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Regulation of hepatic innate immunity by hepatitis C virus

Abstract

Hepatitis C virus (HCV) is a global public health problem involving chronic infection of the liver, which can cause liver disease and is linked with liver cancer. Viral innate immune evasion strategies and human genetic determinants underlie the transition of acute HCV infection to viral persistence and the support of chronic infection. Host genetic factors, such as sequence polymorphisms in IFNL3, a gene in the host interferon system, can influence both the outcome of the infection and the response to antiviral therapy. Recent insights into how HCV regulates innate immune signaling within the liver reveal a complex interaction of patient genetic background with viral and host factors of innate immune triggering and control that imparts the outcome of HCV infection and immunity.

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Figure 1: Sensing of HCV can activate innate antiviral defenses through IFN induction in hepatocytes.

Marina Corral Spence

Figure 2: HCV control of IFN induction and immune evasion.

Marina Corral Spence

Figure 3: Factors that influence the host response to IFN therapy during HCV infection.

Marina Corral Spence

Figure 4: SNPs in the IFNL gene locus.
Figure 5: IFN induction by HCV in the liver.

Marina Corral Spence

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References

  1. Lavanchy, D. The global burden of hepatitis C. Liver Int. 29 (suppl. 1), 74–81 (2009).

    Article  PubMed  Google Scholar 

  2. Seeff, L.B. The history of the “natural history” of hepatitis C (1968–2009). Liver Int. 29 Suppl. 1, 89–99 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Soriano, V., Peters, M.G. & Zeuzem, S. New therapies for hepatitis C virus infection. Clin. Infect. Dis. 48, 313–320 (2009).

    Article  PubMed  Google Scholar 

  4. Hofmann, W.P. & Zeuzem, S. A new standard of care for the treatment of chronic HCV infection. Nat. Rev. Gastroenterol. Hepatol. 8, 257–264 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Sarrazin, C., Hezode, C., Zeuzem, S. & Pawlotsky, J.M. Antiviral strategies in hepatitis C virus infection. J. Hepatol. 56 Suppl. 1, S88–S100 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Suppiah, V. et al. IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy. Nat. Genet. 41, 1100–1104 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Tanaka, Y. et al. Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat. Genet. 41, 1105–1109 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Thomas, D.L. et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461, 798–801 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ge, D. et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399–401 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Rauch, A. et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 138, 1338–1345, 1345.e1–7 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. André, P., Perlemuter, G., Budkowska, A., Brechot, C. & Lotteau, V. Hepatitis C virus particles and lipoprotein metabolism. Semin. Liver Dis. 25, 93–104 (2005).

