Skip to main content

Advertisement

SpringerLink
Log in

Innate immune responses in hepatitis C virus infection

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Hepatitis C virus (HCV) is a major causative agent of chronic hepatitis and hepatocellular carcinoma worldwide and thus poses a significant public health threat. A hallmark of HCV infection is the extraordinary ability of the virus to persist in a majority of infected people. Innate immune responses represent the front line of defense of the human body against HCV immediately after infection. They also play a crucial role in orchestrating subsequent HCV-specific adaptive immunity that is pivotal for viral clearance. Accumulating evidence suggests that the host has evolved multifaceted innate immune mechanisms to sense HCV infection and elicit defense responses, while HCV has developed elaborate strategies to circumvent many of these. Defining the interplay of HCV with host innate immunity reveals mechanistic insights into hepatitis C pathogenesis and informs approaches to therapy. In this review, we summarize recent advances in understanding innate immune responses to HCV infection, focusing on induction and effector mechanisms of the interferon antiviral response as well as the evasion strategies of HCV.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Abe T, Kaname Y, Hamamoto I, Tsuda Y, Wen X, Taguwa S, Moriishi K, Takeuchi O, Kawai T, Kanto T, Hayashi N, Akira S, Matsuura Y (2007) Hepatitis C virus nonstructural protein 5A modulates the Toll-like receptor-MyD88-dependent signaling pathway in macrophage cell lines. J Virol 81:8953–8966

    Article  PubMed  CAS  Google Scholar 

  2. Ait-Goughoulte M, Kanda T, Meyer K, Ryerse JS, Ray RB, Ray R (2008) Hepatitis C virus genotype 1a growth and induction of autophagy. J Virol 82:2241–2249

    Article  PubMed  CAS  Google Scholar 

  3. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738

    Article  PubMed  CAS  Google Scholar 

  4. Aly HH, Watashi K, Hijikata M, Kaneko H, Takada Y, Egawa H, Uemoto S, Shimotohno K (2007) Serum-derived hepatitis C virus infectivity in interferon regulatory factor-7-suppressed human primary hepatocytes. J Hepatol 46:26–36

    Article  PubMed  CAS  Google Scholar 

  5. Arnaud N, Dabo S, Maillard P, Budkowska A, Kalliampakou KI, Mavromara P, Garcin D, Hugon J, Gatignol A, Akazawa D, Wakita T, Meurs EF (2010) Hepatitis C virus controls interferon production through PKR activation. PLoS One 5:e10575

    Article  PubMed  CAS  Google Scholar 

  6. Arnaud N, Dabo S, Akazawa D, Fukasawa M, Shinkai-Ouchi F, Hugon J, Wakita T, Meurs EF (2011) Hepatitis C virus reveals a novel early control in acute immune response. PLoS Pathog 7:e1002289

    Article  PubMed  CAS  Google Scholar 

  7. Barry G, Breakwell L, Fragkoudis R, Attarzadeh-Yazdi G, Rodriguez-Andres J, Kohl A, Fazakerley JK (2009) PKR acts early in infection to suppress Semliki Forest virus production and strongly enhances the type I interferon response. J Gen Virol 90:1382–1391

    Article  PubMed  CAS  Google Scholar 

  8. Bellecave P, Sarasin-Filipowicz M, Donze O, Kennel A, Gouttenoire J, Meylan E, Terracciano L, Tschopp J, Sarrazin C, Berg T, Moradpour D, Heim MH (2010) 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

    Article  PubMed  CAS  Google Scholar 

  9. Berzsenyi MD, Roberts SK, Preiss S, Woollard DJ, Beard MR, Skinner NA, Bowden DS, Visvanathan K (2011) Hepatic TLR2 & TLR4 expression correlates with hepatic inflammation and TNF-alpha in HCV & HCV/HIV infection. J Viral Hepat 18:852–860

    Article  PubMed  CAS  Google Scholar 

  10. Bigger CB, Brasky KM, Lanford RE (2001) DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J Virol 75:7059–7066

    Article  PubMed  CAS  Google Scholar 

  11. Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L, Moradpour D, Blum HE, Alonzi T, Tripodi M, La Monica N, Heim MH (2003) Expression of hepatitis c virus proteins inhibits interferon alpha signaling in the liver of transgenic mice. Gastroenterology 124:1465–1475

    Article  PubMed  CAS  Google Scholar 

  12. Bode JG, Ludwig S, Ehrhardt C, Albrecht U, Erhardt A, Schaper F, Heinrich PC, Haussinger D (2003) IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. FASEB J 17:488–490

    PubMed  CAS  Google Scholar 

  13. Bode JG, Brenndorfer ED, Haussinger D (2007) Subversion of innate host antiviral strategies by the hepatitis C virus. Arch Biochem Biophys 462:254–265

    Article  PubMed  CAS  Google Scholar 

  14. Borden EC, Sen GC, Uze G, Silverman RH, Ransohoff RM, Foster GR, Stark GR (2007) Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov 6:975–990

    Article  PubMed  CAS  Google Scholar 

  15. Botos I, Liu L, Wang Y, Segal DM, Davies DR (2009) The Toll-like receptor 3:dsRNA signaling complex. Biochim Biophys Acta 1789:667–674

    Article  PubMed  CAS  Google Scholar 

  16. Bowen DG, Walker CM (2005) Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 436:946–952

    Article  PubMed  CAS  Google Scholar 

  17. Branch AD, Stump DD, Gutierrez JA, Eng F, Walewski JL (2005) The hepatitis C virus alternate reading frame (ARF) and its family of novel products: the alternate reading frame protein/F-protein, the double-frameshift protein, and others. Semin Liver Dis 25:105–117

    Article  PubMed  CAS  Google Scholar 

  18. Breiman A, Grandvaux N, Lin R, Ottone C, Akira S, Yoneyama M, Fujita T, Hiscott J, Meurs EF (2005) Inhibition of RIG-I-dependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKKepsilon. J Virol 79:3969–3978

