Viral determinants of resistance to treatment in patients with hepatitis C

Clinical Microbiology Reviews

Volumn 20, Issue 1, 2007, Pages 23-38

  Wohnsland, Anette ^a   Hofmann, Wolf Peter ^a   Sarrazin, Christoph ^a  

^a SAARLAND UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

2',5' OLIGOADENYLATE SYNTHETASE; ALPHA INTERFERON; AMANTADINE; CD81 ANTIGEN; CILUPREVIR; GLYCOPROTEIN E2; HCV 796; INITIATION FACTOR 2ALPHA; INTERFERON; INTERLEUKIN 8; LEUCINE; NM 107; NONSTRUCTURAL PROTEIN 5A; NUCLEOTIDYLTRANSFERASE INHIBITOR; PEGINTERFERON; PHENYLALANINE; PROTEIN KINASE R; PROTEINASE INHIBITOR; R 1626; RIBAVIRIN; SCH 503034; UNCLASSIFIED DRUG; VALOPICITABINE; VIRUS PROTEIN; VX 950;

AMINO ACID SEQUENCE; ANTIBIOTIC RESISTANCE; ANTIVIRAL ACTIVITY; CHRONIC HEPATITIS; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG RESPONSE; DRUG TREATMENT FAILURE; EVALUATION; HEPATITIS C; HEPATITIS C VIRUS; HOST RESISTANCE; HUMAN; IMMUNE RESPONSE; INNATE IMMUNITY; MONOTHERAPY; MUTATION RATE; NONHUMAN; OUTCOME ASSESSMENT; PHENOTYPE; PHENOTYPIC VARIATION; PROTEIN FUNCTION; REVIEW; SEQUENCE ANALYSIS; SIGNAL TRANSDUCTION; STANDARD; VIRUS MUTATION;

AMANTADINE; ANTIVIRAL AGENTS; DRUG RESISTANCE, VIRAL; HEPACIVIRUS; HEPATITIS C; HUMANS; INTERFERON-ALPHA; RIBAVIRIN;

HEPATITIS C VIRUS;

EID: 33846521154     PISSN: 08938512     EISSN: None     Source Type: Journal    
DOI: 10.1128/CMR.00010-06     Document Type: Review

References (172)

1. Abbate, I., I. Lo Iacono, R. Di Stefano, G. Cappiello, E. Girardi, R. Longo, D. Ferraro, G. Antonucci, V. Di Marco, M. Solmone, A. Craxi, G. Ippolito, and M. R. Capobianchi. 2004. HVR-1 quasispecies modifications occur early and are correlated to initial but not sustained response in HCV-infected patients treated with pegylated- or standard-interferon and ribavirin. J. Hepatol. 40:831-836.
2. Alexopoulou, L., A. C. Holt, R. Medzhitov, and R. A. Flavell. 2001. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732-738.
3. Andant, C., J. Lamoril, J. C. Deybach, P. Jouet, and J. C. Soule. 2000. Amantadine for chronic hepatitis C: pilot study in 14 patients. Eur. J. Gastroenterol. Hepatol. 12:1319-1322.
4. Appel, N., T. Pietschmann, and R. Bartenschlager. 2005. Mutational analysis of hepatitis C virus nonstructural protein 5A: potential role of differential phosphorylation in RNA replication and identification of a genetically flexible domain. J. Virol. 79:3187-3194.
5. Asahina, Y., N. Izumi, N. Enomoto, M. Uchihara, M. Kurosaki, Y. Onuki, Y. Nishimura, K. Ueda, K. Tsuchiya, H. Nakanishi, T. Kitamura, and S. Miyake. 2005. Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C. J. Hepatol. 43:623-629.
6. aus dem Siepen, M., V. Lohmann, M. Wiese, S. Ross, M. Roggendorf, and S. Viazov. 2005. Nonstructural protein 5A does not contribute to the resistance of hepatitis C virus replication to interferon alpha in cell culture. Virology 336:131-136.
7. Berg, T., B. Kronenberger, H. Hinrichsen, T. Gerlach, P. Buggisch, E. Herrmann, U. Spengler, T. Goeser, S. Nasser, K. Wursthorn, G. R. Pape, U. Hopf, and S. Zeuzem. 2003. Triple therapy with amantadine in treatment-naive patients with chronic hepatitis C: a placebo-controlled trial. Hepatology 37:1359-1367.
