Mechanisms of Interferon Action and Resistance in Chronic Hepatitis C Virus Infection: Lessons Learned from Cell Culture Studies

  • Srikanta Dash
  • Sidhartha Hazari
  • Robert F Garry
  • Fredric Regenstein


Alpha interferon, usually in combination with ribavirin, is currently the standard care for patients infected with hepatitis C virus. Unfortunately, a significant number of patients fail to eradicate their infection with this regimen. The molecular details concerning the failure of many patients to achieve sustained clearance of the virus infection after interferon therapy are currently unknown. The primary focus of this chapter is to provide an overview of interferon action and resistance against hepatitis C virus (HCV) based on our understanding developed from in vitro experiments. Interferon first binds to receptors on the cell surface; this initiates a cascade of signal transduction pathways leading to the activation of antiviral genes. Using a cell culture model, we determined that the activation of an interferon promoter (interferon inducible genes) is important for a successful antiviral response against HCV. The level of activation of the IFN promoter by exogenous interferon appears to vary among different replicon cell lines. It was observed that a replicon cell line showing low activation of the IFN promoter frequently develops resistant phenotypes compared to cell lines with higher activation. Furthermore, interferon-alpha, -beta, and -gamma are each found to inhibit replication of HCV in the cell culture. The antiviral action of interferon is targeted to the highly conserved 5’ untranslated region (5’ UTR) utilized by the virus to translate protein by an internal ribosome entry site (IRES) mechanism. This effect is the same among HCVs of other genotypes. Interferon inhibits translation of HCV by blocking at the level of formation of polyribosomes on the IRES containing mRNA. These in vitro studies suggest that differences in the regulation of IRES-mediated translation by interferon among hepatic cell clones may be directly related to the development of interferon resistance in chronic HCV infection.


Internal Ribosome Entry Site Interferon Action EMCV Internal Ribosome Entry Site Replicon Cell Line Interferon Resistance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Akira, S., Uematsu, S., Takeucji, O. (2006). Pathogen recognition and innate immunity. Cell, 124: 783–801.PubMedCrossRefGoogle Scholar
  2. Bach, E.A., Aguet, M., Schreiber, R.D. (1997). The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annual Review of Immunology, 15: 571–591.CrossRefGoogle Scholar
  3. Basu, A., Meyer, K., Ray, R.B., Ray, R. (2001). Hepatitis C virus core protein modulates the interferon-induced transacting factors of JAK/STAT signaling pathways but does not affect the activation of downstream IRF-1 or 561 gene. Virology, 288: 379–390.PubMedCrossRefGoogle Scholar
  4. Bekisz, J., Schmeisser, H., Hernandez, J., Goldman, N.D., Zoon, K.C. (2004). Human interferons alpha, beta and omega. Growth Factors, 22: 243–251.PubMedCrossRefGoogle Scholar
  5. Blindenbacher, A., Duong, F.H.T., Hunziker, L., Stutvoet, S.T.D., Wang, X., Terracciano, L., Moradpour, D., Blum, H.E., Alonzi, T., Tripodi, M., Monika, N.L., Heim, M.H. (2003). Expression of hepatitis C virus proteins inhibits interferon alfa signaling in the liver of transgenic mice. Gastroenterology, 124: 1465–1475.PubMedCrossRefGoogle Scholar
  6. Blatt, L.M., Davis, J.M., Klein, S.B., Taylor, M.W. (1996). The biological activity and molecular characterization of a novel synthetic interferon alpha species, consensus interferon. Journal of Interferon and Cytokine Research, 16: 489–499.PubMedGoogle Scholar
