Interferon-Induced Effector Proteins and Hepatitis C Virus Replication

  • Michael Frese
  • Eva Dazert


Hepatitis C virus (HCV) is a small, enveloped RNA virus that is often capable of establishing a persistent infection, which may lead to chronic liver disease, cirrhosis, hepatocellular carcinoma, and eventually death. For more than 20 years, hepatitis C patients have been treated with interferon-alpha (IFN-α). Current treatment usually consists of polyethylene glycol-conjugated IFN-α that is combined with ribavirin, but even the most advanced IFN-based therapies are still ineffective in eliminating the virus from a large proportion of individuals. Therefore, a better understanding of the IFN-induced innate immune response is urgently needed. By using selectable self-replicating RNAs (replicons) and, more recently, recombinant full-length genomes, many groups have tried to elucidate the mechanism(s) by which IFNs inhibit HCV replication. This chapter attempts to summarize the current state of knowledge in this interesting field of HCV research.


Herpes Simplex Virus Type West Nile Virus Internal Ribosome Entry Site Hepatitis Delta Virus Thogoto Virus 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abraham, N., Stojdl, D.F., Duncan, P.I., Methot, N., Ishii, T., Dube, M., Vanderhyden, B.C., Atkins, H.L., Gray, D.A., McBurney, M.W., Koromilas, A.E., Brown, E.G., Sonenberg, N., Bell, J.C. (1999). Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR. Journal of Biological Chemistry, 274: 5953–5962.PubMedGoogle Scholar
  2. Adler, H., Beland, J.L., Del-Pan, N.C., Kobzik, L., Brewer, J.P., Martin, T.R., Rimm, I.J. (1997). Suppression of herpes simplex virus type 1 (HSV-1)-induced pneumonia in mice by inhibition of inducible nitric oxide synthase (iNOS, NOS2). Journal of Experimental Medicine, 185: 1533–1540.PubMedGoogle Scholar
  3. Akaike, T., Noguchi, Y., Ijiri, S., Setoguchi, K., Suga, M., Zheng, Y.M., Dietzschold, B., Maeda, H. (1996). Pathogenesis of influenza virus-induced pneumonia: involvement of both nitric oxide and oxygen radicals. Proceedings of the National Academy of Sciences of the United States of America, 93: 2448–2453.Google Scholar
  4. Akerstrom, S., Mousavi-Jazi, M., Klingstrom, J., Leijon, M., Lundkvist, A., Mirazimi, A. (2005). Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. Journal of Virology, 79: 1966–1969.PubMedGoogle Scholar
  5. Ali, S., Pellerin, C., Lamarre, D., Kukolj, G. (2004). Hepatitis C virus subgenomic replicons in the human embryonic kidney 293 cell line. Journal of Virology, 78: 491–501.PubMedGoogle Scholar
  6. Balachandran, S., Roberts, P.C., Brown, L.E., Truong, H., Pattnaik, A.K., Archer, D.R., Barber, G.N. (2000). Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity, 13: 129–141.PubMedGoogle Scholar
  7. Bartenschlager, R., Frese, M., Pietschmann, T. (2004). Novel insights into hepatitis C virus replication and persistence. Advances in Virus Research, 63: 71–180.PubMedGoogle Scholar
  8. Baczko, K., Lampe, J., Liebert, U.G., Brinckmann, U., ter Meulen, V., Pardowitz, I., Budka, H., Cosby, S.L., Isserte, S., Rima, B.K. (1993). Clonal expansion of hypermutated measles virus in an SSPE brain. Virology, 197: 188–195.PubMedGoogle Scholar
  9. Bigger, C.B., Brasky, K.M., Lanford, R.E. (2001). DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. Journal of Virology, 75: 7059–7066.PubMedGoogle Scholar
  10. Blight, K.J., Rice, C.M. (1997). Secondary structure determination of the conserved 98-base sequence at the 3 terminus of hepatitis C virus genome RNA. Journal of Virology, 71: 7345–7352.PubMedGoogle Scholar
  11. Blight, K.J., Kolykhalov, A.A., Rice, C.M. (2000). Efficient initiation of HCV RNA replication in cell culture. Science, 290: 1972–1974.PubMedGoogle Scholar
  12. Bodaghi, B., Goureau, O., Zipeto, D., Laurent, L., Virelizier, J.-L., Michelson, S. (1999). Role of IFN-induced indoleamine 2,3 dioxygenase and inducible nitric oxide synthase in the replication of human cytomegalovirus in retinal pigment epithelial cells. Journal of Immunology, 162: 957–964.Google Scholar
  13. Brillet, R., Penin, F., Hezode, C., Chouteau, P., Dhumeaux, D., Pawlotsky, J.M. (2007). The nonstructural 5A protein of hepatitis C virus genotype 1b does not contain an interferon sensitivity-determining region. Journal of Infectious Diseases, 195: 432–441.PubMedGoogle Scholar
  14. Carlin, J.M., Ozaki, Y., Byrne, G.I., Brown, R.R., Borden, E.C. (1989). Interferons and indoleamine 2,3-dioxygenase: role in antimicrobial and antitumor effects. Experientia, 45: 535–541.PubMedGoogle Scholar