8. Berg, T., M. A. Mas, M. Hohne, B. Wiedenmann, U. Hopf, and E. Schreier. 2000. Mutations in the E2-PePHD and NS5A region of hepatitis C virus type 1 and the dynamics of hepatitis C viremia decline during interferon alfa treatment. Hepatology 32:1386-1395.
9. Berg, T., C. Sarrazin, E. Herrmann, H. Hinrichsen, T. Gerlach, R. Zachoval, B. Wiedenmann, U. Hopf, and S. Zeuzem. 2003. Prediction of treatment outcome in patients with chronic hepatitis C: significance of baseline parameters and viral dynamics during therapy. Hepatology 37:600-609.
10. Bichko, V., L. Qu, M. la Colla, M. Tausek, S. Bergelson, C. Pierra, R. Storer, G. Gosselin, J. P. Sommadossi, and D. Standring. 2005. Abstr. 56th Am. Assoc. Study Liver Dis., abstr. 860.
11. Blindenbacher, A., F. H. Duong, L. Hunziker, S. T. Stutvoet, X. Wang, L. Terracciano, D. Moradpour, H. E. Blum, T. Alonzi, M. Tripodi, N. La Monica, and M. H. Heim. 2003. Expression of hepatitis C virus proteins inhibits interferon alpha signaling in the liver of transgenic mice. Gastroenterology 124:1465-1475.
12. Bode, J. G., S. Ludwig, C. Ehrhardt, U. Albrecht, A. Erhard t, F. Schaper, P. C. Heinrich, and D. Haussinger. 2003. IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. FASEB J. 17:488-490.
13. Bougie I., and M. Bisaillon. 2003. Initial binding of the broad spectrum antiviral nucleoside ribavirin to the hepatitis C virus RNA polymerase. J. Biol. Chem. 278:52471-52478.
14. Brillanti, S., F. Levantesi, L. Masi, M. Foli, and L. Bolondi. 2000. Triple antiviral therapy as a new option for patients with interferon nonresponsive chronic hepatitis C. Hepatology 32:630-634.
15. Castelain, S., H. Khorsi, J. Roussel, C. Francois, O. Jaillon, D. Capron, F. Penin, C. Wychowski, E. Meurs, and G. Duverlie. 2002. Variability of the nonstructural 5A protein of hepatitis C virus type 3a isolates and relation to interferon sensitivity. J. Infect. Dis. 185:573-583.
16. Chambers, T. J., X. Fan, D. A. Droll, E. Hembrador, T. Slater, M. W. Nickells, L. B. Dustin, and A. M. Dibisceglie. 2005. Quasispecies heterogeneity within the E1/E2 region as a pretreatment variable during pegylated interferon therapy of chronic hepatitis C virus infection. J. Virol. 79:3071-3083.
17. Chayama, K., A. Tsubota, M. Kobayashi, K. Okamoto, M. Hashimoto, Y. Miyano, H. Koike, M. Kobayashi, I. Koida, Y. Arase, S. Saitoh, Y. Suzuki, N. Murashima, K. Ikeda, and H. Kumada. 1997. Pretreatment virus load and multiple amino acid substitutions in the interferon sensitivity-determining region predict the outcome of interferon treatment in patients with chronic genotype 1b hepatitis C virus infection. Hepatology 25:745-749.
18. Choo, Q. L., G. Kuo, A. J. Weiner, L. R. Overby, D. W. Bradley, and M. Houghton, 1989. Isolation of a cDNA clone derived from blood-borne non-A, non-B viral hepatitis genome. Science 244:359-362.
19. Chung, R. T., A. Monto, J. L. Dienstag, and L. M. Kaplan. 1999. Mutations in the NS5A region do not predict interferon-responsiveness in American patients infected with genotype 1b hepatitis C virus. J. Med. Virol. 58:353-358.
20. Contreras, A. M., Y. Hiasa, W. He, A. Terella, E. V. Schmidt, and R. T. Chung, 2002. Viral RNA mutations are region specific and increased by ribavirin in a full-length hepatitis C virus replication system. J. Virol. 76:8505-8517.