  7. Bosch, F.X., Ribes, J., Diaz, M., Cleries, R. (2004). Primary liver cancer: worldwide incidence and trends. Gastroenterology, 127: S5–S16.PubMedCrossRefGoogle Scholar
  8. Cheney, I.W., Lai, V.C.H., Zhong, W., Brodhag, T., Dempsey, S., Lim, C., Hong, Z., Lau, J.Y.N., Tam, R.C. (2002). Comparative analysis of anti-hepatitis C virus activity and gene expression mediated by alpha, beta, and gamma interferons. Journal of Virolology, 76: 11148–11154.CrossRefGoogle Scholar
  9. Choo, Q.L., Kuo, G., Weiner, A.J., Overby, L.R., Bradley, D.W., Houghton, M. (1989). Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science, 244: 359–362.PubMedCrossRefGoogle Scholar
  10. Chung, R.T., He, W., Saquib, A., Contreras, A.M., Xavier, R.J., Chawla, A., Wang, T.C., Schmidt, E.V. (2001). Hepatitis C virus replication is directly inhibited by IFN-alfa in a full-length binary expression system. Proceedings of National Academy of Sciences (USA), 98: 9847–9852.Google Scholar
  11. Colamonici, O.R., Uyttendale, H., Domanski, P., Yan, H., Krolewski, J.J. (1994). P135 tyk2 an interferon-dependent tyrosine kinase, is physically associated with an interferon receptor. Journal of Biological Chemistry, 269: 3518–3522.PubMedGoogle Scholar
  12. Darnell, J.E. Jr. (1998). Studies of interferon–induced transcriptional activation uncover the Jak–STAT pathway. Journal of Interferon and Cytokines, 18: 549–554.Google Scholar
  13. Dash, S., Hiramatsu, N., Gerber M.A. (1997). Transfection of HepG2 cells with infectious hepatitis C virus RNA genome. American Journal of Pathology, 151: 363–373.PubMedGoogle Scholar
  14. Dash, S., Kalkeri, G., McClure, H.M., Garry, R.F., Clejan, S., Thung, S.N., Murthy, K.K. (2001). Transmission of HCV to a chimpanzee using virus particles produced in an RNA transfected hepG2 cell culture. Journal of Medical Virology, 65: 276–281.PubMedCrossRefGoogle Scholar
  15. Dash, S., Prabhu, R., Hazari, S., Bastian, F., Garry, R.F., Zou, W., Haque, S., Joshi V., Regenstein, F.G., Thung S.N. (2005). Interferons alpha, beta, gamma each inhibits hepatitis C virus replication at the level internal ribosome entry site mediated translation. Liver International, 25: 1–15.CrossRefGoogle Scholar
  16. Davis, G., Lau, J. (1997). Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology, 26 (suppl. 1): 122S–127S.Google Scholar
  17. Davis, G.L., Esteban-Mur, R., Rustgi, V., Hoef, J., Gordon, S.C., Trepo, C., Shiffman, M.L., Zeuzem, S., Craxi, A., Ling, M.H., Albrecht, J. (1998). Interferon alpha-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis International therapy group. New England Journal of Medicine, 339: 1493–1499.PubMedCrossRefGoogle Scholar
  18. Diaz, M.O., Pomykala, H.M., Bohlander, S.K., Maltepe, E., Malik, K., Brownstein, B. Olopade, O.I. (1994). Structure of the human type 1 interferon gene cluster determined from a YAC clone. Genomics, 22: 540–542.PubMedCrossRefGoogle Scholar
  19. Domanski, P., Colamonici, O.R. (1996). The type-1 interferon receptor. The long and short of it. Cytokine Growth Factor Review, 7: 143–151.Google Scholar
  20. Domanski, P., Witte, M., Kellum, M., Runinstein, M., Hackett, R., Pitha, P., Colamonici O.R. (1995). Cloning and expression of a long form of beta subunit of the interferon alpha/beta receptor that is required for signaling. Journal of Biological Chemistry, 270: 21606–21611.PubMedCrossRefGoogle Scholar
  21. El-Serag, H.B. (2004). Hepatocellular carcinoma: recent trends in the United States. Gastroenterology, 127: S27–34.PubMedCrossRefGoogle Scholar