    Article  PubMed  CAS  Google Scholar 

  19. Carpentier PA, Williams BR, Miller SD (2007) Distinct roles of protein kinase R and Toll-like receptor 3 in the activation of astrocytes by viral stimuli. Glia 55:239–252

    Article  PubMed  Google Scholar 

  20. Chang KS, Cai Z, Zhang C, Sen GC, Williams BR, Luo G (2006) Replication of hepatitis C virus (HCV) RNA in mouse embryonic fibroblasts: protein kinase R (PKR)-dependent and PKR-independent mechanisms for controlling HCV RNA replication and mediating interferon activities. J Virol 80:7364–7374

    Article  PubMed  CAS  Google Scholar 

  21. Chang JH, Kato N, Muroyama R, Taniguchi H, Guleng B, Dharel N, Shao RX, Tateishi K, Jazag A, Kawabe T, Omata M (2010) Double-stranded RNA-activated protein kinase inhibits hepatitis C virus replication but may be not essential in interferon treatment. Liver Int 30:311–318

    Article  PubMed  CAS  Google Scholar 

  22. Chen L, Borozan I, Feld J, Sun J, Tannis LL, Coltescu C, Heathcote J, Edwards AM, McGilvray ID (2005) Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology 128:1437–1444

    Article  PubMed  CAS  Google Scholar 

  23. Chen Z, Benureau Y, Rijnbrand R, Yi J, Wang T, Warter L, Lanford RE, Weinman SA, Lemon SM, Martin A, Li K (2007) GB virus B disrupts RIG-I signaling by NS3/4A-mediated cleavage of the adaptor protein MAVS. J Virol 81:964–976

    Article  PubMed  CAS  Google Scholar 

  24. Chen L, Li S, McGilvray I (2011) The ISG15/USP18 ubiquitin-like pathway (ISGylation system) in hepatitis C virus infection and resistance to interferon therapy. Int J Biochem Cell Biol 43:1427–1431

    Article  PubMed  CAS  Google Scholar 

  25. Cheng G, Zhong J, Chisari FV (2006) Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms. Proc Natl Acad Sci USA 103:8499–8504

    Article  PubMed  CAS  Google Scholar 

  26. Christen V, Treves S, Duong FH, Heim MH (2007) Activation of endoplasmic reticulum stress response by hepatitis viruses up-regulates protein phosphatase 2A. Hepatology 46:558–565

    Article  PubMed  CAS  Google Scholar 

  27. Coccia EM, Severa M, Giacomini E, Monneron D, Remoli ME, Julkunen I, Cella M, Lande R, Uze G (2004) Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells. Eur J Immunol 34:796–805

    Article  PubMed  CAS  Google Scholar 

  28. Daffis S, Samuel MA, Suthar MS, Gale M Jr, Diamond MS (2008) Toll-like receptor 3 has a protective role against West Nile virus infection. J Virol 82:10349–10358

    Article  PubMed  CAS  Google Scholar 

  29. Dansako H, Ikeda M, Kato N (2007) Limited suppression of the interferon-beta production by hepatitis C virus serine protease in cultured human hepatocytes. FEBS J 274:4161–4176

    Article  PubMed  CAS  Google Scholar 

  30. de Lucas S, Bartolome J, Carreno V (2005) Hepatitis C virus core protein down-regulates transcription of interferon-induced antiviral genes. J Infect Dis 191:93–99

    Article  PubMed  Google Scholar 

  31. Degols G, Eldin P, Mechti N (2007) ISG20, an actor of the innate immune response. Biochimie 89:831–835

    Article  PubMed  CAS  Google Scholar 

  32. Dixit E, Boulant S, Zhang Y, Lee AS, Odendall C, Shum B, Hacohen N, Chen ZJ, Whelan SP, Fransen M, Nibert ML, Superti-Furga G, Kagan JC (2010) Peroxisomes are signaling platforms for antiviral innate immunity. Cell 141:668–681

    Article  PubMed  CAS  Google Scholar 

  33. Dolganiuc A, Kodys K, Kopasz A, Marshall C, Do T, Romics L Jr, Mandrekar P, Zapp M, Szabo G (2003) Hepatitis C virus core and nonstructural protein 3 proteins induce pro- and anti-inflammatory cytokines and inhibit dendritic cell differentiation. J Immunol 170:5615–5624

    PubMed  CAS  Google Scholar 

  34. Dolganiuc A, Oak S, Kodys K, Golenbock DT, Finberg RW, Kurt-Jones E, Szabo G (2004) Hepatitis C core and nonstructural 3 proteins trigger Toll-like receptor 2-mediated pathways and inflammatory activation. Gastroenterology 127:1513–1524

    Article  PubMed  CAS  Google Scholar 

  35. Dreux M, Gastaminza P, Wieland SF, Chisari FV (2009) The autophagy machinery is required to initiate hepatitis C virus replication. Proc Natl Acad Sci USA 106:14046–14051

    Article  PubMed  CAS  Google Scholar 

  36. Duong FH, Filipowicz M, Tripodi M, La Monica N, Heim MH (2004) Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A. Gastroenterology 126:263–277

    Article  PubMed  CAS  Google Scholar 

  37. Duong FH, Christen V, Filipowicz M, Heim MH (2006) S-Adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signaling in vitro. Hepatology 43:796–806

    Article  PubMed  CAS  Google Scholar 

  38. Dustin LB, Rice CM (2007) Flying under the radar: the immunobiology of hepatitis C. Annu Rev Immunol 25:71–99

    Article  PubMed  CAS  Google Scholar 

  39. Egger D, Wolk B, Gosert R, Bianchi L, Blum HE, Moradpour D, Bienz K (2002) Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex. J Virol 76:5974–5984

    Article  PubMed  CAS  Google Scholar 

  40. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Izumi N (1996) Interferon sensitivity determining sequence of the hepatitis C virus genome. Hepatology 24:460

    Google Scholar 

  41. Ferraris P, Blanchard E, Roingeard P (2010) Ultrastructural and biochemical analyses of hepatitis C virus-associated host cell membranes. J Gen Virol 91:2230–2237