  15. Carr, D.J., Wuest, T., Tomanek, L., Silverman, R.H., Williams, B.R. (2006). The lack of RNA-dependent protein kinase enhances susceptibility of mice to genital herpes simplex virus type 2 infection. Immunology, 118: 520–526.PubMedGoogle Scholar
  16. Casey, J.L. (2006). RNA editing in hepatitis delta virus. Current Topics in Microbiology and Immunology, 307: 67–89.PubMedGoogle Scholar
  17. Cattaneo, R., Schmid, A., Eschle, D., Baczko, K., ter Meulen, V., Billeter, M.A. (1988). Biased hypermutation and other genetic changes in defective measles viruses in human brain infections. Cell, 55: 255–265.PubMedGoogle Scholar
  18. Cattaneo, R., Schmid, A., Spielhofer, P., Kaelin, K., Baczko, K., ter Meulen, V., Pardowitz, J., Flanagan, S., Rima, B.K., Udem, S.A., Billeter, B.A. (1989). Mutated and hypermutated genes of persistent measles viruses which caused lethal human brain diseases. Virology, 173: 415–425.PubMedGoogle Scholar
  19. Chang, F.L., Chen, P.J., Tu, S.J., Wang, C.J., Chen, D.S. (1991). The large form of hepatitis delta antigen is crucial for assembly of hepatitis delta virus. Proceedings of the National Academy of Sciences of the United States of America, 88: 8490–8494.PubMedGoogle Scholar
  20. Chang, K.S., Cai, Z., Zhang, C., Sen, G.C., Williams, B.R., 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. Journal of Virology, 80: 7364–7374.PubMedGoogle Scholar
  21. Chebath, J., Benech, P., Revel, M., Vigneron, M. (1987). Constitutive expression of (2-5) oligo A synthetase confers resistance to picornavirus infection. Nature, 330: 587–588.PubMedGoogle Scholar
  22. Cheney, I.W., Lai, V.C., Zhong, W., Brodhag, T., Dempsey, S., Lim, C., Hong, Z, Lau, J.Y., Tam, R.C. (2002). Comparative analysis of anti-hepatitis C virus activity and gene expression mediated by alpha, beta, and gamma interferons. Journal of Virology, 76: 11148–11154.PubMedGoogle Scholar
  23. Chieux, V., Hober, D., Harvey, J., Lion, G., Lucidarme, D., Forzy, G., Duhamel, M., Cousin, J., Ducoulombier, H., Wattre, P. (1998). The MxA protein levels in whole blood lysates of patients with various viral infections. Journal of Virological Methods, 70: 183–191.PubMedGoogle Scholar
  24. Colonna, M., Krug, A., Cella, M. (2002). Interferon-producing cells: on the front line in immune responses against pathogens. Current Opinion in Immunology, 14: 373–379.PubMedGoogle Scholar
  25. Donnelly, R.P., Sheikh, F., Kotenko, S.V., Dickensheets, H. (2004). The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain. Journal of Leukocyte Biology, 76: 314–321.PubMedGoogle Scholar
  26. Doyle, S.E., Schreckhise, H., Khuu-Duong, K., Henderson, K., Rosler, R., Storey, H., Yao, L., Liu, H., Barahmandpour, F., Sivakumar, P., Chan, C., Birks, C., Foster, D., Clegg, C.H., Wietzke-Braun, P., Mihm, S., Klucher, K.M. (2006). Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes. Hepatology, 44: 896–906.PubMedGoogle Scholar
  27. Enomoto, N., Sakuma, I., Asahina, Y., Kurosaki, M., Murakami, T., Yamamoto, C., Izumi, N., Marumo, F., Sato, C. (1995). Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region. Journal of Clinical Investigation, 96: 224–230.PubMedGoogle Scholar
  28. Enomoto, N., Sakuma, I., Asahina, Y., Kurosaki, M., Murakami, T., Yamamoto, C., Ogura, Y., Izumi, N., Marumo, F., Sato, C. (1996). Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. New England Journal of Medicine, 334: 77–81.PubMedGoogle Scholar
  29. Floyd-Smith, G., Slattery, E., Lengyel, P. (1981). Interferon action: RNA cleavage pattern of a (2-5)oligoadenylate-dependent endonuclease. Science, 212: 1030–1032.PubMedGoogle Scholar
  30. Foy, E., Li, K., Wang, C., Sumpter, R., Jr., Ikeda, M., Lemon, S.M., Gale, M., Jr. (2003). Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science, 300: 1145–1148.PubMedGoogle Scholar
  31. Frese, M., Kochs, G., Meier-Dieter, U., Siebler, J., Haller, O. (1995). Human MxA protein inhibits tick-borne Thogoto virus but not Dhori virus. Journal of Virology, 69: 3904–3909.PubMedGoogle Scholar
  32. Frese, M., Pietschmann, T., Moradpour, D., Haller, O., Bartenschlager, R. (2001). Interferon-alpha inhibits hepatitis C virus subgenomic RNA replication by an MxA-independent pathway. Journal of General of Virology, 82: 723–733.Google Scholar
  33. Frese, M., Schwärzle, 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.PubMedGoogle Scholar
  34. Frese, M., Barth, K., Kaul, A., Lohmann, V., Schwärzle, V., Bartenschlager, R. (2003). Hepatitis C virus RNA replication is resistant to tumour necrosis factor-alpha. Journal of General of Virology, 84: 1253–1259.Google Scholar
  35. Friebe, P., Boudet, J., Simorre, J.P., Bartenschlager, R. (2005). Kissing-loop interaction in the 3 end of the hepatitis C virus genome essential for RNA replication. Journal of Virology, 79: 380–392.PubMedGoogle Scholar