  22. 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. Journal of Clinical Investigation, 96: 224–230.PubMedGoogle Scholar
  23. Enomoto, N., Sakuma, I., Asahina, Y., Kurasaki, M., Murakami, T., Yamamoto, C., Ogura, Y., Izumi, N., Murumo, F., Sato, C. (1996). Mutation 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.PubMedCrossRefGoogle Scholar
  24. Feld, J.J., Hoofnagle, J.H. (2005). Mechanism of action of interferon and ribavirin treatment of hepatitis C. Nature, 436: 967–972.PubMedCrossRefGoogle Scholar
  25. Fenteany, G., Schreiber, S.L. (1998). Lactacystin, proteasome function and cell fate. Journal of Biological Chemistry, 273: 8545–8548.PubMedCrossRefGoogle Scholar
  26. Ferreon, J.C., Ferreon, A.C.M., Li, K., Lemon, S.M. (2005). Molecular determinants of TRIF proteolysis mediated by the hepatitis C virus NS3/4A protease. Journal of Biological Chemistry, 280: 20483–20492.PubMedCrossRefGoogle Scholar
  27. Francki, R.I.B., Fauquet, C.M., Knudson, D.L., Brown, F. (1991). Classification and nomenclature of viruses: fifth report of the international committee on taxonomy of viruses. Archives Virology (Suppl. 2), 223.Google Scholar
  28. Francois, C., Duverlie, G., Rebouillat, D., Khorsi, H., Castelain, S., Blum, H.E., Gatignol, A., Wychowski, C., Moradpour, D., Meurs, E.F. (2000). Expression of hepatitis C virus proteins interferes with the antiviral action of interferon independently of PKR-mediated control of protein synthesis. Journal of Virology, 74: 5587–5596.PubMedCrossRefGoogle Scholar
  29. Frese, M., Schwarzle, V., Barth, K., Krieger N., Lohmann V., Mihm S., Haller O., Bartenschalager R. (2002). Interferon gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs. Hepatology, 35: 694–703.PubMedCrossRefGoogle Scholar
  30. Friebe, P., Bartenschlager, R. (2002). Genetic analysis of sequences in the 3’ nontranslated region of hepatitis C virus that are important for RNA replication. Journal of Virology, 76: 5326–5338.PubMedCrossRefGoogle Scholar
  31. Friebe, P., Lohmann, V., Krieger, N., Bartenschalager, R. (2001). Sequences in the 5‘UTR nontranslated region of hepatitis C virus required for RNA replication. Journal of Virology, 75: 12047–12057.PubMedCrossRefGoogle Scholar
  32. Foy, E., Li, K., Wang, C., Sumpter, R., Ikeda, M., Lemon, S.M., Gale, M. (2003). Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science, 300: 1145–1148.PubMedCrossRefGoogle Scholar
  33. Foy, E., Li, K., Sumpter, R., Loo, Y.-M., Johnson, C.L., Wang, C., Fish, P.M., Yoneyama, M., Fujita, T., Lemon, S.M., Gale, M. (2005). Control of antiviral defense through hepatitis C virus disruption of retinoic acid-inducible gene-1 signaling. Proceedings of National Academy of Sciences, 102: 2986–2991.CrossRefGoogle Scholar
  34. 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 alpha-2b plus ribavirin for chronic hepatitis C virus infection. New England Journal of Medicine, 347: 975–982.PubMedCrossRefGoogle Scholar
  35. Gale, M., Korth, M.J., Tang, N.M., Tan, S.L., Hopkins, D.A., Dever, T.E., Polyak, S.J., Gretch, D.R., Katze, M.G. (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.PubMedCrossRefGoogle Scholar
  36. Gale, M., 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 non-structural 5A protein: molecular mechanisms of kinase regulation. Molecular and Cellular Biology, 18: 5208–5218.PubMedGoogle Scholar
  37. Garcia-Sastre, A., Biron, C.A. (2006). Type 1 interferons and the virus-host relationship: a lesson in dètente. Science , 312: 879–882.PubMedCrossRefGoogle Scholar
  38. Goodbourn, S., Didcock, L., Randall, R.E. (2000). Interferons: cell signaling, immune modulation, antiviral responses and virus countermeasures. Journal of General Virology, 81: 2341–2364.PubMedGoogle Scholar