21. Crotty, S., D. Maag, J. J. Arnold, W. Zhong, J. Y. Lau, Z. Hong, R. Andino, and C. E. Cameron. 2000. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat. Med. 6:1375-1379.
22. 20a. Danehower, S. C., G. Lutchman, and M. G. Ghany. 2004. Abstr. 11th Int. Symp. Hepat. C Virus Relat. Viruses, abstr. 73.
23. Deltenre, P., J. Henrion, V. Canva, S. Dharancy, F. Texier, A. Louvet, S. De Maeght, J. C. Paris, and P. Mathurin. 2004. Evaluation of amantadine in chronic hepatitis C: a meta-analysis. J. Hepatol. 41:462-473.
24. de Lucas, S., J. Bartolome, and V. Carreno. 2005. Hepatitis C virus core protein down-regulates transcription of interferon-induced antiviral genes. J. Infect. Dis. 191:93-99.
25. Di Bisceglie, A. M., M. Shindo, T. L. Fong, M. W. Fried, M. G. Swain, N. V. Bergasa, C. A. Axiotis, J. G. Waggoner, Y. Park, and J. H. Hoofnagle. 1992. A pilot study of ribavirin therapy for chronic hepatitis C. Hepatology 16:649-654.
26. Dixit, N. M., J. E. Layden-Almer, T. J. Layden, and A. S. Perelson. 2004. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature 432:922-924.
27. Dubuisson, J. 2000. Folding, assembly and subcellular localization of hepatitis C virus glycoproteins. Curr. Top. Microbiol. Immunol. 242:135-148.
28. Duong, F. H., M. Filipowicz, M. Tripodi, N. La Monica, and M. H. Heim. 2004. Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A. Gastroenterology 126:263-277.
29. Dusheiko, G., J. Main, H. Thomas, O. Reichard, C. Lee, A. Dhillon, S. Rassam, A. Fryden, H. Reesink, M. Bassendine, G. Norkrans, T. Cuypers, N. Lelie, P. Telfer, J. Watson, C. Weegink, P. Sillikens, and O. Weiland. 1996. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J. Hepatol. 25:591-598.
30. Duverlie, G., H. Khorsi, S. Castelain, O. Jaillon, J. Izopet, F. Lunel, F. Eb, F. Penin, and C. Wychowski. 1998. Sequence analysis of the NS5A protein of European hepatitis C virus 1b isolates and relation to interferon sensitivity. J. Gen. Virol. 79:1373-1381.
31. Enomoto, N., I. Sakuma, Y. Asahina, M. Kurosaki, T. Murakami, C. Yamamoto, N. Izumi, F. Marumo, and C. Sato. 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. J. Clin. Investig. 96:224-230.
32. Enomoto, N., I. Sakuma, Y. Asahina, M. Kurosaki, T. Murakami, C. Yamamoto, Y. Ogura, N. Izumi, F. Marumo, and C. Sato. 1996. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N. Engl. J. Med. 334:77-81.
33. Farci, P., A. Shimoda, A. Coiana, G. Diaz, G. Peddis, J. C. Melpolder, A. Strazzera, D. Y. Chien, S. J. Munoz, A. Balestrieri, R. H. Purcell, and H. J. Alter. 2000. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science 288:339-344.
34. Farci, P., R. Strazzera, H. J. Alter, S. Farci, D. Degioannis, A. Coiana, G. Peddis, F. Usai, G. Serra, L. Chessa, G. Diaz, A. Balestrieri, and R. H. Purcell. 2002. Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome. Proc. Natl. Acad. Sci. USA 99:3081-3086.
35. Feld, J. J., and J. H. Hoofnagle. 2005. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 436:967-972.
36. Ferenci, P., E. Formann, H. Laferl, M. Gschwantler, F. Hackl, H. Brunner, R. Hubmann, C. Datz, R. Stauber, P. Steindl-Munda, H. H. Kessler, A. Klingler, A. Gangl, et al. 2006. Randomized, double-blind, placebo-controlled study of peginterferon alfa-2a (40KD) plus ribavirin with or without amantadine in treatment-naive patients with chronic hepatitis C genotype 1 infection. J. Hepatol. 44:275-282.