    Article  PubMed  Google Scholar 

  12. Bowen, D.G. & Walker, C.M. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 436, 946–952 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Su, A.I. et al. Genomic analysis of the host response to hepatitis C virus infection. Proc. Natl. Acad. Sci. USA 99, 15669–15674 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rehermann, B. Pathogenesis of chronic viral hepatitis: differential roles of T and natural killer cells Nat. Med. 19, 859–868 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Suthar, M.S. et al. IPS-1 is essential for the control of West Nile virus infection and immunity. PLoS Pathog. 6, e1000757 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Thimme, R., Binder, M. & Bartenschlager, R. Failure of innate and adaptive immune responses in controlling hepatitis C virus infection. FEMS Microbiol. Rev. 36, 663–683 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Kumar, A. et al. Deficient cytokine signaling in mouse embryo fibroblasts with a targeted deletion in the PKR gene: role of IRF-1 and NF-kappaB. EMBO J. 16, 406–416 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. McAllister, C.S. & Samuel, C.E. The RNA-activated protein kinase enhances the induction of interferon-beta and apoptosis mediated by cytoplasmic RNA sensors. J. Biol. Chem. 284, 1644–1651 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Loo, Y.M. et al. Viral and therapeutic control of IFN-β promoter stimulator 1 during hepatitis C virus infection. Proc. Natl. Acad. Sci. USA 103, 6001–6006 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Saito, T., Owen, D.M., Jiang, F., Marcotrigiano, J. & Gale, M. Jr. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454, 523–527 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Uzri, D. & Gehrke, L. Nucleotide sequences and modifications that determine RIG-I/RNA binding and signaling activities. J. Virol. 83, 4174–4184 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. You, S. & Rice, C.M. 3′ RNA elements in hepatitis C virus replication: kissing partners and long poly(U). J. Virol. 82, 184–195 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Saito, T. et al. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc. Natl. Acad. Sci. USA 104, 582–587 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Liu, H.M. et al. The mitochondrial targeting chaperone 14–3-3e regulates a RIG-I translocon that mediates membrane association and innate antiviral immunity. Cell Host Microbe 11, 528–537 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jiang, F. et al. Structural basis of RNA recognition and activation by innate immune receptor RIG-I. Nature 479, 423–427 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gack, M.U. et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I–mediated antiviral activity. Nature 446, 916–920 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Loo, Y.M. & Gale, M. Jr. Immune signaling by RIG-I–like receptors. Immunity 34, 680–692 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang, N. et al. Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells. J. Virol. 83, 9824–9834 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Seki, E. & Brenner, D.A. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 48, 322–335 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Takeuchi, O. & Akira, S. Innate immunity to virus infection. Immunol. Rev. 227, 75–86 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Salaun, B., Coste, I., Rissoan, M.C., Lebecque, S.J. & Renno, T. TLR3 can directly trigger apoptosis in human cancer cells. J. Immunol. 176, 4894–4901 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Li, K. et al. Activation of chemokine and inflammatory cytokine response in hepatitis C virus-infected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates. Hepatology 55, 666–675 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Dansako, H. et al. Class A scavenger receptor 1 (MSR1) restricts hepatitis C virus replication by mediating Toll-like receptor 3 recognition of viral RNAs produced in neighboring cells. PLoS Pathog. 9, e1003345 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dreux, M., Gastaminza, P., Wieland, S.F. & Chisari, F.V. The autophagy machinery is required to initiate hepatitis C virus replication. Proc. Natl. Acad. Sci. USA 106, 14046–14051 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Arnaud, N. et al. Hepatitis C virus reveals a novel early control in acute immune response. PLoS Pathog. 7, e1002289 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Arnaud, N. et al. Hepatitis C virus controls interferon production through PKR activation. PLoS ONE 5, e10575 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Garaigorta, U. & Chisari, F.V. Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation. Cell Host Microbe 6, 513–522 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Koev, G., Duncan, R.F. & Lai, M.M. Hepatitis C virus IRES-dependent translation is insensitive to an eIF2α-independent mechanism of inhibition by interferon in hepatocyte cell lines. Virology 297, 195–202 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Shimoike, T., McKenna, S.A., Lindhout, D.A. & Puglisi, J.D. Translational insensitivity to potent activation of PKR by HCV IRES RNA. Antiviral Res. 83, 228–237 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Schoggins, J.W. et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472, 481–485 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schoggins, J.W. & Rice, C.M. Interferon-stimulated genes and their antiviral effector functions. Curr. Opin. Virol. 1, 519–525 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Horner, S.M. & Gale, M. Jr. Intracellular innate immune cascades and interferon defenses that control hepatitis C virus. J. Interferon Cytokine Res. 29, 489–498 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Liu, L., Fisher, B.E., Thomas, D.L., Cox, A.L. & Ray, S.C. Spontaneous clearance of primary acute hepatitis C virus infection correlated with high initial viral RNA level and rapid HVR1 evolution. Hepatology 55, 1684–1691 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Morikawa, K. et al. Nonstructural protein 3–4A: the Swiss army knife of hepatitis C virus. J. Viral Hepat. 18, 305–315 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Brass, V. et al. Structural determinants for membrane association and dynamic organization of the hepatitis C virus NS3–4A complex. Proc. Natl. Acad. Sci. USA 105, 14545–14550 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Horner, S.M., Park, H.S. & Gale, M. Jr. Control of innate immune signaling and membrane targeting by the hepatitis C virus NS3/4A protease are governed by the NS3 helix α0. J. Virol. 86, 3112–3120 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Foy, E. et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300, 1145–1148 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Foy, E. et al. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid–inducible gene-I signaling. Proc. Natl. Acad. Sci. USA 102, 2986–2991 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Meylan, E. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Baril, M., Racine, M.E., Penin, F. & Lamarre, D. MAVS dimer is a crucial signaling component of innate immunity and the target of hepatitis C virus NS3/4A protease. J. Virol. 83, 1299–1311 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Li, X.D., Sun, L., Seth, R.B., Pineda, G. & Chen, Z.J. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc. Natl. Acad. Sci. USA 102, 17717–17722 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chen, Z. et al. GB virus B disrupts RIG-I signaling by NS3/4A-mediated cleavage of the adaptor protein MAVS. J. Virol. 81, 964–976 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Yang, Y. et al. Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor. Proc. Natl. Acad. Sci. USA 104, 7253–7258 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Iwasaki, Y. et al. Long-term persistent GBV-B Infection and development of a chronic and progressive hepatitis C–like disease in marmosets. Front. Microbiol. 2, 240 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Lin, R. et al. Dissociation of a MAVS/IPS-1/VISA/Cardif-IKKe molecular complex from the mitochondrial outer membrane by hepatitis C virus NS3–4A proteolytic cleavage. J. Virol. 80, 6072–6083 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Seth, R.B., Sun, L., Ea, C.K. & Chen, Z.J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kB and IRF 3. Cell 122, 669–682 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Dixit, E. et al. Peroxisomes are signaling platforms for antiviral innate immunity. Cell 141, 668–681 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Horner, S.M., Liu, H.M., Park, H.S., Briley, J. & Gale, M. Jr. Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus. Proc. Natl. Acad. Sci. USA 108, 14590–14595 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bellecave, P. et al. Cleavage of mitochondrial antiviral signaling protein in the liver of patients with chronic hepatitis C correlates with a reduced activation of the endogenous interferon system. Hepatology 51, 1127–1136 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Li, K. 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. USA 102, 2992–2997 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang, Z. et al. DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity 34, 866–878 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gale, M.J. Jr . et al. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 230, 217–227 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Taylor, D.R., Shi, S.T., Romano, P.R., Barber, G.N. & Lai, M.M. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science 285, 107–110 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Noguchi, T. et al. Effects of mutation in hepatitis C virus nonstructural protein 5A on interferon resistance mediated by inhibition of PKR kinase activity in mammalian cells. Microbiol. Immunol. 45, 829–840 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. de Veer, M.J. et al. Functional classification of interferon-stimulated genes identified using microarrays. J. Leukoc. Biol. 69, 912–920 (2001).