  39. Guo, J., Bichko, V.V., Seeger, C. (2001). Effect of alpha interferon on the hepatitis C virus replicon. Journal of Virology, 75: 8516–8523.PubMedCrossRefGoogle Scholar
  40. Guo, J., Zhu, Q., Seeger, C. (2003). Cytopathic and noncytopathic interferon responses in cells expressing hepatitis C virus subgenomic replicons. Journal of Virology, 77: 10769–10779.PubMedCrossRefGoogle Scholar
  41. Guo, J., Sohn, J.A., Zhu, Q., Seeger, C. (2004). Mechanism of the interferon alpha response against hepatitis C virus replicons. Virology, 325: 71–81.PubMedCrossRefGoogle Scholar
  42. Hadziyannis, S.J., Sette, H. Jr., Morgan, T.R., Balan, V., Diago, M., Marcellin, P., Ramadori G., Bodenheimer H. Jr., Bernstein, D., Rizzetto, M., Zeuzem, S., Pockros, P.J., Lin, A., Ackrill, A.M., PEGASYS International Study Group. (2004). Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C. A randomized study of treatment duration and ribavirin dose. Annals of Internal Medicine, 140: 346–355.Google Scholar
  43. Hazari, S., Bastian, F.O., Garry, R.F., Dash, S. (2004). Translational regulation of HCV-IRES mRNA in interferon treated Huh-7 cells. Hepatology, A-619, P-433A.Google Scholar
  44. Hazari, S., Taylor, L., Garry, R.F., Loftig, R., Dash, S. (2005a). Lower activation of ISRE promoter among cell clones replicating HCV sub-genomic RNA leads to interferon resistance. Hepatology, 42: P-247A, A: 128.Google Scholar
  45. Hazari, S., Patil, A., Joshi, V., Sullivan, D.E., Fermin, C.D., Garry, R.F., Elliott, R.M., Dash, S. (2005b). Alpha interferon inhibits translation mediated by the internal ribosome entry site of six different hepatitis C virus genotypes. Journal of General Virology, 86: 3047–3053.Google Scholar
  46. He, Y., Yan, W., Coito, C., Li, Y., Gale, M. Jr., Katze, M.G. (2003). The regulation of hepatitis C virus (HCV) internal ribosome-entry site-mediated translation by HCV replicons and nonstructural proteins. Journal of General Virology, 84: 535–543.PubMedCrossRefGoogle Scholar
  47. Heathcote, J., Keeffe, E.B., Lee, S.S., Feinman, S.V., Tang, M.J., Reddy, K.R., Albert, D.G., Witt, K., Blatt, L.M. (1998). The consensus interferon study group. Retreatment of chronic hepatitis C with consensus interferon. Hepatology 27: 1136–1143.PubMedCrossRefGoogle Scholar
  48. Hemmi, S., Bohni, R., Stark, G., Di-Marco, F., Aguet, M. (1994). A novel member of the interferon receptor family complements functionally of the murine interferon gamma receptor in human cells. Cell, 76: 803–810.PubMedCrossRefGoogle Scholar
  49. Hoffmann, W.P., Zeuzem, S., Sarrazin, C. (2005). Hepatitis C virus-related resistance mechanisms to interferon alpha-based antiviral therapy. Journal of Clinical Virology, 32: 86–91.CrossRefGoogle Scholar
  50. Hoofnagle, J.H. (2004). Hepatocellular carcinoma: summary and recommendation. Gastroenterology, 127: S319–S323.PubMedCrossRefGoogle Scholar
  51. Hoofnagle, J.H. (2002). Course and outcome of hepatitis C. Hepatology, 36: S21–29.PubMedCrossRefGoogle Scholar
  52. Ji, H., Fraser, C.S., Yu, Y., Leary, J., Douda, J.A. (2004). Coordinated assembly of human translation initiation complexes by the hepatitis C virus internal ribosome entry site RNA. Proceedings of National Academy of Sciences (USA), 101: 16990–16995.CrossRefGoogle Scholar
  53. Kalkeri, G., Khalap, N., Garry, R., Fermin, C., Dash, S. (2001). Hepatitis C viral protein affect cell viability and membrane permeability. Experimental and Molecular Pathology, 71: 194–208.PubMedCrossRefGoogle Scholar