    Article  PubMed  CAS  Google Scholar 

  42. Ferreon JC, Ferreon AC, Li K, Lemon SM (2005) Molecular determinants of TRIF proteolysis mediated by the hepatitis C virus NS3/4A protease. J Biol Chem 280:20483–20492

    Article  PubMed  CAS  Google Scholar 

  43. Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, Gale M Jr (2003) Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300:1145–1148

    Article  PubMed  CAS  Google Scholar 

  44. Fredericksen BL, Keller BC, Fornek J, Katze MG, Gale M Jr (2008) Establishment and maintenance of the innate antiviral response to West Nile virus involves both RIG-I and MDA5 signaling through IPS-1. J Virol 82:609–616

    Article  PubMed  CAS  Google Scholar 

  45. Frese M, Schwarzle V, Barth K, Krieger N, Lohmann V, Mihm S, Haller O, Bartenschlager R (2002) Interferon-gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs. Hepatology 35:694–703

    Article  PubMed  CAS  Google Scholar 

  46. Funami K, Matsumoto M, Oshiumi H, Akazawa T, Yamamoto A, Seya T (2004) The cytoplasmic ‘linker region’ in Toll-like receptor 3 controls receptor localization and signaling. Int Immunol 16:1143–1154

    Article  PubMed  CAS  Google Scholar 

  47. Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, Takeuchi O, Akira S, Chen Z, Inoue S, Jung JU (2007) TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446:916–920

    Article  PubMed  CAS  Google Scholar 

  48. Gale MJ Jr, Korth MJ, Tang NM, Tan SL, Hopkins DA, Dever TE, Polyak SJ, Gretch DR, Katze MG (1997) 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

    Article  PubMed  CAS  Google Scholar 

  49. Gale M Jr, Blakely CM, Kwieciszewski B, Tan SL, Dossett M, Tang NM, Korth MJ, Polyak SJ, Gretch DR, Katze MG (1998) Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol Cell Biol 18:5208–5218

    PubMed  CAS  Google Scholar 

  50. Gao L, Aizaki H, He JW, Lai MM (2004) Interactions between viral nonstructural proteins and host protein hVAP-33 mediate the formation of hepatitis C virus RNA replication complex on lipid raft. J Virol 78:3480–3488

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  52. George CX, Gan Z, Liu Y, Samuel CE (2011) Adenosine deaminases acting on RNA, RNA editing, and interferon action. J Interferon Cytokine Res 31:99–117

    Article  PubMed  CAS  Google Scholar 

  53. Gilfoy FD, Mason PW (2007) West Nile virus-induced interferon production is mediated by the double-stranded RNA-dependent protein kinase PKR. J Virol 81:11148–11158

    Article  PubMed  CAS  Google Scholar 

  54. Gosert R, Egger D, Lohmann V, Bartenschlager R, Blum HE, Bienz K, Moradpour D (2003) Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons. J Virol 77:5487–5492

    Article  PubMed  CAS  Google Scholar 

  55. Guo J, Hui DJ, Merrick WC, Sen GC (2000) A new pathway of translational regulation mediated by eukaryotic initiation factor 3. EMBO J 19:6891–6899

    Article  PubMed  CAS  Google Scholar 

  56. Guo JT, Bichko VV, Seeger C (2001) Effect of alpha interferon on the hepatitis C virus replicon. J Virol 75:8516–8523

    Article  PubMed  CAS  Google Scholar 

  57. Han JQ, Barton DJ (2002) Activation and evasion of the antiviral 2′–5′ oligoadenylate synthetase/ribonuclease L pathway by hepatitis C virus mRNA. RNA 8:512–525

    Article  PubMed  CAS  Google Scholar 

  58. Hardarson HS, Baker JS, Yang Z, Purevjav E, Huang CH, Alexopoulou L, Li N, Flavell RA, Bowles NE, Vallejo JG (2007) Toll-like receptor 3 is an essential component of the innate stress response in virus-induced cardiac injury. Am J Physiol Heart Circ Physiol 292:H251–H258

    Article  PubMed  CAS  Google Scholar 

  59. He B (2006) Viruses, endoplasmic reticulum stress, and interferon responses. Cell Death Differ 13:393–403

    Article  PubMed  CAS  Google Scholar 

  60. Helbig KJ, Lau DT, Semendric L, Harley HA, Beard MR (2005) Analysis of ISG expression in chronic hepatitis C identifies viperin as a potential antiviral effector. Hepatology 42:702–710

    Article  PubMed  CAS  Google Scholar 

  61. Helbig KJ, Ruszkiewicz A, Lanford RE, Berzsenyi MD, Harley HA, McColl SR, Beard MR (2009) Differential expression of the CXCR3 ligands in chronic hepatitis C virus (HCV) infection and their modulation by HCV in vitro. J Virol 83:836–846

    Article  PubMed  CAS  Google Scholar 

  62. Helbig KJ, Eyre NS, Yip E, Narayana S, Li K, Fiches G, McCartney EM, Jangra RK, Lemon SM, Beard MR (2011) The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A. Hepatology 54:1506–1517

    Article  PubMed  CAS  Google Scholar 

  63. Hinson ER, Cresswell P (2009) The antiviral protein, viperin, localizes to lipid droplets via its N-terminal amphipathic alpha-helix. Proc Natl Acad Sci USA 106:20452–20457

    Article  PubMed  CAS  Google Scholar 

  64. Honda M, Sakai A, Yamashita T, Nakamoto Y, Mizukoshi E, Sakai Y, Nakamura M, Shirasaki T, Horimoto K, Tanaka Y, Tokunaga K, Mizokami M, Kaneko S (2010) 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

    Article  PubMed  CAS  Google Scholar 

  65. Horner SM, Liu HM, Park HS, Briley J, Gale M Jr (2011) 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

    Article  PubMed  CAS  Google Scholar 

  66. Horsmans Y, Berg T, Desager JP, Mueller T, Schott E, Fletcher SP, Steffy KR, Bauman LA, Kerr BM, Averett DR (2005) Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection. Hepatology 42:724–731