  36. Fried, M.W., Shiffman, M.L., Reddy, K.R., Smith, C., Marinos, G., Goncales, F.L., Jr., Haussinger, D., Diago, M., Carosi, G., Dhumeaux, D., Craxi, A., Lin, A., Hoffman, J., Yu, J. (2002). Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. New England Journal of Medicine, 347: 975–982.PubMedGoogle Scholar
  37. Gale, M., Jr., Blakely, C.M., Kwieciszewski, B., Tan, S.L., Dossett, M., Tang, N.M., Korth, M.J., Polyak, S.J., Gretch, D.R., Katze, M.G. (1998). Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Molecular and Cellular Biology, 18: 5208–5218.PubMedGoogle Scholar
  38. Garcia, M.A., Gil, J., Ventoso, I., Guerra, S., Domingo, E., Rivas, C., Esteban, M. (2006). Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiology and Molecular Biology Reviews, 70: 1032–1060.PubMedGoogle Scholar
  39. George, C.X., Samuel, C.E. (1999). Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible. Proceedings of the National Academy of Sciences of the United States of America, 96: 4621–4626.PubMedGoogle Scholar
  40. Ghosh, A., Sarkar, S.N., Sen, G.C. (2000). Cell growth regulatory and antiviral effects of the P69 isozyme of 2-5 (A) synthetase. Virology, 266: 319–328.PubMedGoogle Scholar
  41. Gil, J., Garcia, M.A., Gomez-Puertas, P., Guerra, S., Rullas, J., Nakano, H., Alcami, J., Esteban, M. (2004). TRAF family proteins link PKR with NF-kappa B activation. Molecular and Cellular Biology, 24: 4502–4012.PubMedGoogle Scholar
  42. Gilli, F., Sala, A., Bancone, C., Salacone, P., Gallo, M., Gaia, E., Bertolotto, A. (2002). Evaluation of IFN-alpha bioavailability by MxA mRNA in HCV patients. Journal of Immunological Methods, 262: 187–190.PubMedGoogle Scholar
  43. Goh, K.C., deVeer, M.J., Williams, B.R. (2000). The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin. EMBO Journal, 19: 4292–4297.PubMedGoogle Scholar
  44. Goodbourn, S., Didcock, L., Randall, R.E. (2000). Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. Journal of General Virology, 81: 2341–2364.PubMedGoogle Scholar
  45. Guidotti, L.G., Chisari, F.V. (2001). Noncytolytic control of viral infections by the innate and adaptive immune response. Annual Review of Immunology, 19: 65–91.PubMedGoogle Scholar
  46. Guidotti, L.G., McClary, H., Loudis, J.M., Chisari, F.V. (2000). Nitric oxide inhibits hepatitis B virus replication in the livers of transgenic mice. Journal of Experimental Medicine, 191: 1247–1252.PubMedGoogle Scholar
  47. Guo, J.T., Bichko, V.V., Seeger, C. (2001). Effect of alpha interferon on the hepatitis C virus replicon. Journal of Virology, 75: 8516–8523.PubMedGoogle Scholar
  48. Guo, J.T., Zhu, Q., Seeger, C. (2003). Cytopathic and noncytopathic interferon responses in cells expressing hepatitis C virus subgenomic replicons. Journal of Virology, 77: 10769–10779.PubMedGoogle Scholar
  49. Haller, O., Frese, M., Kochs, G. (1999). Mx proteins: mediators of innate resistance to RNA viruses. Revue Scientific et Technique, 17: 220–230.Google Scholar
  50. Haller, O., Staeheli, P., Kochs, G. (2007). Interferon-induced Mx proteins in antiviral host defense. Biochimie (in press).Google Scholar
  51. Haller, O., Kochs, G. (2002). Interferon-induced Mx proteins: dynamin-like GTPases with antiviral activity. Traffic, 3: 710–717.PubMedGoogle Scholar
  52. Han, J.Q., Wroblewski, G., Xu, Z., Silverman, R.H., Barton, D.J. (2004). Sensitivity of hepatitis C virus RNA to the antiviral enzyme ribonuclease L is determined by a subset of efficient cleavage sites. Journal of Interferon and Cytokine Research, 24: 664–676.PubMedGoogle Scholar
  53. Hartner, J.C., Schmittwolf, C., Kispert, A., Muller, A.M., Higuchi, M., Seeburg, P.H. (2004). Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. Journal of Biological Chemistry, 279: 4894–4902.PubMedGoogle Scholar
  54. Hayashi, J., Stoyanova, R., Seeger, C. (2005). The transcriptome of HCV replicon expressing cell lines in the presence of alpha interferon. Virology, 335: 264–275.PubMedGoogle Scholar
  55. Hefti, H.P., Frese, M., Landis, H., Di Paolo, C., Aguzzi, A., Haller, O., Pavlovic, J. (1999). Human MxA protein protects mice lacking a functional alpha/beta interferon system against La Crosse virus and other lethal viral infections. Journal of Virology, 73: 6984–6991.PubMedGoogle Scholar
  56. Higuchi, M., Maas, S., Single, F.N., Hartner, J., Rozov, A., Burnashev, N., Feldmeyer, D., Sprengel, R., Seeburg, P.H. (2000). Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature, 406: 78–81.PubMedGoogle Scholar