    CAS  PubMed  Google Scholar 

  66. Jaeckel, E. et al. Treatment of acute hepatitis C with interferon alfa-2b. N. Engl. J. Med. 345, 1452–1457 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Simmonds, P. Genetic diversity and evolution of hepatitis C virus—15 years on. J. Gen. Virol. 85, 3173–3188 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Pang, P.S., Planet, P.J. & Glenn, J.S. The evolution of the major hepatitis C genotypes correlates with clinical response to interferon therapy. PLoS ONE 4, e6579 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sarasin-Filipowicz, M. et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc. Natl. Acad. Sci. USA 105, 7034–7039 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Dill, M.T. et al. Interferon-induced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C. Gastroenterology 140, 1021–1031 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Chen, L. et al. Cell-type specific gene expression signature in liver underlies response to interferon therapy in chronic hepatitis C infection. Gastroenterology 138, 1123–1133.e1–3 (2010).

    Google Scholar 

  72. Donlin, M.J. et al. Pretreatment sequence diversity differences in the full-length hepatitis C virus open reading frame correlate with early response to therapy. J. Virol. 81, 8211–8224 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Metz, P. et al. Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication. Hepatology 56, 2082–2093 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Honda, M. et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology 139, 499–509 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Lau, D.T. et al. Innate immune tolerance and the role of Kupffer cells in differential responses to interferon therapy among patients with HCV genotype 1 infection. Gastroenterology 144, 402–413.e12 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Urban, T.J. et al. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology 52, 1888–1896 (2010).

    Article  CAS  PubMed  Google Scholar 

  77. Fukuhara, T. et al. Variants in IL28B in liver recipients and donors correlate with response to peg-interferon and ribavirin therapy for recurrent hepatitis C. Gastroenterology 139, 1577–1585, 1585.e1–3 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Langhans, B. et al. Interferon-l serum levels in hepatitis C. J. Hepatol. 54, 859–865 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. de Castellarnau, M. et al. Deciphering the interleukin 28B variants that better predict response to pegylated interferon-α and ribavirin therapy in HCV/HIV-1 coinfected patients. PLoS ONE 7, e31016 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. di Iulio, J. et al. Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance. Hepatology 53, 1446–1454 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Sugiyama, M., Tanaka, Y., Wakita, T., Nakanishi, M. & Mizokami, M. Genetic variation of the IL-28B promoter affecting gene expression. PLoS ONE 6, e26620 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Raglow, Z., Thoma-Perry, C., Gilroy, R. & Wan, Y.J. IL28B genotype and the expression of ISGs in normal liver. Liver Int. published online, http://dx.doi.org/10.1111/liv.12148 (24 March 2013).

  83. Naggie, S. et al. Dysregulation of innate immunity in hepatitis C virus genotype 1 IL28B-unfavorable genotype patients: impaired viral kinetics and therapeutic response. Hepatology 56, 444–454 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Prokunina-Olsson, L. et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat. Genet. 45, 164–171 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bibert, S. et al. IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction. J. Exp. Med. published online, http://dx.doi.org/10.1084/jem.20130012 (27 May 2013).

  86. Kelly, C., Klenerman, P. & Barnes, E. Interferon ls: the next cytokine storm. Gut 60, 1284–1293 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Sommereyns, C., Paul, S., Staeheli, P. & Michiels, T. IFN-lambda (IFN-l) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog. 4, e1000017 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Marcello, T. et al. Interferons α and l inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology 131, 1887–1898 (2006).

    Article  PubMed  Google Scholar 

  89. Makowska, Z., Duong, F.H., Trincucci, G., Tough, D.F. & Heim, M.H. Interferon-beta and interferon-l signaling is not affected by interferon-induced refractoriness to interferon-α in vivo. Hepatology 53, 1154–1163 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Pagliaccetti, N.E. et al. Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication. J. Biol. Chem. 283, 30079–30089 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. McGilvray, I. et al. Hepatic cell-type specific gene expression better predicts HCV treatment outcome than IL28B genotype. Gastroenterology 142, 1122–1131.e1 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Negash, A.A. et al. IL-1β production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. PLoS Pathog. 9, e1003330 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Asahina, Y. et al. Association of gene expression involving innate immunity and genetic variation in interleukin 28B with antiviral response. Hepatology 55, 20–29 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. Takahashi, K. et al. Plasmacytoid dendritic cells sense hepatitis C virus–infected cells, produce interferon, and inhibit infection. Proc. Natl. Acad. Sci. USA 107, 7431–7436 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Lau, D.T. et al. Interferon regulatory factor-3 activation, hepatic interferon-stimulated gene expression, and immune cell infiltration in hepatitis C virus patients. Hepatology 47, 799–809 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Marukian, S. et al. Hepatitis C virus induces interferon-l and interferon-stimulated genes in primary liver cultures. Hepatology 54, 1913–1923 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Thomas, E. et al. HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons. Gastroenterology 142, 978–988 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Stone, A.E. et al. Hepatitis C virus pathogen associated molecular pattern (PAMP) triggers production of l-interferons by human plasmacytoid dendritic cells. PLoS Pathog. 9, e1003316 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Nishitsuji, H. et al. HCV infection induces inflammatory cytokines and chemokines mediated by the cross-talk between hepatocytes and stellate cells. J. Virol. published online, http://dx.doi.org/10.1128/JVI.00974-13 (15 May 2013).