  54. Karin, M., Lawrence, T., Nizet, V. (2006). Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell, 124: 823–835.PubMedCrossRefGoogle Scholar
  55. Kato, T., Date, T., Miyamoto, M., Sugiyama, M., Tanaka, Y., Orito, E., Ohno, T., Sugihara, K., Hasegawa, I., Fujiwara, K., Ito, K., Ozasa, A., Mizokami, M., Wakita, T. (2005). Detection of anti-hepatitis C virus effect of interferon and ribavirin by a sensitive replicon system. Journal of Clinical Microbiology, 43: 5679–5684.PubMedCrossRefGoogle Scholar
  56. Kato, J., Kato, N., Moriyama, M., Goto, T., Taniguchi, H., Shiratori, Y., Omata, M. (2002). Interferons specifically suppress the translation from the internal ribosome entry site of hepatitis C virus through a double-stranded RNA- activated protein kinase-independent pathway. Journal of Infectious Disease, 186: 155–163.CrossRefGoogle Scholar
  57. Katze, M.G., He, Y., Gale, M. (2002). Viruses and interferon: a fight for supremacy. Nature Review, 675–687.Google Scholar
  58. Kawai, T., Akira, S. (2006). Innate immune recognition of viral infection. Nature Immunology, 7: 131–137.PubMedCrossRefGoogle Scholar
  59. Keskinen, P., Melen, K., Julkunen, I (2002). Expression of HCV structural proteins impairs IFN-mediated antiviral response. Virology, 299: 164–171.PubMedCrossRefGoogle Scholar
  60. Khaber, K.S.A., Al-Zoghaibi, F., Al-Ahdal, M.N., Murayama, T., Dhalla, M., Mukaida, N., Taha, M., Al-Sedairy, S.T., Siddiqui, Y., Kessie, G., Matsushima, K. (1997). The alpha chemokine, interleukin 8 inhibits the antiviral action of interferon alpha. Journal of Experimental Medicine, 186: 1077–1085.CrossRefGoogle Scholar
  61. Kiyosawa, K., Umemura, T., Ichigo, T., Matsumoto, A., Yoshizawa, K., Tanaka, E. (2004). Hepatocellular carcinoma recent trends in Japan. Gastroenterology, 127 (Suppl.): 17–26.Google Scholar
  62. Koev, G., Duncan, R.F., Lai, M.M. (2002). Hepatitis C virus IRES-dependent translation is insensitive to an eIF2alpha-independent mechanism of inhibition by interferon in hepatocyte cell lines. Virology, 297: 195–202.PubMedCrossRefGoogle Scholar
  63. Kolykhalov, A.A., Agapov, E.V., Blight, K.J., Mihalik, K., Feinstone, S.M., Rice, C.M. (1997). Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science, 277: 570–574.PubMedCrossRefGoogle Scholar
  64. Landolfo, S., Gribaudo, G., Angeretti, A., Gariglio, M. (1995). Mechanisms of viral inhibition by interferons. Pharmacological Therapy, 65: 415–442.CrossRefGoogle Scholar
  65. Langland, J.O., Cameron, J.M., Heck, M.C., Jancovich, J.K., Jacob, B.L. (2006). Inhibition of PKR by RNA and DNA viruses. Virus Research, 119: 100–110.PubMedCrossRefGoogle Scholar
  66. Li, K., Foy, E., Ferreon, J.C., Nakamura, M., Ferreon, A.C.M., Ikeda, M., Ray, S.C., Gale, M., Lemon, S.M. (2005). Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the toll-like receptor 3 adapter protein TRIF. Proceedings of National Academy of Sciences (USA), 102: 2992–2997.CrossRefGoogle Scholar
  67. Lin, W., Choe, W.H., Hiasa, Y., Kamegaya, Y., Blackard, J.T., Schmidt, E.V., Chung, R.T. (2005). Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterology, 128: 1034–1041.PubMedCrossRefGoogle Scholar
  68. Lindenbach, B.D., Evans, M.J., Syder, A.J., Wolk, B., Tellinghuisen, T.L., Liu, C.C., Maruyama, T., Hynes, R.O., Burton, D.R., McKeating, J.A., Rice, C.M. (2005). Complete replication of hepatitis C virus in cell culture. Science, 309: 623–626.PubMedCrossRefGoogle Scholar
  69. Lohmann, V., Korner, 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.PubMedCrossRefGoogle Scholar
  70. Lucas, S., Bartolome, J., Correno, V. (2005). Hepatitis C virus core protein down–regulates transcription of interferon-induced antiviral genes. Journal of Infectious Disease, 191: 93–99.CrossRefGoogle Scholar