  57. Hijikata, M., Ohta, Y., Mishiro, S. (2000). Identification of a single nucleotide polymorphism in the MxA gene promoter (G/T at nt -88) correlated with the response of hepatitis C patients to interferon. Intervirology, 43: 124–127.PubMedGoogle Scholar
  58. Hijikata, M., Mishiro, S., Miyamoto, C., Furuichi, Y., Hashimoto, M., Ohta, Y. (2001). Genetic polymorphism of the MxA gene promoter and interferon responsiveness of hepatitis C patients: revisited by analyzing two SNP sites (-123 and -88) in vivo and in vitro. Intervirology, 44: 379–382.PubMedGoogle Scholar
  59. Hiscott, J., Lin, R., Nakhaei, P., Paz, S. (2006). MasterCARD: a priceless link to innate immunity. Trends in Molecular Medicine, 12: 53–56.PubMedGoogle Scholar
  60. Hoenen, A., Liu, W., Kochs, G., Khromykh, A.A., Mackenzie, J.M. (2007). West Nile virus-induced cytoplasmic membrane structures provide partial protection aginst the interferon-induced antiviral MxA protein. Journal of General Virology, (in press).Google Scholar
  61. Holzinger, D., Jorns, C., Sterz, S. Boisson-Dupuis, S. Thimme, R., Weidmann, M., Casanova, J.L., Haller, O., Kochs, G. (2007). Induction of MxA gene expression by influenza A virus requires type I or type II interferon signaling. Journal of Virology, 81: 7776–7785.Google Scholar
  62. Honda, M., Beard, M.R., Ping, L.H., Lemon, S.M. (1999). A phylogenetically conserved stem-loop structure at the 5 border of the internal ribosome entry site of hepatitis C virus is required for cap-independent viral translation. Journal of Virology, 73: 1165–1174.PubMedGoogle Scholar
  63. Jaiswal, M., LaRusso, N.F., Burgart, L.J., Gores, G.J. (2000). Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Research, 60: 184–190.PubMedGoogle Scholar
  64. Jorns, C., Holzinger, D., Thimme, R., Spangenberg, H.C., Weidmann, M., Rasenack, J., Blum, H.E., Haller, O., Kochs, G. (2006). Rapid and simple detection of IFN-neutralizing antibodies in chronic hepatitis C non-responsive to IFN-alpha. Journal of Medical Virology, 78: 74–82.PubMedGoogle Scholar
  65. Karupiah, G., Chen, J.H., Mahalingam, S., Nathan, C.F., MacMicking, J.D. (1998). Rapid interferon gamma-dependent clearance of influenza A virus and protection from consolidating pneumonitis in nitric oxide synthase 2-deficient mice. Journal of Experimental Medicine, 188: 1541–1546.PubMedGoogle Scholar
  66. Karupiah, G., Hunt, N.H., King, N.J.C., Chaudhri, G. (2000). NADPH oxidase, Nramp1 and nitric oxide in the host microbiol response. Reviews in Immunogenetics, 2: 387–415.PubMedGoogle Scholar
  67. Kato, T., Date, T., Miyamoto, M., Zhao, Z., Mizokami, M., Wakita, T. (2005). Nonhepatic cell lines HeLa and 293 support efficient replication of the hepatitis C virus genotype 2a subgenomic replicon. Journal of Virology, 79: 592–659.PubMedGoogle Scholar
  68. Keskinen, P., Nyqvist, M., Sareneva, T., Pirhonen, J., Melen, K., Julkunen, I. (1999). Impaired antiviral response in human hepatoma cells. Virology, 263: 364–375.PubMedGoogle Scholar
  69. Kim, Y.K., Lee, S.H., Kim, C.S., Seol, S.K., Jang, S.K. (2003). Long-range RNA-RNA interaction between the 5 nontranslated region and the core-coding sequences of hepatitis C virus modulates the IRES-dependent translation. RNA, 9: 599–606.PubMedGoogle Scholar
  70. Knapp, S., Yee, L.J., Frodsham, A.J., Hennig, B.J., Hellier, S., Zhang, L., Wright, M., Chiaramonte, M., Graves, M., Thomas, H.C., Hill, A.V., Thursz, M.R. (2003). Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR. Genes and Immunity, 4: 411–419.PubMedGoogle Scholar
  71. Kochs, G., Haller, O. (1999). Interferon-induced human MxA GTPase blocks nuclear import of Thogoto virus nucleocapsids. Proceedings of the National Academy of Sciences of the United States of America, 96: 2082–2086.PubMedGoogle Scholar
  72. Kochs, G., Janzen, C., Hohenberg, H., Haller, O. (2002). Antivirally active MxA protein sequesters La Crosse virus nucleocapsid protein into perinuclear complexes . Proceedings of the National Academy of Sciences of the United States of America, 99: 3153–3158.PubMedGoogle Scholar
  73. Kotenko, S.V., Gallagher, G., Baurin, V.V., Lewis-Antes, A., Shen, M., Shah, N.K., Langer, J.A., Sheikh, F., Dickensheets, H., Donnelly, R.P. (2003). IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nature Immunology, 4: 69–77.PubMedGoogle Scholar
  74. Kuo, M.Y., Chao, M., Taylor, J. (1989). Initiation of replication of the human hepatitis delta virus genome from cloned DNA: role of delta antigen. Journal of Virology, 63: 1945–1950.PubMedGoogle Scholar
  75. Lanford, R.E., Guerra, B., Lee, H., Averett, D.R., Pfeiffer, B., Chavez, D., Notvall, L., Bigger, C. (2003). Antiviral effect and virus-host interactions in response to alpha interferon, gamma interferon, poly(I)-poly(C), tumor necrosis factor alpha, and ribavirin in hepatitis C virus subgenomic replicons. Journal of Virology, 77: 1092–1104.PubMedGoogle Scholar
