rev Immunol. 2007;25:71–99.PubMedCrossRefGoogle Scholar
  8. 8.
    Taylor DR, Silberstein E. Innate immunity and hepatitis C virus: eluding the host cell defense. Front Biosci. 2009;14:4950–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Kawai T, Akira S. Toll-like receptor and RIG-1-like receptor signaling. Ann N Y Acad Sci. 2008;1143:1–20.PubMedCrossRefGoogle Scholar
  10. 10.
    •• Saito T, Owen DM, Jiang F, et. al.: Innate immunity induced by composition-dependent RIG-1 recognition of hepatitis C virus RNA. Nature 2008, 454:523–527. Authors identified the poly-uridine motif of the HCV genome 3′ nontranslated region (NTR) as the PAMP substrate of RIG-I, and show that this motif present in the genome of HCV is the chief feature of RIG-I recognition and immune triggering. PubMedCrossRefGoogle Scholar
  11. 11.
    Liu L, Botos I, Wang Y, et al. Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science. 2008;320:379–81.PubMedCrossRefGoogle Scholar
  12. 12.
    •• Poeck H, Bscheider M, Gross O, et. al: Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nat Immunol. 2010, 11(1):63–69. Authors identify the CARD9-Bcl-10 module as an essential component of the RIG-I-dependent proinflammatory response and identify RIG-I as a sensor able to activate intracellular machinery in response to certain RNA viruses, such as HCV. PubMedCrossRefGoogle Scholar
  13. 13.
    Lau D, Fish PM, Sinha M, et al. Interferon regulatory factor-3 activation, hepatic interferon-stimulated gene expression, and immune cell infiltration in hepatitis C virus patients. Hepatology. 2008;47:799–809.PubMedCrossRefGoogle Scholar
  14. 14.
    Hiscott J. Triggering the innate antiviral response through IRF-3 activation. J Biol Chem. 2007;282(26):15325–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Panne D, Maniatis T, Harrison SC. Crystal structure of ATF-2/c-Jun and IRF-3 bound to the interferon-beta enhancer. EMBO J. 2004;23(22):4384–93.PubMedCrossRefGoogle Scholar
  16. 16.
    Darnell J, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation to IFNs and other extracellular signaling proteins. Science. 1994;264:1415–21.PubMedCrossRefGoogle Scholar
  17. 17.
    Sen GC, Sarkar SN. The interferon-stimulated genes: targets of direct signaling by interferons, double-stranded RNA, and viruses. Curr Top Microbiol Immunol. 2007;316:233–50.PubMedCrossRefGoogle Scholar
  18. 18.
    • Raychoudhuri A, Shrivastava S, Steele R, et. al.: Hepatitis C virus infection impairs IRF-7 translocation and Alpha interferon synthesis in immortalized human hepatocytes. J Virol 2010, 84(21):10991–10998. The authors find that HCV infection enhances STAT1 expression but impairs nuclear translocation of IRF-7, leading to impairments in the IFN-α signaling pathway. PubMedCrossRefGoogle Scholar
  19. 19.
    Li K, Foy E, Ferreon JC, et al. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci U S A. 2005;102(8):2992–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Foy E, Li K, Wang C, et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003;300(5622):1145–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Lei Y, Moore CB, Liesman RM, et al. MAVS-mediated apoptosis and its inhibition by viral proteins. PLoS One. 2009;4(5):e5466 1–12.CrossRefGoogle Scholar
  22. 22.
    Otsuka M, Kato N, Moriyama M, et al. Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses. Hepatology. 2005;41(5):1004–12.PubMedCrossRefGoogle Scholar
  23. 23.
    Lin W, Kim SS, Yeung E, et al. Hepatitis C virus core protein blocks interferon signaling by interaction with the STAT1 SH2 domain. J Virol. 2006;80(18):9226–35.PubMedCrossRefGoogle Scholar
  24. 24.
    Bode JG, Ludwig S, Ehrhardt C, et al. IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. FASEB J. 2003;17(3):488–90.PubMedGoogle Scholar
  25. 25.