  100. Lange, C.M. & Zeuzem, S. Perspectives and challenges of interferon-free therapy for chronic hepatitis C. J. Hepatol. 58, 583–592 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Sumpter, R. Jr . et al. Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J. Virol. 79, 2689–2699 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jiang, D. et al. Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus. J. Virol. 82, 1665–1678 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Kanazawa, N. et al. Regulation of hepatitis C virus replication by interferon regulatory factor 1. J. Virol. 78, 9713–9720 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gale, M. Jr . et al. Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol. Cell. Biol. 18, 5208–5218 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Itsui, Y. et al. Expressional screening of interferon-stimulated genes for antiviral activity against hepatitis C virus replication. J. Viral Hepat. 13, 690–700 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Pichlmair, A. et al. IFIT1 is an antiviral protein that recognizes 5′-triphosphate RNA. Nat. Immunol. 12, 624–630 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Raychoudhuri, A. et al. ISG56 and IFITM1 proteins inhibit hepatitis C virus replication. J. Virol. 85, 12881–12889 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wang, C. et al. α-interferon induces distinct translational control programs to suppress hepatitis C virus RNA replication. J. Virol. 77, 3898–3912 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Liu, X.Y., Chen, W., Wei, B., Shan, Y.F. & Wang, C. IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging MAVS and TBK1. J. Immunol. 187, 2559–2568 (2011).

    Article  CAS  PubMed  Google Scholar 

  110. Wilkins, C. et al. IFITM1 is a tight junction protein that inhibits hepatitis C virus entry. Hepatology 57, 461–469 (2013).

    Article  CAS  PubMed  Google Scholar 

  111. Huang, I.C. et al. Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus. PLoS Pathog. 7, e1001258 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Yao, L. et al. Identification of the IFITM3 gene as an inhibitor of hepatitis C viral translation in a stable STAT1 cell line. J. Viral Hepat. 18, e523–e529 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ishibashi, M., Wakita, T. & Esumi, M. 2′,5′-Oligoadenylate synthetase-like gene highly induced by hepatitis C virus infection in human liver is inhibitory to viral replication in vitro. Biochem. Biophys. Res. Commun. 392, 397–402 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Han, J.Q. & Barton, D.J. Activation and evasion of the antiviral 2′-5′ oligoadenylate synthetase/ribonuclease L pathway by hepatitis C virus mRNA. RNA 8, 512–525 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Helbig, K.J. et al. The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A. Hepatology 54, 1506–1517 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Helbig, K.J., Lau, D.T., Semendric, L., Harley, H.A. & Beard, M.R. Analysis of ISG expression in chronic hepatitis C identifies viperin as a potential antiviral effector. Hepatology 42, 702–710 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Gale laboratory members, A. McFarland and R. Savan for helpful discussions and comments on this manuscript. This work is supported by US National Institutes of Health grants AI060389, AI88778 and DA024563 (M.G.) and the Irvington Institute Fellowship Program of the Cancer Research Institute (S.M.H.).

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Correspondence to Michael Gale Jr.

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Horner, S., Gale, M. Regulation of hepatic innate immunity by hepatitis C virus. Nat Med 19, 879–888 (2013). https://doi.org/10.1038/nm.3253

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