    Article  PubMed  CAS  Google Scholar 

  67. Itsui Y, Sakamoto N, Kurosaki M, Kanazawa N, Tanabe Y, Koyama T, Takeda Y, Nakagawa M, Kakinuma S, Sekine Y, Maekawa S, Enomoto N, Watanabe M (2006) Expressional screening of interferon-stimulated genes for antiviral activity against hepatitis C virus replication. J Viral Hepat 13:690–700

    Article  PubMed  CAS  Google Scholar 

  68. Itsui Y, Sakamoto N, Kakinuma S, Nakagawa M, Sekine-Osajima Y, Tasaka-Fujita M, Nishimura-Sakurai Y, Suda G, Karakama Y, Mishima K, Yamamoto M, Watanabe T, Ueyama M, Funaoka Y, Azuma S, Watanabe M (2009) Antiviral effects of the interferon-induced protein guanylate binding protein 1 and its interaction with the hepatitis C virus NS5B protein. Hepatology 50:1727–1737

    Article  PubMed  CAS  Google Scholar 

  69. Jiang D, Guo H, Xu C, Chang J, Gu B, Wang L, Block TM, Guo JT (2008) Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus. J Virol 82:1665–1678

    Article  PubMed  CAS  Google Scholar 

  70. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P (2005) Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 309:1577–1581

    Article  PubMed  CAS  Google Scholar 

  71. Jouan L, Melancon P, Rodrigue-Gervais IG, Raymond VA, Selliah S, Boucher G, Bilodeau M, Grandvaux N, Lamarre D (2010) Distinct antiviral signaling pathways in primary human hepatocytes and their differential disruption by HCV NS3 protease. J Hepatol 52:167–175

    Article  PubMed  CAS  Google Scholar 

  72. Jounai N, Takeshita F, Kobiyama K, Sawano A, Miyawaki A, Xin KQ, Ishii KJ, Kawai T, Akira S, Suzuki K, Okuda K (2007) The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci USA 104:14050–14055

    Article  PubMed  CAS  Google Scholar 

  73. Kanazawa N, Kurosaki M, Sakamoto N, Enomoto N, Itsui Y, Yamashiro T, Tanabe Y, Maekawa S, Nakagawa M, Chen CH, Kakinuma S, Oshima S, Nakamura T, Kato T, Wakita T, Watanabe M (2004) Regulation of hepatitis C virus replication by interferon regulatory factor 1. J Virol 78:9713–9720

    Article  PubMed  CAS  Google Scholar 

  74. Kang JI, Kwon SN, Park SH, Kim YK, Choi SY, Kim JP, Ahn BY (2009) PKR protein kinase is activated by hepatitis C virus and inhibits viral replication through translational control. Virus Res 142:51–56

    Article  PubMed  CAS  Google Scholar 

  75. Kato T, Date T, Miyamoto M, Furusaka A, Tokushige K, Mizokami M, Wakita T (2003) Efficient replication of the genotype 2a hepatitis C virus subgenomic replicon. Gastroenterology 125:1808–1817

    Article  PubMed  CAS  Google Scholar 

  76. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105

    Article  PubMed  CAS  Google Scholar 

  77. Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T, Akira S (2008) Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 205:1601–1610

    Article  PubMed  CAS  Google Scholar 

  78. Kato H, Takahasi K, Fujita T (2011) RIG-I-like receptors: cytoplasmic sensors for non-self RNA. Immunol Rev 243:91–98

    Article  PubMed  Google Scholar 

  79. Kaukinen P, Sillanpaa M, Kotenko S, Lin R, Hiscott J, Melen K, Julkunen I (2006) Hepatitis C virus NS2 and NS3/4A proteins are potent inhibitors of host cell cytokine/chemokine gene expression. Virol J 3:66

    Article  PubMed  CAS  Google Scholar 

  80. Kawai T, Akira S (2008) Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci 1143:1–20

    Article  PubMed  CAS  Google Scholar 

  81. Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650

    Article  PubMed  CAS  Google Scholar 

  82. Kawasaki T, Kawai T, Akira S (2011) Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity. Immunol Rev 243:61–73

    Article  PubMed  CAS  Google Scholar 

  83. Ke PY, Chen SS (2011) Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro. J Clin Invest 121:37–56

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  85. Kim KA, Lin W, Tai AW, Shao RX, Weinberg E, De Sa Borges CB, Bhan AK, Zheng H, Kamegaya Y, Chung RT (2009) Hepatic SOCS3 expression is strongly associated with non-response to therapy and race in HCV and HCV/HIV infection. J Hepatol 50:705–711

    Article  PubMed  CAS  Google Scholar 

  86. Kolykhalov AA, Agapov EV, Blight KJ, Mihalik K, Feinstone SM, Rice CM (1997) Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science 277:570–574

    Article  PubMed  CAS  Google Scholar 

  87. Lan KH, Lan KL, Lee WP, Sheu ML, Chen MY, Lee YL, Yen SH, Chang FY, Lee SD (2007) HCV NS5A inhibits interferon-alpha signaling through suppression of STAT1 phosphorylation in hepatocyte-derived cell lines. J Hepatol 46:759–767

    Article  PubMed  CAS  Google Scholar 

  88. Lanford RE, Guerra B, Bigger CB, Lee H, Chavez D, Brasky KM (2007) Lack of response to exogenous interferon-alpha in the liver of chimpanzees chronically infected with hepatitis C virus. Hepatology 46:999–1008

    Article  PubMed  CAS  Google Scholar 

  89. Lau DT, Fish PM, Sinha M, Owen DM, Lemon SM, Gale M Jr (2008) Interferon regulatory factor-3 activation, hepatic interferon-stimulated gene expression, and immune cell infiltration in hepatitis C virus patients. Hepatology 47:799–809

    Article  PubMed  CAS  Google Scholar 

  90. Lee J, Wu CC, Lee KJ, Chuang TH, Katakura K, Liu YT, Chan M, Tawatao R, Chung M, Shen C, Cottam HB, Lai MM, Raz E, Carson DA (2006) Activation of anti-hepatitis C virus responses via Toll-like receptor 7. Proc Natl Acad Sci USA 103:1828–1833