37. Foy, E., K. Li, R. Sumpter, Jr., Y. M. Loo, C. L. Johnson, C. Wang, P. M. Fish, M. Yoneyama, T. Fujita, S. M. Lemon, and M. Gale, Jr. 2005. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc. Natl. Acad. Sci. USA 102:2986- 2991.
38. Foy, E., K. Li, C. Wang, R. Sumpter, Jr., M. Ikeda, S. M. Lemon, and M. Gale, Jr. 2003. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300:1145-1148.
39. Francois, C., G. Duverlie, D. Rebouillat, H. Khorsi, S. Castelain, H. E. Blum, A. Gatignol, C. Wychowski, D. Moradpour, and E. F. Meurs. 2000. Expression of hepatitis C virus proteins interferes with the antiviral action of interferon independently of PKR-mediated control of protein synthesis. J. Virol. 74:5587-5596.
40. Fried, M. W., M. L. Shiffman, K. R. Reddy, C. Smith, G. Marinos, F. L. Gonzales, D. Häussinger, M. Diago, G. Carosi, D. Dhumeaux, A. Craxi, A. Lin, J. Hoffmann, and J. Yu. 2002. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med. 347:975-982.
41. Gale, M., Jr., and E. M. Foy. 2005. Evasion of intracellular host defence by hepatitis C virus. Nature 436:939-945.
42. Gale, M. J., Jr., M. J. Korth, and M. G. Katze. 1998. Repression of the PKR protein kinase by the hepatitis C virus NS5A protein: a potential mechanism of interferon resistance. Clin. Diagn. Virol. 10:157-162.
43. Gale, M. J., Jr., M. J. Korth, N. M. Tang, S. L. Tan, D. A. Hopkins, T. E. Dever, S. J. Polyak, D. R. Gretch, and M. G. Katze. 1997. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural SA protein. Virology 230:217-227.
44. Gaudy, C., M. Lambele, A. Moreau, P. Veillon, F. Lunel, and A. Goudeau. 2005. Mutations within the hepatitis C virus genotype 1b E2-PePHD domain do not correlate with treatment outcome. J. Clin. Microbiol. 43:750-754.
45. Gerotto, M., F. Dal Pero, P. Pontisso, F. Noventa, A. Gatta, and A. Alberti. 2000. Two PKR inhibitor HCV proteins correlate with early but not sustained response to interferon. Gastroenterology 119:1649-1655.
46. Gimenez-Barcons, M., C. Wang, M. Chen, J. M. Sanchez-Tapias, J. C. Saiz, and M. Gale, Jr. 2005. The oncogenic potential of hepatitis C virus NS5A sequence variants is associated with PKR regulation. J. Interferon Cytokine Res. 25:152-164.
47. Godofsky, E., N. Afdhal, V. Rustgi, L. Shick, L. Duncan, X. J. Zhou, G. Chao, C. Fang, B. Fielman, M. Myers, and N. A. Brown. 2005. Abstr. 39th Eur. Assoc. Study Liver, abstr. 96.
48. Goff, J. S., R. M. Reveille, and J. Johnson. 2000. Treatment of chronic hepatitis C with amantadine. Dig. Dis. Sci. 45:1389-1391.
49. Gonzalez-Peralta, R. P., K. Qian, J. Y. She, G. L. Davis, T. Ohno, M. Mizokami, and J. Y. Lau. 1996. Clinical implications of viral quasispecies heterogeneity in chronic hepatitis C. J. Med. Virol. 49:242-247.
50. Grandvaux, N., M. J. Servant, B. tenOever, G. C. Sen, S. Balachandran, G. N. Barber, R. Lin, and J. Hiscott. 2002. Transcriptional profiling of interferon regulatory factor 3 target genes: direct involvement in the regulation of interferon-stimulated genes. J. Virol. 76:5532-5539.
51. Griffin, S. D., L. P. Beales, D. S. Clarke, O. Worsfold, S. D. Evans, J. Jaeger, M. P. Harris, and D. J. Rowlands. 2003. The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, amantadine. FEES Lett. 535:34-38.
52. Griffin, S. D., R. Harvey, D. S. Clarke, W. S. Barclay, M. Harris, and D. J. Rowlands. 2004. A conserved basic loop in hepatitis C virus p7 protein is required for amantadine-sensitive ion channel activity in mammalian cells but is dispensable for localization to mitochondria. J. Gen. Virol. 85:451-461.