  76. Langland, J.O., Cameron, J.M., Heck, M.C., Jancovich, J.K., Jacobs, B.L. (2006). Inhibition of PKR by RNA and DNA viruses. Virus Research, 119: 100–110.PubMedGoogle Scholar
  77. Larkin, J., Jin, L., Farmen, M., Venable, D., Huang, Y., Tan, S.L., Glass, J.I. (2003). Synergistic antiviral activity of human interferon combinations in the hepatitis C virus replicon system. Journal of Interferon and Cytokine Research, 23: 247–257.PubMedGoogle Scholar
  78. Layden, J.E., Layden, T.J. (2002). Viral kinetics of hepatitis C: new insights and remaining limitations. Hepatology, 35: 967–970.PubMedGoogle Scholar
  79. Li, K., Foy, E., Ferreon, J.C., Nakamura, M., Ferreon, A.C., Ikeda, M., Ray, S.C., Gale, M., Jr., Lemon, S.M. (2005). Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proceedings of the National Academy of Sciences of the United States of America, 102: 2992–2997.PubMedGoogle Scholar
  80. Li, Y., Zhang, T., Ho, C., Orange, J.S., Douglas, S.D., Ho, W.Z. (2004). Natural killer cells inhibit hepatitis C virus expression. Journal of Leukocyte Biology, 76: 1171–1179.PubMedGoogle Scholar
  81. Lohmann, V., Körner, F., Koch, J.O., Herian, U., Theilmann, L., Bartenschlager, R. (1999). Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science, 285: 110–113.PubMedGoogle Scholar
  82. MacDonald, A., Harris, M. (2004). Hepatitis C virus NS5A: tales of a promiscuous protein. Journal of General Virology, 85: 2485–2502.PubMedGoogle Scholar
  83. Machida, K., Cheng, K.T., Sung, V.M., Lee, K.J., Levine, A.M., Lai, M.M. (2004). Hepatitis C virus infection activates the immunologic (type II) isoform of nitric oxide synthase and thereby enhances DNA damage and mutations of cellular genes. Journal of Virology, 78: 8835–8843.PubMedGoogle Scholar
  84. MacQuillan, G.C., de Boer, W.B., Platten, M.A., McCaul, K.A., Reed, W.D., Jeffrey, G.P., Allan, J.E. (2002). Intrahepatic MxA and PKR protein expression in chronic hepatitis C virus infection. Journal of Medical Virology, 68: 197–205.PubMedGoogle Scholar
  85. MacQuillan, G.C., Mamotte, C., Reed, W.D., Jeffrey, G.P., Allan, J.E. (2003). Upregulation of endogenous intrahepatic interferon stimulated genes during chronic hepatitis C virus infection. Journal of Medical Virology, 70: 219–227.PubMedGoogle Scholar
  86. Majano, P.L., Garcia-Monzon, C., Lopez-Cabrera, M., Lara-Pezzi, E., Fernandez-Ruiz, E., Garcia-Iglesias, C., Borque, M.J., Moreno-Otero, R. (1998). Inducible nitric oxide synthase expression in chronic viral hepatitis. Evidence for a virus-induced gene upregulation. Journal of Clinical Investigation, 101: 1343–1352.PubMedGoogle Scholar
  87. Manns, M.P., McHutchison, J.G., Gordon, S.C., Rustgi, V.K., Shiffman, M., Reindollar, R., Goodman, Z.D., Koury, K., Ling, M., Albrecht, J.K. (2001). Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet, 358: 958–965.PubMedGoogle Scholar
  88. Marcello, T., Grakoui, A., Barba-Spaeth, G., Machlin, E.S., Kotenko, S.V., Macdonald, M.R., Rice, C.M. (2006). Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology, 131: 1887–1898.PubMedGoogle Scholar
  89. Mashimo, T., Lucas, M., Simon-Chazottes, D., Frenkiel, M.P., Montagutelli, X., Ceccaldi, P.E., Deubel, V., Guenet, J.L., Despres, P. (2002). A nonsense mutation in the gene encoding 2-5-oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice. Proceedings of the National Academy of Sciences of the United States of America, 99: 11311–11316.PubMedGoogle Scholar
  90. McHutchison, J.G., Fried, M.W. (2003). Current therapy for hepatitis C: pegylated interferon and ribavirin. Clinics in Liver Disease, 7: 149–161.PubMedGoogle Scholar
  91. 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.PubMedGoogle Scholar
  92. Mihm, S., Fayyazi, A., Ramadori, G. (1997). Hepatic expression of inducible nitric oxide synthase transcripts in chronic hepatitis C virus infection: relation to hepatic viral load and liver injury. Hepatology, 26: 451–458.PubMedGoogle Scholar
  93. Mihm, S., Frese, M., Meier, V., Wietzke-Braun, P., Scharf, J.-G., Bartenschlager, R., Ramadori, G. (2004). Interferon type I gene expression in chronic hepatitis C. Laboratory Investigation, 84: 1148–1159.PubMedGoogle Scholar
  94. Miyamoto, M., Kato, T., Date, T., Mizokami, M., Wakita, T. (2006). Comparison between subgenomic replicons of hepatitis C virus genotypes 2a (JFH-1) and 1b (Con1 NK5.1). Intervirology, 49: 37–43.PubMedGoogle Scholar
  95. Mundt, E. (2007). Human MxA confers resistance to double-standed RNA viruses of two virus families. Journal of General Virology, 88: 1319–1323.PubMedGoogle Scholar