    Duong FH, Christen V, Filipowicz M, Heim MH. S-Adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signaling in vitro. Hepatology. 2006;43(4):796–806.PubMedCrossRefGoogle Scholar
  26. 26.
    • Garaigorta U, Chisari FV: Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation. Cell Host Microbe. 2009, 6(6):513–522. Authors show that HCV infection triggers phosphorylation and activation of the RNA-dependent protein kinase PKR, which inhibits eukaryotic translation initiation factor eIF2 α and attenuates ISG protein expression despite normal ISG mRNA induction. PubMedCrossRefGoogle Scholar
  27. 27.
    Abe T, Kaname Y, Hamamoto I, et al. Hepatitis C virus nonstructural protein 5A modulates the toll-like receptor-MyD88-dependent signaling pathway in macrophage cell lines. J Virol. 2007;81(17):8953–66.PubMedCrossRefGoogle Scholar
  28. 28.
    Polyak SJ, Khabar KS, Paschal DM, et al. Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J Virol. 2001;75(13):6095–106.PubMedCrossRefGoogle Scholar
  29. 29.
    Taylor DR, Shi ST, Romano PR, et al. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science. 1999;285(5424):107–10.PubMedCrossRefGoogle Scholar
  30. 30.
    Larkin J, Bost A, Glass JI, et al. Cytokine-activated natural killer cells exert direct killing of hepatoma cells harboring hepatitis C virus replicons. J Interferon Cytokine Res. 2006;26(12):854–65.PubMedCrossRefGoogle Scholar
  31. 31.
    Stegmann KA, Björkström NK, Veber H, et al. Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenetrology. 2010;138(5):1885–97.CrossRefGoogle Scholar
  32. 32.
    Pelletier S, Drouin C, Bédard N, et al. Increased degranulation of natural killer cells during acute HCV correlates with the magnitude of virus-specific T cell responses. J Hepatol. 2010;53(5):805–16.PubMedCrossRefGoogle Scholar
  33. 33.
    Rauch A, Gaudieri S, Thio C, Bochud PY. Host genetic determinants of spontaneous hepatitis C clearance. Pharmacogenomics. 2009;10:1819–37.PubMedCrossRefGoogle Scholar
  34. 34.
    Rauch A, Laird R, McKinnon E, et al. Influence of inhibitory killer immunoglobulin-like receptors and their HLA-C ligands on resolving hepatitis C infection. Tissue Antigens. 2007;69:237–40.PubMedCrossRefGoogle Scholar
  35. 35.
    Khakoo SI, Thio CL, Martin MP, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science. 2004;305(5685):872–4.PubMedCrossRefGoogle Scholar
  36. 36.
    • Ahlensteil G, Martin MP, Gao X, et. al.: Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses. J Clin. Invest. 2008, 118:1017–1026. Authors report evidence for differential NK cell responsiveness depending on KIR/HLA genotype with a model for influenza A infection. Google Scholar
  37. 37.
    Jinushi M, Takehara T, Tatsumi T, et al. Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol. 2004;173(10):6072–81.PubMedGoogle Scholar
  38. 38.
    Crotta S, Stilla A, Wack A, et al. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med. 2002;195(1):35–41.PubMedCrossRefGoogle Scholar
  39. 39.
    Godkin A, Jeanguet N, Thursz M, et al. Characterization of novel HLA-DR11-restricted HCV epitopes reveals both qualitative and quantitative differences in HCV-specific CD4+ T cell responses in chronically infected and non-viremic patients. Eur J Immunol. 2001;31(5):1438–46.PubMedCrossRefGoogle Scholar
  40. 40.
    De Maria A, Fogli M, Mazza S, et al. Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients. Eur J Immunol. 2007;37(2):445–55.PubMedCrossRefGoogle Scholar
  41. 41.