  71. 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., the International Hepatitis Interventional Therapy Group. (2001). Peginterferon alpha-2b plus ribavirin compared with interferon alpha 2b plus ribavirin for initial treatment of chronic hepatitis C. A randomized trial. Lancet, 358: 958–965.PubMedCrossRefGoogle Scholar
  72. Macquillan, G.C., Niu, X., Speers, D., English, S., Garas, G., Harnett, G.B., Reed, W.D., Allam, J.E., Jeffrey, G.P. (2004). Does sequencing the PKRBD of hepatitis C virus NS5A predict therapeutic response to combination therapy in an Australian population? Journal of Gastroenterology Hepatology, 19: 551–557.CrossRefGoogle Scholar
  73. Meng, L.R., Mohan, R., Kwok, B.H., Elofsson, M., Sin, N., Crew, C.M. (1999). Epoxomicin, a potent & selective proteosome inhibitor, exhibits in vivo antiinflammatory activity. Proceedings of National Academy of Science (USA), 96: 10403–10408.CrossRefGoogle Scholar
  74. 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 (Con-1 NK 5.1). Intervirology, 49: 37–43.PubMedCrossRefGoogle Scholar
  75. Nousbaum, J., Polyak, S.J., Ray, S.C., Sullivan, D.G., Larson, A.M., Carithers, R.L., Gretch, D.R. (2000). Prospective characterization of full-length hepatitis C virus NS5A quasispecies during induction and combination antiviral therapy. Journal of Virology, 74: 9028–9038.PubMedCrossRefGoogle Scholar
  76. Novick, D., Cohen, B., Bubinstein, M. (1994). The human interferon alpha/beta receptor: characterization and molecular cloning. Cell, 77: 391–400.PubMedCrossRefGoogle Scholar
  77. Otto, G.A., Pulglisi, J.D. (2004). The pathway of HCV IRES-mediated translation initiation. Cell, 119: 369–380.PubMedCrossRefGoogle Scholar
  78. Pai, M., Prabhu, R., Panebra, A., Nangle, S., Haque, S., Bastian, F., Garry, R., Agrawal, K., Goodbourn, S., Dash, S. (2005). Activation of interferon stimulated response element (ISRE) in Huh-7 cells replicating HCV subgenomic RNA. Intervirology, 48: 301–311.PubMedCrossRefGoogle Scholar
  79. Paterson, M., Laxton, C.D., Thomas, H.C., Ackril, A.M., Foster, G.R. (1999). Hepatitis C virus NS5A protein inhibits interferon antiviral activity, but the effects do not correlate with clinical response. Gastroenterology, 117: 1187–1197.PubMedCrossRefGoogle Scholar
  80. Pawlotsky, J.M. (2000). Hepatitis C virus resistance to antiviral therapy. Hepatology, 32: 889–896.PubMedCrossRefGoogle Scholar
  81. Pawlotsky, J.M. (2003). The nature of interferon-alpha resistance in hepatitis C virus infection. Current Opinion on Infectious Disease, 16: 587–592.CrossRefGoogle Scholar
  82. Pesch, V., Lanaya, H., Renauld, J.C., Michiels, T. (2004). Characterization of the murine alpha interferon gene family. Journal of Virology, 78: 8219–8228.PubMedCrossRefGoogle Scholar
  83. Peterson, M., Laxton, C.D., Thomas, H.C., Ackrill, A.M., Foster, G.R. (1999). Hepatitis C virus NS5A protein inhibits interferon antiviral activity but the effects do not correlate with clinical response. Gastroenterology, 117: 1187–1197.CrossRefGoogle Scholar
  84. Platanias, L.C., Uddin, S., Domanski, P., Colamonici, O.R. (1996). Differences in interferon alfa and beta signalling. Interferon beta selectively induces the interaction of the alpha and beta L subunits of the type 1 interferon receptor. Journal of Biological Chemistry, 271: 23630–23633.PubMedCrossRefGoogle Scholar
  85. Polyak, S.J., Khabar, K.S.A., Rezeiq, M., Gretch, D.R. (2001). 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.PubMedCrossRefGoogle Scholar