53. Hadziyannis, S. J., H. Sette, Jr., T. R. Morgan, V. Balan, M. Diago, P. Marcellin, G. Ramadori, H. C. Bodenheimer, Jr., D. Bernstein, M. Rizzetto, S. Zeuzem, P. J. Pockros, A. Lin, and A. M. Ackrill. 2004. Peginterferon-alfa2a and ribavirin combination therapy in chronic hepatitis C. A randomized study of treatment duration and ribavirin dose. Ann. Intern. Med. 140:346-355.
54. Han, J. Q., and D. J. Barton. 2002. Activation and evasion of the antiviral 2′-5′ oligoadenylate synthetase/ribonuclease L pathway by hepatitis C virus mRNA. RNA 8:512-525.
55. Han, J. Q., G. Wroblewski, Z. Xu, R. H. Silverman, and D. J. Barton. 2004. Sensitivity of hepatitis C virus RNA to the antiviral enzyme ribonuclease L is determined by a subset of efficient cleavage sites. J. Interferon Cytokine Res. 24:664-676.
56. Hay, A. J., A. J. Wolstenholme, J. J. Skehel, and M. H. Smith. 1985. The molecular basis of the specific anti-influenza action of amantadine. EMBO J. 4:3021-3024.
57. He, Y., S. L. Tan, S. U. Tareen, S. Vijaysri, J. O. Langland, B. L. Jacobs, and M. G. Katze. 2001. Regulation of mRNA translation and cellular signaling by hepatitis C virus nonstructural protein NS5A. J. Virol. 75:5090-5098.
58. Heim, M. H., D. Moradpour, and H. E. Blum. 1999. Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway. J. Virol. 73:8469-8475.
59. Helbling, B., I. Stamenic, F. Viani, J. J. Gonvers, J. F. Dufour, J. Reichen, G. Cathomas, M. Steuerwald, J. Borovicka, M. Sagmeister, and E. L. Renner. 2002. Interferon and amantadine in naive chronic hepatitis C: a double-blind, randomized, placebo-controlled trial. Hepatology 35:447-454.
60. Herrmann, E., J. H. Lee, G. Marinos, M. Modi, and S. Zeuzem. 2003. Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon. Hepatology 37:1351-1358.
61. Herrmann, E., S. Zeuzem, C. Sarrazin, H. Hinrichsen, Y. Benhamou, M. P. Manns, M. Reiser, H. Reesink, J. L. Calleja, X. Forns, G. G. Steinmann, and G. Nehmiz. 2006. Viral kinetics in patients with chronic hepatitis C treated with the serine protease inhibitor BILN 2061. Antivir. Ther. 11:371-376.
62. Hino, K., Y. Yamaguchi, D. Fujiwara, Y. Katoh, M. Korenaga, M. Okazaki, M. Okuda, and K. Okita. 2000. Hepatitis C virus quasispecies and response to interferon therapy in patients with chronic hepatitis C: a prospective study. J. Viral Hepat. 7:36-42.
63. Hinrichsen, H., Y. Benhamou, H. Wedemeyer, M. Reiser, R. E. Sentjens, J. L. Calleja, X. Forns, A. Erhardt, J. Cronlein, R. L. Chaves, C. L. Yong, G. Nehmiz, and G. G. Steinmann. 2004. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 127:1347-1355.
64. Hofmann, W. P., C. Sarrazin, B. Kronenberger, B. Schonberger, K. Bruch, and S. Zeuzem. 2003. Mutations within the CD81-binding sites and hypervariable region 2 of the envelope 2 protein: correlation with treatment response in hepatitis C virus-infected patients. J. Infect. Dis. 187:982-987.
65. Hofmann, W. P., A. Polta, E. Herrmann, U. Mihm, B. Kronenberger, T. Sonntag, V. Lohmann, B. Schonberger, S. Zeuzim and C. Sarrazin. Mutagenic effect of ribavirin on hepatitis C non-stmctural 5B quasispecies in vitro and during antiviral therapy. Gastroenterology, in press.
66. Jeffers, L. J., W. Cassidy, C. D. Howell, S. Hu, and K. R. Reddy. 2004. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology 39:1702-1708.