    Bode JG, Brenndorfer ED, Haussinger D. Hepatitis C virus (HCV) employs multiple strategies to subvert the host innate antiviral response Biol. Chem. 2008;389:1283–98.Google Scholar
  42. 42.
    Gorden KB, Gorski KS, Gibson SJ, et al. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol. 2005;174:1259–68.PubMedGoogle Scholar
  43. 43.
    Decalf J, Fernandes S, Longman R, et al. Plasmacytoid dendritic cells initiate a complex chemokine and cytokine network and are a viable drug target in chronic HCV patients. J Exp Med. 2007;204(10):2423–37.PubMedCrossRefGoogle Scholar
  44. 44.
    Yonkers NL, Rodriguez B, Milkovich KA, et al. TLR ligand-dependent activation of naive CD4 T cells by plasmacytoid dendritic cells is impaired in hepatitis C virus infection. J Immunol. 2007;178(7):4436–44.PubMedGoogle Scholar
  45. 45.
    Dolganiuc A, Chang S, Kodys K, et al. Hepatitis C virus (HCV) core protein-induced, monocytes mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol. 2006;177(10):6758–68.PubMedGoogle Scholar
  46. 46.
    Szabo G, Dolganiuc A. Hepatitis C and innate immunity: recent advances. Clin Liver Dis. 2008;12(3):675–92.PubMedCrossRefGoogle Scholar
  47. 47.
    Wertheimer AM, Bakke A, Rosen HR. Direct enumeration and functional assessment of circulating dendritic cells in patients with liver disease. Hepatology. 2004;40(2):335–45.PubMedCrossRefGoogle Scholar
  48. 48.
    Nattermann J, Zimmermann H, Iwan A, et al. Hepatitis C virus E2 and CD81 interaction may be associated with altered trafficking of dendritic cells in chronic hepatitis C. Hepatology. 2006;44(4):945–54.PubMedCrossRefGoogle Scholar
  49. 49.
    Dolganiuc A, Kodys K, Kopasz A, et al. Hepatitis C virus core and nonstructural protein 3 proteins induce pro- and anti-inflammatory cytokines and inhibit dendritic cell differentiation. J Immunol. 2003;170(11):5615–24.PubMedGoogle Scholar
  50. 50.
    Eisen-Vandervelde AL, Waggoner SN, Yao ZQ, et al. Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation. J Biol Chem. 2004;279(42):43479–86.PubMedCrossRefGoogle Scholar
  51. 51.
    Zhang LZ, Zhang TC, Pan FM, et al. Interleukin-10 gene polymorphisms in association with susceptibility to chronic hepatitis C virus infection: a meta-analysis study. Arch Virol. 2010;155(11):1839–42.PubMedCrossRefGoogle Scholar
  52. 52.
    Wang QC, Feng ZH, Nie QH, Zhou YX. DC-SIGN: binding receptors for hepatitis C virus. Chin Med J (Engl). 2004;117(9):1395–400.Google Scholar
  53. 53.
    Thompson A, Patel K, Tillman H, McHutchison JG. Directly acting antivirals for the treatment of patients with hepatitis C infection: a clinical development update addressing key future challenges. J Hepatol. 2009;50:184–94.PubMedCrossRefGoogle Scholar
  54. 54.
    Aronsohn A, Reau N. Long-term outcomes after treatment with interferon and ribavirin in HCV patients. J Clin Gastroenterol. 2009;43(7):661–71.PubMedCrossRefGoogle Scholar
  55. 55.
    Clark P, Thompson AJ, McHutchison JG. IL28B genomic-based treatment paradigms for patients with chronic hepatitis C infection: the future of personalized HCV therapies. Am J Gastroenterol. 2011;106:38–45.PubMedCrossRefGoogle Scholar
  56. 56.
    •• Suppiah V, Moldovan M, Ahlenstiel G, et al.: IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009, 41:1100–1104. A GWAS of sustained virological response SVR to PEG-IFN-α/RBV combination therapy in Australian individuals with genotype 1 chronic HCV. Authors report an association to SVR within the gene region encoding IL28B (rs8099917). PubMedCrossRefGoogle Scholar
  57. 57.
    Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment induced viral clearance. Nature. 2009;461:399–401.PubMedCrossRefGoogle Scholar
  59. 59.
    Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. 2010;138:1338–45.PubMedCrossRefGoogle Scholar
  60. 60.
    Li M, Liu X, Zhou Y, Su SB. Interferon-lambdas: the modulators of antivirus, antitumor, and immune responses. J Leukoc Biol. 2009;86:23–32.PubMedCrossRefGoogle Scholar
  61. 61.
    Tanaka Y, Nishida N, Sugiyama M, et al. Lambda Interferons and the single nucleotide polymorphisms: A milestone to tailor-made therapy for chronic Hepatitis C. Hepatol Reseearch. 2010;40:449–60.CrossRefGoogle Scholar
  62. 62.
    Ruiz-Extremera A, Munoz-Gamez J,Salmeron-Ruiz MA. et. al. Genetic variation in IL28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV infected children. Hepatology 2011,Epub ahead of print.Google Scholar
  63. 63.
    Thompson AJ, Muir AJ, Sulkowski MS, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010;139(1):120–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Flisiak R, Feinman SV, Jablkowski M, et al. The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatmentnaive hepatitis C patients. Hepatology. 2009;49:1460–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Lanford RE, Hildebrandt-Eriksen ES, Petri A, et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science. 2010;327:198–201.PubMedCrossRefGoogle Scholar
  66. 66.
    • Lemon SM, McKeating JA, Pietschmann T, et. al.: Development of novel therapies for hepatitis C. Antiviral Res. 2010, 86(1):79–92. This detailed review highlights findings from a recent session on novel targets for HCV therapy from the International Conference on Antiviral Research. PubMedCrossRefGoogle Scholar
  67. 67.
    •• McHutchison JG, Everson GT, Gordon SC, et. al.: Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009, 360(18):1827–1838. Randomized trial evaluating the efficacy of the peptidomimetic NS3/4A protease inhibitor in conjunction with standard of care for treatment-naïve chronic HCV genotype 1 infection, showing increased rates of SVR. PubMedCrossRefGoogle Scholar
  68. 68.
    Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360(18):1839–50.PubMedCrossRefGoogle Scholar
  69. 69.
    McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362(14):1292–303.PubMedCrossRefGoogle Scholar
  70. 70.
    Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;376(9742):705–16.PubMedCrossRefGoogle Scholar
  71. 71.
    Pawlotsky JM. The results of phase III clinical trials with telaprevir and boceprevir presented at the liver meeting 2010: a new standard of care for hepatitis C virus genotype 1 infection, but with issues still pending. Gastroenterology. 2011;140(3):746–54.PubMedCrossRefGoogle Scholar
  72. 72.
    Hewison M. Vitamin D and the Immune System: New Perspectives on an Old Theme. Endocrinology and Metabolism Clinics. 2010;39(2):365–79.PubMedCrossRefGoogle Scholar
  73. 73.
    Van Etten E, Decallonne B, Verlinden L, et al. Analogs of 1 alpha,25-dihydroxyvitamin D3 as pluripotent immunomodulators. J Cell Biochem. 2003;88:223–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Trinchieri G, Sher A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol. 2007;7(3):179–90.PubMedCrossRefGoogle Scholar
  75. 75.
    Petta S, Cammà C, Scazzone C, et al. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology. 2010;51(4):1158–67.PubMedCrossRefGoogle Scholar
  76. 76.
    Mouch SA, Fireman Z, Jarchovsky J et. al. Vitamin D Supplement improve SVR in Chronic Hepatitis C (Genotype 1) Naïve Patients treated with Peg Interferon and Ribavirin. Presented at EASL 45th Annual Meeting. Vienna, Austria; April 14–18, 2010.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Internal Medicine/Division of GastroenterologyWashington University School of MedicineSt. LouisUSA

Personalised recommendations