  86. Polyak, S.J., Khabar, K.S.A., Paschal, D.M., Ezelle, H.J., Duverlie, G., Barber, G.N., Levy, D.E., Mukaida, N., Gretch, D.R. (2001). 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.PubMedCrossRefGoogle Scholar
  87. Prabhu, R., Joshi, V., Garry, R.F., Bastian, F., Haque, S., Regenstein, F., Thung, S.N., Dash, S. (2004). Interferon alpha-2b inhibits negative strand RNA and protein expression from full-length HCV1a infectious clone. Experimental and Molecular Pathology, 76: 242–252.PubMedCrossRefGoogle Scholar
  88. Qi, Z., Kalkeri, G., Hanible, J., Prabhu, R., Bastian, F., Garry, R.F., Dash, S. (2003). Stem-loop structures (II-IV) of the 5′ untranslated sequences are required for the expression of the full-length hepatitis C virus genome. Archives of Virology, 148: 449–467.PubMedCrossRefGoogle Scholar
  89. Reed, K.E., Rice, C.M. (2000). Overview of hepatitis C virus genome structure, polyprotein processing and protein properties. Current Topics of Microbiology & Immunology, 242: 55–84.Google Scholar
  90. Rice, C.M. (1996). Flaviviridae: the viruses and their replication. In: B.N. Fields, D.M. Knipe, P.M. Howley, et al. (eds). (pp. 936–959) Fields Virology, 3rd ed., Philadelphia: Lippincott-Raven.Google Scholar
  91. Rivas-Estilla, A.M., Svitkin, Y., Lastra, M.L., Hatzoglou, M., Sherker, A., Koromilas, A.E. (2002). PKR-dependent mechanisms of gene expression from a subgenomic hepatitis C virus clone. Journal of Virology, 76: 10637–10653.PubMedCrossRefGoogle Scholar
  92. Robek, M.D., Boyd, B.S., Chisari, F.V. (2005). Lambda interferon inhibits hepatitis B and hepatitis C virus replication. Journal of Virology, 79: 3851–3854.PubMedCrossRefGoogle Scholar
  93. Schinkel, J., Spoon, W.J., Kroes, A.C. (2004). Meta-analysis of mutations in the NS5A gene and hepatitis C virus resistance to interferon therapy: uniting discordant conclusions. Antiviral Therapy, 9: 275–286.PubMedGoogle Scholar
  94. Schroder, K., Hertzog, P.J., Ravasi, T., Hume, D.A. (2004). Interferon gamma: an overview of signals, mechanisms and functions. Journal of Leukocyte Biology, 75: 163–189.PubMedCrossRefGoogle Scholar
  95. Sen, G.C. (2001). Viruses and interferons. Annual Revew of Microbiology, 55: 255–281.CrossRefGoogle Scholar
  96. Shimazaki, T., Honda, M., Kaneko, S., Kobayashi, K. (2002). Inhibition of internal ribosomal entry site-directed translation of HCV by recombinant IFN-alpha correlates with a reduced La protein. Hepatology, 35: 199–208.PubMedCrossRefGoogle Scholar
  97. Shimizu, Y.K., Feinstone, S.M., Kohara, M., Purcell, R.H., Yoshikura, H. (1996). Hepatitis C virus: detection of intracellular virus particles by electron microscopy. Hepatology, 23: 205–209.PubMedCrossRefGoogle Scholar
  98. Shimizu, Y.K., Purcell, R.H., Yoshikura, H. (1993). Correlation between the infectivity of hepatitis C virus in vivo and its infectivity in vitro. Proceedings of National Academy of Sciences (USA), 90: 6037–6041.CrossRefGoogle Scholar
  99. Shimizu, Y.K., Iwamoto, A., Hijikata, M., Purcell, R.H., Yoshikura, H. (1992). Evidence for in vitro replication of hepatitis C virus genome in a human T-cell line. Proceedings of National Academy of Sciences (USA), 89: 5477–5481.CrossRefGoogle Scholar
  100. Shimizu, Y.K., Yoshikura, H. (1994). Multicycle infection of hepatitis C virus in cell culture and inhibition by alpha and beta interferons. Journal of Virology, 68: 8406–8408.PubMedGoogle Scholar
  101. Simmonds, P. (2004). Genetic diversity and evolution of hepatitis C virus—15 years on. Journal of General Virology, 85: 3173–3188.PubMedCrossRefGoogle Scholar
  102. Stark, G.R., Kerr, I.M., William, B.R.G., Silverman, R.H., Schreiber, R.D. (1998). How cells respond to interferons. Annual Review of Biochemistry, 67: 227–264.PubMedCrossRefGoogle Scholar