  96. Murashima, S., Kumashiro, R., Ide, T., Miyajima, I., Hino, T., Koga, Y., Ishii, K., Ueno, T., Sakisaka, S., Sata, M. (2000). Effect of interferon treatment on serum 2,5-oligoadenylate synthetase levels in hepatitis C-infected patients. Journal of Medical Virology, 62: 185–190.PubMedGoogle Scholar
  97. Murphy, D.G., Dimock, K., Kang, C.Y. (1991). Numerous transitions in human parainfluenza virus 3 RNA recovered from persistently infected cells. Virology, 181: 760–763.PubMedGoogle Scholar
  98. Murphy, J.A., Duerst, R.J., Smith, T.J., Morrison, L.A. (2003). Herpes simplex virus type 2 virion host shutoff protein regulates alpha/beta interferon but not adaptive immune responses during primary infection in vivo. Journal of Virology, 77: 9337–9345.PubMedGoogle Scholar
  99. Neumann, A.U., Lam, N.P., Dahari, H., Gretch, D.R., Wiley, T.E., Layden, T.J., Perelson, A.S. (1998). Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science, 282: 103–107.PubMedGoogle Scholar
  100. O’Hara, P.J., Nichol, S.T., Horodyski, F.M., Holland, J.J. (1984). Vesicular stomatitis virus defective interfering particles can contain extensive genomic sequence rearrangements and base substitutions. Cell, 36: 915–924.PubMedGoogle Scholar
  101. Okuse, C., Rinaudo, J.A., Farrar, K., Wells, F., Korba, B.E. (2005). Enhancement of antiviral activity against hepatitis C virus in vitro by interferon combination therapy. Antiviral Research, 65: 23–34.PubMedGoogle Scholar
  102. Pascu, M., Martus, P., Hohne, M., Wiedenmann, B., Hopf, U., Schreier, E., Berg, T. (2004). Sustained virological response in hepatitis C virus type 1b infected patients is predicted by the number of mutations within the NS5A-ISDR: a meta-analysis focused on geographical differences. Gut, 53: 1345–1351.PubMedGoogle Scholar
  103. Patterson, J.B., Samuel, C.E. (1995). Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Molecular and Cellular Biology, 15: 5376–5388.PubMedGoogle Scholar
  104. Patzwahl, R., Meier, V., Ramadori, G., Mihm, S. (2001). Enhanced expression of interferon-regulated genes in the liver of patients with chronic hepatitis C virus infection: detection by suppression-subtractive hybridization. Journal of Virology, 75: 1332–1338.PubMedGoogle Scholar
  105. Pavio, N., Taylor, D.R., Lai, M.M. (2002). Detection of a novel unglycosylated form of hepatitis C virus E2 envelope protein that is located in the cytosol and interacts with PKR. Journal of Virology, 76: 1265–1272.PubMedGoogle Scholar
  106. Pavlovic, J., Arzet, H.A., Hefti, H.P., Frese, M., Rost, D., Ernst, B., Kolb, E., Staeheli, P., Haller, O. (1995). Enhanced virus resistance of transgenic mice expressing the human MxA protein. Journal of Virology, 69: 4506–4510.PubMedGoogle Scholar
  107. Penna, G., Vulcano, M., Sozzani, S., Adorini, L. (2002). Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells. Human Immunology, 63: 1164–1171.PubMedGoogle Scholar
  108. Perelygin, A.A., Scherbik, S.V., Zhulin, I.B., Stockman, B.M., Li, Y., Brinton, M.A. (2002). Positional cloning of the murine flavivirus resistance gene. Proceedings of the National Academy of Sciences of the United States of America, 99: 9322–9327.PubMedGoogle Scholar
  109. Pestka, S., Krause, C.D., Walter, M.R. (2004). Interferons, interferon-like cytokines, and their receptors. Immunological Reviews, 202: 8–32.PubMedGoogle Scholar
  110. Polyak, S.J., Khabar, K.S., Paschal, D.M., Ezelle, H.J., Duverlie, G., Barber, G.N., Levy, D.E., Mukaida, N., Gretch, D.R. (2001a). Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. Journal of Virology, 75: 6095–6106.Google Scholar
  111. Polyak, S.J., Khabar, K.S., Rezeiq, M., Gretch, D.R. (2001b). Elevated levels of interleukin-8 in serum are associated with hepatitis C virus infection and resistance to interferon therapy. Journal of Virology, 75: 6209–6211.Google Scholar
  112. Pope, M., Marsden, P.A., Cole, E., Sloan, S., Fung, L.S., Ning, Q., Ding, J.W., Leibowitz, J.L., Phillips, M.J., Levy, G.A. (1998). Resistance to murine hepatitis virus strain 3 is dependent on production of nitric oxide. Journal of Virology, 72: 7084–7090.PubMedGoogle Scholar
  113. Rebouillat, D., Hovanessian, A.G. (1999). The human 2,5-oligoadenylate synthetase family: interferon-induced proteins with unique enzymatic properties. Journal of Interferon and Cytokine Research, 19: 295–308.PubMedGoogle Scholar
  114. Reichelt, M., Stertz, S., Krijnse-Locker, J., Haller, O., Kochs, G. (2004). Missorting of LaCrosse virus nucleocapsid protein by the interferon-induced MxA GTPase involves smooth ER membranes. Traffic, 5: 772–784.PubMedGoogle Scholar