    Article  PubMed  CAS  Google Scholar 

  91. Lemon SM (2010) Induction and evasion of innate antiviral responses by hepatitis C virus. J Biol Chem 285:22741–22747

    Article  PubMed  CAS  Google Scholar 

  92. Lemon SM, Walker C, Alter MJ, Yi M (2007) Hepatitis C viruses. In: Knipe D, Howley P, Griffin DE, Martin MA, Lamb RA et al (eds) Fields’ virology, 5th edn. Lippincott Williams and Wilkins, Philadelphia, pp 1253–1304

  93. Lemon SM, McKeating JA, Pietschmann T, Frick DN, Glenn JS, Tellinghuisen TL, Symons J, Furman PA (2010) Development of novel therapies for hepatitis C. Antiviral Res 86:79–92

    Article  PubMed  CAS  Google Scholar 

  94. Li K, Chen Z, Kato N, Gale M Jr, Lemon SM (2005) Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-beta production in hepatocytes. J Biol Chem 280:16739–16747

    Article  PubMed  CAS  Google Scholar 

  95. Li K, Foy E, Ferreon JC, Nakamura M, Ferreon AC, Ikeda M, Ray SC, Gale M Jr, Lemon SM (2005) 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

    Article  PubMed  CAS  Google Scholar 

  96. Li K, Li NL, Wei D, Pfeffer SR, Fan M, Pfeffer LM (2012) Activation of chemokine and inflammatory cytokine response in HCV-infected hepatocytes depends on TLR3 sensing of HCV dsRNA intermediates. Hepatology 55:666–675

    Google Scholar 

  97. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ (2005) 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

    Article  PubMed  CAS  Google Scholar 

  98. Liang Y, Shilagard T, Xiao SY, Snyder N, Lau D, Cicalese L, Weiss H, Vargas G, Lemon SM (2009) Visualizing hepatitis C virus infections in human liver by two-photon microscopy. Gastroenterology 137:1448–1458

    Article  PubMed  CAS  Google Scholar 

  99. Lin W, Kim SS, Yeung E, Kamegaya Y, Blackard JT, Kim KA, Holtzman MJ, Chung RT (2006) Hepatitis C virus core protein blocks interferon signaling by interaction with the STAT1 SH2 domain. J Virol 80:9226–9235

    Article  PubMed  CAS  Google Scholar 

  100. Lindenbach BD, Rice CM (2005) Unravelling hepatitis C virus replication from genome to function. Nature 436:933–938

    Article  PubMed  CAS  Google Scholar 

  101. Lindenbach BD, Evans MJ, Syder AJ, Wolk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, Rice CM (2005) Complete replication of hepatitis C virus in cell culture. Science 309:623–626

    Article  PubMed  CAS  Google Scholar 

  102. Liu YJ (2005) IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 23:275–306

    Article  PubMed  CAS  Google Scholar 

  103. Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110–113

    Article  PubMed  CAS  Google Scholar 

  104. Loo YM, Gale M Jr (2011) Immune signaling by RIG-I-like receptors. Immunity 34:680–692

    Article  PubMed  CAS  Google Scholar 

  105. Loo YM, Owen DM, Li K, Erickson AK, Johnson CL, Fish PM, Carney DS, Wang T, Ishida H, Yoneyama M, Fujita T, Saito T, Lee WM, Hagedorn CH, Lau DT, Weinman SA, Lemon SM, Gale M Jr (2006) Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci USA 103:6001–6006

    Article  PubMed  CAS  Google Scholar 

  106. Loo YM, Fornek J, Crochet N, Bajwa G, Perwitasari O, Martinez-Sobrido L, Akira S, Gill MA, Garcia-Sastre A, Katze MG, Gale M Jr (2008) Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol 82:335–345

    Article  PubMed  CAS  Google Scholar 

  107. Malakhova OA, Kim KI, Luo JK, Zou W, Kumar KG, Fuchs SY, Shuai K, Zhang DE (2006) UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity. EMBO J 25:2358–2367

    Article  PubMed  CAS  Google Scholar 

  108. Malathi K, Dong B, Gale M Jr, Silverman RH (2007) Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature 448:816–819

    Article  PubMed  CAS  Google Scholar 

  109. Marcello T, Grakoui A, Barba-Spaeth G, Machlin ES, Kotenko SV, MacDonald MR, Rice CM (2006) Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology 131:1887–1898

    Article  PubMed  Google Scholar 

  110. Martell M, Esteban JI, Quer J, Genesca J, Weiner A, Esteban R, Guardia J, Gomez J (1992) Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution. J Virol 66:3225–3229

    PubMed  CAS  Google Scholar 

  111. Marukian S, Jones CT, Andrus L, Evans MJ, Ritola KD, Charles ED, Rice CM, Dustin LB (2008) Cell culture-produced hepatitis C virus does not infect peripheral blood mononuclear cells. Hepatology 48:1843–1850

    Article  PubMed  Google Scholar 

  112. Marukian S, Andrus L, Sheahan TP, Jones CT, Charles ED, Ploss A, Rice CM, Dustin LB (2011) Hepatitis C virus induces interferon-lambda and interferon-stimulated genes in primary liver cultures. Hepatology 54:1913–1923

    Article  PubMed  CAS  Google Scholar 

  113. Matsumoto M, Oshiumi H, Seya T (2011) Antiviral responses induced by the TLR3 pathway. Rev Med Virol 21:67–77

    Article  CAS  Google Scholar 

  114. Mattijssen S, Pruijn GJ (2012) Viperin, a key player in the antiviral response. Microbes Infect 14:419–426

    Google Scholar 

  115. Melen K, Fagerlund R, Nyqvist M, Keskinen P, Julkunen I (2004) Expression of hepatitis C virus core protein inhibits interferon-induced nuclear import of STATs. J Med Virol 73:536–547

    Article  PubMed  CAS  Google Scholar 

  116. Mengshol JA, Golden-Mason L, Rosen HR (2007) Mechanisms of disease: HCV-induced liver injury. Nat Clin Pract Gastroenterol Hepatol 4:622–634