67. Kanazawa, Y., N. Hayashi, E. Mita, T. Li, H. Higiwara, A. Kasahara, H. Fusamoto, and T. Kamada. 1994. Influence of viral quasispecies on effectiveness of interferon therapy in chronic hepatitis C patients. Hepatology 20:1121-1130.
68. Khabar, K. S., F. Al Zoghaibi, M. N. Al Ahdal, T. Murayama, M. Dhalla, N. Mukaida, M. Taha, S. T. Al Sedairy, Y. Siddiqui, G. Kessie, and K. Matsushima. 1997. The alpha chemokine, interleukin 8, inhibits the anti-viral action of interferon alpha. J. Exp. Med. 186:1077-1085.
69. Khorsi, H., S. Castelain, A. Wyseur, J. Izopet, V. Canva, A. Rombout, D. Capron, J. P. Capron, F. Lunel, L. Stuyver, and G. Duverlie. 1997. Mutations of hepatitis C virus 1b NS5A 2209-2248 amino acid sequence do not predict the response to recombinant interferon-alfa therapy in French patients. J. Hepatol. 27:72-77.
70. Knapp, S., L. J. Yee, A. J. Frodsham, B. J. Hennig, S. Hellier, L. Zhang, M. Wright, M. Chiaramonte, M. Graves, H. C. Thomas, A. V. Hill, and M. R. Thursz. 2003. Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR. Genes Immun. 4:411-419.
71. Kobayashi, M., K. Watanabe, M. Ishigami, K. Murase, H. Ito, K. Ukai, M. Yano, K. Takagi, M. Hatten, S. Kakumu, and K. Yoshioka. 2002. Amino acid substitutions in the nonstructural region 5A of hepatitis C virus genotypes 2a and 2b and its relation to viral load and response to interferon. Am. J. Gastroenterol. 97:988-998.
72. Koizumi, K., N. Enomoto, M. Kurosaki, T. Murakami, N. Izumi, F. Marumo, and C. Sato. 1995. Diversity of quasispecies in various disease stages of chronic hepatitis C virus infection and its significance in interferon treatment. Hepatology 22:30-35.
73. Kurosaki, M., N. Enomoto, T. Murakami, I. Sakuma, Y. Asahina, C. Yamamoto, T. Ikeda, S. Tozuka, N. Izumi, F. Marumo, and C. Sato. 1997. Analysis of genotypes and amino acid residues 2209 to 2248 of the NS5A region of hepatitis C virus in relation to the response to interferon-beta therapy. Hepatology 25:750-753.
74. Lamarre, D., P. C. Anderson, M. Bailey, P. Beaulieu, G. Bolger, P. Bonneau, M. Bos, D. R. Cameron, M. Cartier, M. G. Cordingley, A. M. Faucher, N. Goudreau, S. H. Kawai, G. Kukolj, L. Lagace, S. R. LaPlante, H. Narjes, M. A. Poupart, J. Rancourt, R. E. Sentjens, R. St. George, B. Simoneau, G. Steinmann, D. Thibeault, Y. S. Tsantrizos, S. M. Weldon, C. L. Yong, and M. Llinas-Brunet. 2003. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426:186-189.
75. Lanford, R. E., B. Guerra, H. Lee, D. R. Averett, B. Pfeiffer, D. Chavez, L. Notvall, and C. Bigger, 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. J. Virol. 77:1092-1104.
76. Le Guen, B., G. Squadrito, B. Nalpas, P. Berthelot, S. Pol, and C. Brechot. 1997. Hepatitis C virus genome complexity correlates with response to interferon therapy: a study in French patients with chronic hepatitis C. Hepatology 25:1250-1254.
77. Li, K., E. Foy, J. C. Ferreon, M. Nakamura, A. C. Ferreon, M. Ikeda, S. C. Ray, M. Gale, Jr., and S. M. Lemon. 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.
78. Lin, C., C. A. Gates, B. G. Rao, D. L. Brennan, J. R. Fulghum, Y. P. Luong, J. D. Frantz, K. Lin, S. Ma, Y. Y. Wei, R. B. Perni, and A. D. Kwong. 2005. In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061. J. Biol. Chem. 280:36784-36791.