  115. Robek, M.D., Boyd, B.S., Chisari, F.V. (2005). Lambda interferon inhibits hepatitis B and C virus replication. Journal of Virology, 79: 3851–3854.PubMedGoogle Scholar
  116. Roers, A., Hochkeppel, H.K., Horisberger, M.A., Hovanessian, A., Haller, O. (1994). MxA gene expression after live virus vaccination: a sensitive marker for endogenous type I interferon. Journal of Infectious Diseases, 169: 807–813.PubMedGoogle Scholar
  117. Samuel, C.E. (2001). Antiviral actions of interferons. Clinical Microbiological Reviews, 14: 778–809.Google Scholar
  118. Samuel, M.A., Whitby, K., Keller, B.C., Marri, A., Barchet, W., Williams, B.R., Silverman, R.H., Gale, M., Jr., Diamond, M.S. (2006). PKR and RNase L contribute to protection against lethal West Nile Virus infection by controlling early viral spread in the periphery and replication in neurons. Journal of Virology, 80: 7009–7019.PubMedGoogle Scholar
  119. Saura, M., Zaragoza, C., McMillan, A., Quick, R.A., Hohenadl, C., Lowenstein, J.M., Lowenstein, C.J. (1999). An antiviral mechanism of nitric oxide: inhibition of a viral protease. Immunity, 10: 21–28.PubMedGoogle Scholar
  120. Scadden, A.D.J., Smith, C.W.J. (1997). A ribonuclease specific for inosine-containing RNA: a potential role in antiviral defense? EMBO Journal, 16: 2140–2149.PubMedGoogle Scholar
  121. Scadden, A.D.J., Smith, C.W.J. (2001). Specific cleavage of hyper-edited dsRNAs. EMBO Journal, 20: 4243–4252.PubMedGoogle Scholar
  122. Scherbik, S.V., Paranjape, J.M., Stockman, B.M., Silverman, R.H., Brinton, M.A. (2006). RNase L plays a role in the antiviral response to West Nile virus. Journal of Virology, 80: 2987–2999.PubMedGoogle Scholar
  123. Schweyer, S., Mihm, S., Radzun, H.J., Hartmann, H., Fayyazi, A. (2000). Liver infiltrating T lymphocytes express interferon-gamma and inducible nitric oxide synthase in chronic hepatitis C virus infection. Gut, 46: 255–259.PubMedGoogle Scholar
  124. Sheppard, P., Kindsvogel, W., Xu, W., Henderson, K., Schlutsmeyer, S., Whitmore, T.E., Kuestner, R., Garrigues, U., Birks, C., Roraback, J., Ostrander, C., Dong, D., Shin, J., Presnell, S., Fox, B., Haldeman, B., Cooper, E., Taft, D., Gilbert, T., Grant, F.J., Tackett, M., Krivan, W., McKnight, G., Clegg, C., Foster, D., Klucher, K.M. (2003). IL-28, IL-29, and their class II cytokine receptor IL-28R. Nature Immunology, 4: 63–68.PubMedGoogle Scholar
  125. Shin, E.C., Seifert, U., Kato, T., Rice, C.M., Feinstone, S.M., Kloetzel, P.M., Rehermann, B. (2006). Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection. Journal of Clinical Investigation, 116: 3006–3014.PubMedGoogle Scholar
  126. Smith, J.A., Schmechel, S.C., Williams, B.R., Silverman, R.H., Schiff, L.A. (2005). Involvement of the interferon-regulated antiviral proteins PKR and RNase L in reovirus-induced shutoff of cellular translation. Journal of Virology, 79: 2240–2250.PubMedGoogle Scholar
  127. Stark, J.M., Khan, A.M., Chiappetta, C.L., Xue, H., Alcorn, J.L., Colasurdo, G.N. (2005). Immune and functional role of nitric oxide in a mouse model of respiratory syncytial virus infection. Journal of Infectious Diseases, 191: 387–395.PubMedGoogle Scholar
  128. Stojdl, D.F., Abraham, N., Knowles, S., Marius, R., Brasey, A., Lichty, B.D., Brown, E.G., Sonenberg, N., Bell, J.C. (2000). The murine double-stranded RNA-dependent protein kinase PKR is required for resistance to vesicular stomatitis virus. Journal of Virology, 74: 9580–9585.PubMedGoogle Scholar
  129. Su, A.I., Pezacki, J.P., Wodicka, L., Brideau, A.D., Supekova, L., Thimme, R., Wieland, S., Bukh, J., Purcell, R.H., Schultz, P.G., Chisari, F.V. (2002). Genomic analysis of the host response to hepatitis C virus infection. Proceedings of the National Academy of Sciences of the United States of America, 99: 15669–15674.PubMedGoogle Scholar
  130. 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. Journal of General Virology, 85: 959–969.PubMedGoogle Scholar
  131. Tan, H., Derrick, J., Hong, J., Sanda, C., Grosse, W.M., Edenberg, H.J., Taylor, M., Seiwert, S., Blatt, L.M. (2005). Global transcriptional profiling demonstrates the combination of type I and type II interferon enhances antiviral and immune responses at clinically relevant doses. Journal of Interferon and Cytokine Research, 25: 632–649.PubMedGoogle Scholar
  132. Tan, S.-L., Katze, M.G. (2001). How hepatitis C virus counteracts the interferon response: the jury is still out on NS5A. Virology, 284: 1–12.PubMedGoogle Scholar
  133. Taylor, D.R., Shi, S.T., Romano, P.R., Barber, G.N., Lai, M.C. (1999). Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science, 285: 107–110.PubMedGoogle Scholar