    Article  PubMed  CAS  Google Scholar 

  117. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167–1172

    Article  PubMed  CAS  Google Scholar 

  118. Moradpour D, Penin F, Rice CM (2007) Replication of hepatitis C virus. Nat Rev Microbiol 5:453–463

    Article  PubMed  CAS  Google Scholar 

  119. Nguyen LH, Espert L, Mechti N, Wilson DM 3rd (2001) The human interferon- and estrogen-regulated ISG20/HEM45 gene product degrades single-stranded RNA and DNA in vitro. Biochemistry 40:7174–7179

    Article  PubMed  CAS  Google Scholar 

  120. Onoguchi K, Yoneyama M, Takemura A, Akira S, Taniguchi T, Namiki H, Fujita T (2007) Viral infections activate types I and III interferon genes through a common mechanism. J Biol Chem 282:7576–7581

    Article  PubMed  CAS  Google Scholar 

  121. Oshiumi H, Okamoto M, Fujii K, Kawanishi T, Matsumoto M, Koike S, Seya T (2011) The TLR3/TICAM-1 pathway is mandatory for innate immune responses to poliovirus infection. J Immunol 187:5320–5327

    Article  PubMed  CAS  Google Scholar 

  122. Osterlund PI, Pietila TE, Veckman V, Kotenko SV, Julkunen I (2007) IFN regulatory factor family members differentially regulate the expression of type III IFN (IFN-lambda) genes. J Immunol 179:3434–3442

    PubMed  Google Scholar 

  123. Otsuka M, Kato N, Moriyama M, Taniguchi H, Wang Y, Dharel N, Kawabe T, Omata M (2005) Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses. Hepatology 41:1004–1012

    Article  PubMed  CAS  Google Scholar 

  124. Pavio N, Taylor DR, Lai MM (2002) Detection of a novel unglycosylated form of hepatitis C virus E2 envelope protein that is located in the cytosol and interacts with PKR. J Virol 76:1265–1272

    Article  PubMed  CAS  Google Scholar 

  125. Pedersen IM, Cheng G, Wieland S, Volinia S, Croce CM, Chisari FV, David M (2007) Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449:919–922

    Article  PubMed  CAS  Google Scholar 

  126. Pietschmann T, Zayas M, Meuleman P, Long G, Appel N, Koutsoudakis G, Kallis S, Leroux-Roels G, Lohmann V, Bartenschlager R (2009) Production of infectious genotype 1b virus particles in cell culture and impairment by replication enhancing mutations. PLoS Pathog 5:e1000475

    Article  PubMed  CAS  Google Scholar 

  127. Pindel A, Sadler A (2011) The role of protein kinase R in the interferon response. J Interferon Cytokine Res 31:59–70

    Article  PubMed  CAS  Google Scholar 

  128. Polyak SJ, Khabar KS, Paschal DM, Ezelle HJ, Duverlie G, Barber GN, Levy DE, Mukaida N, Gretch DR (2001) Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J Virol 75:6095–6106

    Article  PubMed  CAS  Google Scholar 

  129. Polyak SJ, Khabar KS, Rezeiq M, Gretch DR (2001) Elevated levels of interleukin-8 in serum are associated with hepatitis C virus infection and resistance to interferon therapy. J Virol 75:6209–6211

    Article  PubMed  CAS  Google Scholar 

  130. Preiss S, Thompson A, Chen X, Rodgers S, Markovska V, Desmond P, Visvanathan K, Li K, Locarnini S, Revill P (2008) Characterization of the innate immune signalling pathways in hepatocyte cell lines. J Viral Hepat 15:888–900

    Article  PubMed  CAS  Google Scholar 

  131. Randall G, Chen L, Panis M, Fischer AK, Lindenbach BD, Sun J, Heathcote J, Rice CM, Edwards AM, McGilvray ID (2006) Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection. Gastroenterology 131:1584–1591

    Article  PubMed  CAS  Google Scholar 

  132. Randall G, Panis M, Cooper JD, Tellinghuisen TL, Sukhodolets KE, Pfeffer S, Landthaler M, Landgraf P, Kan S, Lindenbach BD, Chien M, Weir DB, Russo JJ, Ju J, Brownstein MJ, Sheridan R, Sander C, Zavolan M, Tuschl T, Rice CM (2007) Cellular cofactors affecting hepatitis C virus infection and replication. Proc Natl Acad Sci USA 104:12884–12889

    Article  PubMed  CAS  Google Scholar 

  133. Raychoudhuri A, Shrivastava S, Steele R, Kim H, Ray R, Ray RB (2011) ISG56 and IFITM1 proteins inhibit hepatitis C virus replication. J Virol 85:12881–12889

    Article  PubMed  CAS  Google Scholar 

  134. Rehermann B (2009) Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Invest 119:1745–1754

    Article  PubMed  CAS  Google Scholar 

  135. Riordan SM, Skinner NA, Kurtovic J, Locarnini S, McIver CJ, Williams R, Visvanathan K (2006) Toll-like receptor expression in chronic hepatitis C: correlation with pro-inflammatory cytokine levels and liver injury. Inflamm Res 55:279–285

    Article  PubMed  CAS  Google Scholar 

  136. Robek MD, Boyd BS, Chisari FV (2005) Lambda interferon inhibits hepatitis B and C virus replication. J Virol 79:3851–3854

    Article  PubMed  CAS  Google Scholar 

  137. Rosen HR (2003) Hepatitis C pathogenesis: mechanisms of viral clearance and liver injury. Liver Transpl 9:S35–S43

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  139. Sarasin-Filipowicz M, Oakeley EJ, Duong FH, Christen V, Terracciano L, Filipowicz W, Heim MH (2008) Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci USA 105:7034–7039

    Article  PubMed  CAS  Google Scholar 

  140. Sarasin-Filipowicz M, Wang X, Yan M, Duong FH, Poli V, Hilton DJ, Zhang DE, Heim MH (2009) Alpha interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18/UBP43. Mol Cell Biol 29:4841–4851