  103. Strader, D.B., Wright, T., Thomas, D.L., Seeff, L.B. (2004). Diagnosis, management, and treatment of hepatitis C. Hepatology, 39: 1147–1171.PubMedCrossRefGoogle Scholar
  104. Sumpter, R., Loo, Y.-M., Foy, E., Li, K., Yoneyama, M., Fujita, T., Lemon, S.M., Gale, M. (2005). Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. Journal of Virology, 79: 2689–2699.PubMedCrossRefGoogle Scholar
  105. Taylor, D.R., Shi, S.T., Romano, P.R., Barber, G.N., Lai, M.C. (1999). Inhibition of the interferon-inducible protein kinase R by HCV E2 protein. Science, 285: 107–109.PubMedCrossRefGoogle Scholar
  106. Uze, G., Lutfalla, G., Gresser, I. (1990). Genetic transfer of a functional human interferon alpha-receptor into mouse cells: cloning and expression of its cDNA. Cell, 60: 225–234.PubMedCrossRefGoogle Scholar
  107. Uze, G., Lutfalla, G., Mongensen, K.E. (1995). Alpha and beta interferons and their receptor and their friends and relations. Journal of Interferon Research, 15: 3–26.CrossRefGoogle Scholar
  108. Vrolijk, J.M., Kaul, A., Hanson, B.E., Lohmann, V., Haagmans, B.L., Schalm, S.W., Bartenschalager, R. (2003). A replicon-based bioassay for the measurement of interferons in patients with chronic hepatitis C. Journal of Virological Methods, 110: 201–209.PubMedCrossRefGoogle Scholar
  109. Wakita, T., Pietschmann, T., Kato, T., Date, T., Miyamoto, M., Zhao, Z., Murthy, K., Habermann, A., Krausslich, H.G., Mizokami, M., Bartenschlager, R., Liang, T.J. (2005). Production of infectious hepatitis C virus in tissue culture from cloned viral genome. Nature Medicine, 11: 791–796.PubMedCrossRefGoogle Scholar
  110. Wang, C., Pflugheber, J., Sumpter, R., Sodora, D.L., Hui, D., Sen, G., Gale, M. (2003). Alpha interferon induces distinct translational control programs to suppress hepatitis C virus RNA replication. Journal of Virology, 77: 3898–3912.PubMedCrossRefGoogle Scholar
  111. William, B.R.G. (1991). Transcriptional regulation of interferon stimulated genes. European Journal of Biochemistry, 200: 1–11.CrossRefGoogle Scholar
  112. Yanagi, M., Purcell, R.H., Emerson, S.U., Bukh, J. (1997). Transcripts from a single full-length cDNA clone of hepatitis C virus are infectious when directly transfected in to the livers of a chimpanzee. Proceedings of National Academy of Sciences (USA), 94: 8738–8743.Google Scholar
  113. Yi, M., Lemon, S.M. (2003). 3′ non-translated RNA signals required for replication of hepatitis C virus RNA. Journal of Virology, 77: 3557–3568.PubMedCrossRefGoogle Scholar
  114. Yoo, B.J., Selby, M.J., Choe, J., Suh, B.S., Choi, S.H, Joh, J.S., Nuovo, G.J., Lee, H.-S. Houghton, M., Han, J.H. (1995). Transfection of a differentiated human hepatoma cell line (Huh-7) with in vitro-transcribed hepatitis C virus (HCV) RNA and establishment of a long-term culture persistently infected with HCV. Journal of Virology, 69: 32–38.PubMedGoogle Scholar
  115. Zhong, J., Gastaminza, P., Cheng, G., Kapadia, S., Kato, T., Burton, D.R., Wieland, S.F., Uprichard, S.L., Wakita, T., Chisari, F.V. (2005). Robust hepatitis C virus infection in vitro. Proceedings of National Academy of Sciences (USA), 102: 9294–9299.Google Scholar
  116. 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 alpha antiviral activity in an HCV replicon cell line. Hepatology, 37: 1180–1188.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Srikanta Dash
    • 1
  • Sidhartha Hazari
  • Robert F Garry
  • Fredric Regenstein
  1. 1.Department of Pathology and Laboratory MedicineTulane University Health Sciences CenterSL 79

Personalised recommendations