  134. Taylor, D.R., Tian, B., Romano, P.R., Hinnebusch, A.G., Lai, M.M., Mathews, M.B. (2001). Hepatitis C virus envelope protein E2 does not inhibit PKR by simple competition with autophosphorylation sites in the RNA-binding domain. Journal of Virology, 75: 1265–1273.PubMedGoogle Scholar
  135. Taylor, D.R., Puig, M., Darnell, M.E., Mihalik, K., Feinstone, S.M. (2005). New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1. Journal of Virology, 79: 6291–6298.PubMedGoogle Scholar
  136. Terajima, M., Leporati, A.M. (2005). Role of indoleamine 2,3-dioxygenase in antiviral activity of interferon-gamma against vaccinia virus. Viral Immunology, 18: 722–729.PubMedGoogle Scholar
  137. Thomis, D.C., Doohan, J.P., Samuel, C.E. (1992). Mechanism of interferon action: cDNA structure, expression, and regulation of the interferon-induced, RNA-dependent P1/eIF-2 alpha protein kinase from human cells. Virology, 188: 33–46.PubMedGoogle Scholar
  138. Toth, A.M., Zhang, P., Das, S., George, C.X., Samuel, C.E. (2006). Interferon action and the double-stranded RNA-dependent enzymes ADAR1 adenosine deaminase and PKR protein kinase. Progress in Nucleic Acid Research and Molecular Biology, 81: 369–434.PubMedGoogle Scholar
  139. Uprichard, S.L., Chung, J., Chisari, F.V., Wakita, T. (2006). Replication of a hepatitis C virus replicon clone in mouse cells. Virology Journal, 3: 89.PubMedGoogle Scholar
  140. Valente, L., Nishikura, K. (2005). ADAR gene family and A-to-I RNA editing: diverse roles in posttranscriptional gene regulation. Progress in Nucleic Acid Research and Molecular Biology, 79: 299–338.PubMedGoogle Scholar
  141. Van Regenmortel, M.H.V., Fauquet, C.M., Bishop, D.H.L., Carstens, E.B., Estes, M.K., Lemon, S.M., Maniloff, J., Mayo, M.A., McGeoch, D.J., Pringle, C.R., Wickner, R.B. (2000). Virus Taxonomy: The VIIth Report of the International Committee on Taxonomy of Viruses. Academic Press, San Diego.Google Scholar
  142. Wang, Q., Khillan, J., Gadue, P., Nishikura, K. (2000). Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science, 290: 1765–1768.PubMedGoogle Scholar
  143. Wang, Q., Miyakoda, M., Yang, W., Khillan, J., Stachura, D.L., Weiss, M.J., Nishikura, K. (2004). Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. Journal of Biological Chemistry, 279: 4952–4961.PubMedGoogle Scholar
  144. Westaway, E.G., Mackenzie, J.M., Khromykh, A.A. (2002). Replication and gene function in Kunjin virus. Current Topics in Microbiology and Immunology, 267: 323–351.PubMedGoogle Scholar
  145. Windisch, M.P., Frese, M., Kaul, A., Trippler, M., Lohmann, V., Bartenschlager, R. (2005). Dissecting the interferon-induced inhibition of hepatitis C virus replication by using a novel host cell line. Journal of Virology, 79: 13778–13793.PubMedGoogle Scholar
  146. Wreschner, D.H., McCauley, J.W., Skehel, J.J., Kerr, I.M. (1981). Interferon action -sequence specificity of the ppp(A2p)nA-dependent ribonuclease. Nature, 289: 414–417.PubMedGoogle Scholar
  147. Yang, J.H., Luo, X., Nie, Y., Su, Y., Zhao, Q., Kabir, K., Zhang, D., Rabinovici, R. (2003a). Widespread inosine-containing mRNA in lymphocytes regulated by ADAR1 in response to inflammation. Immunology, 109: 15–23.Google Scholar
  148. Yang, J.H., Nie, Y., Zhao, Q., Su, Y., Pypaert, M., Su, H., Rabinovici, R. (2003b). Intracellular localization of differentially regulated RNA-specific adenosine deaminase isoforms in inflammation. Journal of Biological Chemistry, 278: 45833–45842.Google Scholar
  149. Yang, Y.L., Reis, L.F., Pavlovic, J., Aguzzi, A., Schäfer, R., Kumar, A., Williams, B.R., Aguet, M., Weissmann, C. (1995). Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO Journal, 14: 6095–6106.PubMedGoogle Scholar
  150. Yee, L.J., Knapp, S., Burgner, D., Hennig, B.J., Frodsham, A.J., Wright, M., Thomas, H.C., Hill, A.V., Thursz, M.R. (2004). Inducible nitric oxide synthase gene (NOS2A) haplotypes and the outcome of hepatitis C virus infection. Genes and Immunity, 5: 183–187.PubMedGoogle Scholar
  151. You, S., Stump, D.D., Branch, A.D., Rice, C.M. (2004). A cis-acting replication element in the sequence encoding the NS5B RNA-dependent RNA polymerase is required for hepatitis C virus RNA replication. Journal of Virology, 78: 1352–1366.PubMedGoogle Scholar
  152. Zhu, H., Zhao, H., Collins, C.D., Eckenrode, S.E., Run, Q., McIndoe, R.A., Crawford, J.M., Nelson, D.R., She, J.X., Liu, C. (2003). Gene expression associated with interferon alfa antiviral activity in an HCV replicon cell line. Hepatology, 37: 1180–1188.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Michael Frese
    • 1
  • Eva Dazert
  1. 1.School of Health Sciences, University of CanberraAustralia

Personalised recommendations