    Article  PubMed  CAS  Google Scholar 

  141. Satoh T, Kato H, Kumagai Y, Yoneyama M, Sato S, Matsushita K, Tsujimura T, Fujita T, Akira S, Takeuchi O (2010) LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc Natl Acad Sci USA 107:1512–1517

    Article  PubMed  CAS  Google Scholar 

  142. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472:481–485

    Article  PubMed  CAS  Google Scholar 

  143. Schulz O, Pichlmair A, Rehwinkel J, Rogers NC, Scheuner D, Kato H, Takeuchi O, Akira S, Kaufman RJ, Reis e Sousa C (2010) Protein kinase R contributes to immunity against specific viruses by regulating interferon mRNA integrity. Cell Host Microbe 7:354–361

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  145. Sen GC (2001) Viruses and interferons. Annu Rev Microbiol 55:255–281

    Article  PubMed  CAS  Google Scholar 

  146. Servant MJ, Tenoever B, Lin R (2002) Overlapping and distinct mechanisms regulating IRF-3 and IRF-7 function. J Interferon Cytokine Res 22:49–58

    Article  PubMed  CAS  Google Scholar 

  147. Seth RB, Sun L, Ea CK, Chen ZJ (2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF3. Cell 122:669–682

    Article  PubMed  CAS  Google Scholar 

  148. Shimakami T, Yamane D, Jangra RK, Kempf BJ, Spaniel C, Barton DJ, Lemon SM (2012) Stabilization of hepatitis C RNA by an Ago2-miR-122 complex. Proc Natl Acad Sci U S A 109:941–946

    Google Scholar 

  149. Shimoike T, McKenna SA, Lindhout DA, Puglisi JD (2009) Translational insensitivity to potent activation of PKR by HCV IRES RNA. Antiviral Res 83:228–237

    Article  PubMed  CAS  Google Scholar 

  150. Silverman RH (2007) Viral encounters with 2′,5′-oligoadenylate synthetase and RNase L during the interferon antiviral response. J Virol 81:12720–12729

    Article  PubMed  CAS  Google Scholar 

  151. Sir D, Chen WL, Choi J, Wakita T, Yen TS, Ou JH (2008) Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology 48:1054–1061

    Article  PubMed  CAS  Google Scholar 

  152. Siren J, Pirhonen J, Julkunen I, Matikainen S (2005) IFN-alpha regulates TLR-dependent gene expression of IFN-alpha, IFN-beta, IL-28, and IL-29. J Immunol 174:1932–1937

    PubMed  CAS  Google Scholar 

  153. Smith KR, Suppiah V, O’Connor K, Berg T, Weltman M, Abate ML, Spengler U, Bassendine M, Matthews G, Irving WL, Powell E, Riordan S, Ahlenstiel G, Stewart GJ, Bahlo M, George J, Booth DR (2011) Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort. Genome Med 3:57

    Article  PubMed  CAS  Google Scholar 

  154. Stiffler JD, Nguyen M, Sohn JA, Liu C, Kaplan D, Seeger C (2009) Focal distribution of hepatitis C virus RNA in infected livers. PLoS One 4:e6661

    Article  PubMed  CAS  Google Scholar 

  155. Su AI, Pezacki JP, Wodicka L, Brideau AD, Supekova L, Thimme R, Wieland S, Bukh J, Purcell RH, Schultz PG, Chisari FV (2002) Genomic analysis of the host response to hepatitis C virus infection. Proc Natl Acad Sci USA 99:15669–15674

    Article  PubMed  CAS  Google Scholar 

  156. Sumpter R Jr, Loo YM, Foy E, Li K, Yoneyama M, Fujita T, Lemon SM, Gale M Jr (2005) Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J Virol 79:2689–2699

    Article  PubMed  CAS  Google Scholar 

  157. Syed GH, Amako Y, Siddiqui A (2010) Hepatitis C virus hijacks host lipid metabolism. Trends Endocrinol Metab 21:33–40

    Article  PubMed  CAS  Google Scholar 

  158. Taguchi T, Nagano-Fujii M, Akutsu M, Kadoya H, Ohgimoto S, Ishido S, Hotta H (2004) Hepatitis C virus NS5A protein interacts with 2′,5′-oligoadenylate synthetase and inhibits antiviral activity of IFN in an IFN sensitivity-determining region-independent manner. J Gen Virol 85:959–969

    Article  PubMed  CAS  Google Scholar 

  159. Takahashi K, Asabe S, Wieland S, Garaigorta U, Gastaminza P, Isogawa M, Chisari FV (2010) Plasmacytoid dendritic cells sense hepatitis C virus-infected cells, produce interferon, and inhibit infection. Proc Natl Acad Sci USA 107:7431–7436

    Article  PubMed  CAS  Google Scholar 

  160. Tamura T, Yanai H, Savitsky D, Taniguchi T (2008) The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol 26:535–584

    Article  PubMed  CAS  Google Scholar 

  161. Tanida I, Fukasawa M, Ueno T, Kominami E, Wakita T, Hanada K (2009) Knockdown of autophagy-related gene decreases the production of infectious hepatitis C virus particles. Autophagy 5:937–945

    Article  PubMed  CAS  Google Scholar 

  162. Targett-Adams P, Boulant S, McLauchlan J (2008) Visualization of double-stranded RNA in cells supporting hepatitis C virus RNA replication. J Virol 82:2182–2195

    Article  PubMed  CAS  Google Scholar 

  163. Tasaka M, Sakamoto N, Itakura Y, Nakagawa M, Itsui Y, Sekine-Osajima Y, Nishimura-Sakurai Y, Chen CH, Yoneyama M, Fujita T, Wakita T, Maekawa S, Enomoto N, Watanabe M (2007) Hepatitis C virus non-structural proteins responsible for suppression of the RIG-I/Cardif-induced interferon response. J Gen Virol 88:3323–3333

    Article  PubMed  CAS  Google Scholar 

  164. Taura M, Eguma A, Suico MA, Shuto T, Koga T, Komatsu K, Komune T, Sato T, Saya H, Li JD, Kai H (2008) p53 regulates Toll-like receptor 3 expression and function in human epithelial cell lines. Mol Cell Biol 28:6557–6567

    Article  PubMed  CAS  Google Scholar 

  165. Taylor DR, Shi ST, Romano PR, Barber GN, Lai MM (1999) Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science 285:107–110

    Article  PubMed  CAS  Google Scholar 

  166. Taylor DR, Puig M, Darnell ME, Mihalik K, Feinstone SM (2005) New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1. J Virol 79:6291–6298

    Article  PubMed  CAS  Google Scholar 

  167. Urban TJ, Thompson AJ, Bradrick SS, Fellay J, Schuppan D, Cronin KD, Hong L, McKenzie A, Patel K, Shianna KV, McHutchison JG, Goldstein DB, Afdhal N (2010) IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology 52:1888–1896

    Article  PubMed  CAS  Google Scholar 

  168. Uze G, Monneron D (2007) IL-28 and IL-29: newcomers to the interferon family. Biochimie 89:729–734

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  170. Venkataraman T, Valdes M, Elsby R, Kakuta S, Caceres G, Saijo S, Iwakura Y, Barber GN (2007) Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses. J Immunol 178:6444–6455

    PubMed  CAS  Google Scholar 

  171. Vestal DJ, Jeyaratnam JA (2011) The guanylate-binding proteins: emerging insights into the biochemical properties and functions of this family of large interferon-induced guanosine triphosphatase. J Interferon Cytokine Res 31:89–97

    Article  PubMed  CAS  Google Scholar 

  172. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Krausslich HG, Mizokami M, Bartenschlager R, Liang TJ (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11:791–796

    Article  PubMed  CAS  Google Scholar 

  173. Wald O, Weiss ID, Galun E, Peled A (2007) Chemokines in hepatitis C virus infection: pathogenesis, prognosis and therapeutics. Cytokine 39:50–62

    Article  PubMed  CAS  Google Scholar 

  174. Wang C, Pflugheber J, Sumpter R Jr, Sodora DL, Hui D, Sen GC, Gale M Jr (2003) Alpha interferon induces distinct translational control programs to suppress hepatitis C virus RNA replication. J Virol 77:3898–3912

    Article  PubMed  CAS  Google Scholar 

  175. Wang N, Liang Y, Devaraj S, Wang J, Lemon SM, Li K (2009) Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells. J Virol 83:9824–9834

    Article  PubMed  CAS  Google Scholar 

  176. Wang S, Wu X, Pan T, Song W, Wang Y, Zhang F, Yuan Z (2012) Viperin inhibits hepatitis C virus replication by interfering with binding of NS5A to host protein hVAP-33. J Gen Virol 93:83–92

    Article  PubMed  CAS  Google Scholar 

  177. Weber F, Wagner V, Rasmussen SB, Hartmann R, Paludan SR (2006) Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses. J Virol 80:5059–5064

    Article  PubMed  CAS  Google Scholar 

  178. Yang Y, Liang Y, Qu L, Chen Z, Yi M, Li K, Lemon SM (2007) Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor. Proc Natl Acad Sci USA 104:7253–7258

    Article  PubMed  CAS  Google Scholar 

  179. Yao L, Dong H, Zhu H, Nelson D, Liu C, Lambiase L, Li X (2011) 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

    Article  PubMed  CAS  Google Scholar 

  180. Yi M, Villanueva RA, Thomas DL, Wakita T, Lemon SM (2006) Production of infectious genotype 1a hepatitis C virus (Hutchinson strain) in cultured human hepatoma cells. Proc Natl Acad Sci USA 103:2310–2315

    Article  PubMed  CAS  Google Scholar 

  181. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, Foy E, Loo YM, Gale M Jr, Akira S, Yonehara S, Kato A, Fujita T (2005) Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol 175:2851–2858

    PubMed  CAS  Google Scholar 

  182. Zeremski M, Petrovic LM, Talal AH (2007) The role of chemokines as inflammatory mediators in chronic hepatitis C virus infection. J Viral Hepat 14:675–687

    PubMed  CAS  Google Scholar 

  183. Zhang YL, Guo YJ, Bin L, Sun SH (2009) Hepatitis C virus single-stranded RNA induces innate immunity via Toll-like receptor 7. J Hepatol 51:29–38

    Article  PubMed  CAS  Google Scholar 

  184. Zhong J, Gastaminza P, Cheng G, Kapadia S, Kato T, Burton DR, Wieland SF, Uprichard SL, Wakita T, Chisari FV (2005) Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci USA 102:9294–9299

    Article  PubMed  CAS  Google Scholar 

  185. Zhou Z, Wang N, Woodson SE, Dong Q, Wang J, Liang Y, Rijnbrand R, Wei L, Nichols JE, Guo JT, Holbrook MR, Lemon SM, Li K (2011) Antiviral activities of ISG20 in positive-strand RNA virus infections. Virology 409:175–188

    Article  PubMed  CAS  Google Scholar 

  186. Zhu H, Liu C (2003) Interleukin-1 inhibits hepatitis C virus subgenomic RNA replication by activation of extracellular regulated kinase pathway. J Virol 77:5493–5498

    Article  PubMed  CAS  Google Scholar 

  187. Zhu H, Butera M, Nelson DR, Liu C (2005) Novel type I interferon IL-28A suppresses hepatitis C viral RNA replication. Virol J 2:80

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge Zongdi Feng for expert review of this manuscript. Work in the authors’ laboratories was supported by grants from the National Institutes of Health: AI-069285, AI-095690, AI-040035, and DA-018054. The authors apologize to colleagues whose contributions could not be cited because of space constraints.

Author information

Authors and Affiliations

  1. Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA

    Kui Li

  2. Division of Infectious Diseases, Department of Medicine, Inflammatory Diseases Institute, and the Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7292, USA

    Stanley M. Lemon

Authors
  1. Kui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stanley M. Lemon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stanley M. Lemon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, K., Lemon, S.M. Innate immune responses in hepatitis C virus infection. Semin Immunopathol 35, 53–72 (2013). https://doi.org/10.1007/s00281-012-0332-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-012-0332-x

Keywords

Search

Navigation