79. Lin, C., K. Lin, Y. P. Luong, B. G. Rao, Y. Y. Wei, D. L. Brennan, J. R. Fulghum, H. M. Hsiao, S. Ma, J. P. Maxwell, K. M. Cottrell, R. B. Perni, C. A. Gates, and A. D. Kwong. 2004. In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J. Biol. Chem. 279:17508- 17514.
80. Lin, W., W. H. Choe, Y. Hiasa, Y. Kamegaya, J. T. Blackard, E. V. Schmidt, and R. T. Chung. 2005. Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterology 128:1034-1041.
81. Lohmann, V., F. Körner, J. O. Koch, U. Herian, L. Theilmann, and R. Bartenschlager. 1999. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110-113.
82. Lopez-Labrador, F. X., S. Ampurdanes, M. Gimenez-Barcons, M. Guilera, J. Costa, M. T. Jimenez de Anta, J. M. Sanchez-Tapias, J. Rodes, and J. C. Saiz. 1999. Relationship of the genomic complexity of hepatitis C virus with liver disease severity and response to interferon in patients with chronic HCV genotype 1b infection. Hepatology 29:897-903. (Erratum, 29:1915.)
83. Lu, L., T. J. Pilot-Matias, K. D. Stewart, J. T. Randolph, R. Pithawalla, W. He, P. P. Huang, L. L. Klein, H. Mo, and A. Molla. 2004. Mutations conferring resistance to a potent hepatitis C virus serine protease inhibitor in vitro. Antimicrob. Agents Chemother. 48:2260-2266.
84. Lutchman, G. A., S. Danehower, C. Ward, T. J. Liang, J. H. Hoofnagle, M. Z. Thomson, and M. G. Ghany. 2004. Abstr. 55th Am. Assoc. Study Liver Dis., abstr. 512.
85. Maag, D., C. Castro, Z. Hong, and C. E. Cameron. 2001. Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. J. Biol. Chem. 276:46094-46098.
86. Mangia, A., G. Leandro, B. Helbling, E. L. Renner, M. Tabone, L. Sidoli, S. Caronia, G. R. Foster, S. Zeuzem, T. Berg, V. Di Marco, N. Cino, and A. Andriulli. 2004. Combination therapy with amantadine and interferon in naive patients with chronic hepatitis C: meta-analysis of individual patient data from six clinical trials. J. Hepatol. 40:478-483.
87. Mangia, A., G. L. Ricci, M. Persico, N. Minerva, V. Carretta, D. Bacca, M. Cela, M. Piattelli, M. Annese, G. Maio, D. Conte, V. Guadagnino, V. Pazienza, D. Festi, F. Spirito, and A. Andriulli. 2005. A randomized controlled trial of pegylated interferon alpha-2a (40 KD) or interferon alpha-2a plus ribavirin and amantadine vs interferon alpha-2a and ribavirin in treatment-naive patients with chronic hepatitis C. J. Viral Hepat. 12:292-299.
88. Manns, M. P., J. G. McHutchison, S. C. Gordon, V. K. Rustgi, M. Shiftman, R. Reindollar, Z. D. Goodman, K. Koury, M. Ling, and J. K. Albrecht. 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.
89. McKechnie, V. M., P. R. Mills, and E. A. McCruden. 2000. The NS5a gene of hepatitis C virus in patients treated with interferon-alpha. J. Med. Virol. 60:367-378.
90. Meylan, E., J. Curran, K. Hofmann, D. Moradpour, M. Binder, R. Bartenschlager, and J. Tschopp. 2005. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167-1172.
91. Migliaccio, G., J. E. Tomassini, S. S. Carroll, L. Tomei, S. Altamura, B. Bhat, L. Bartholomew, M. R. Bosserman, A. Ceccacci, L. F. Colwell, R. Cortese, R. De Francesco, A. B. Eldrup, K. L. Getty, X. S. Hou, R. L. LaFemina, S. W. Ludmerer, M. MacCoss, D. R. McMasters, M. W. Stahlhut, D. B. Olsen, D. J. Hazuda, and O. A. Flores. 2003. Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J. Biol. Chem. 278:49164-49170.
92. Mihm, U., N. Grigorian, C. Welsch, E. Herrmann, B. Kronenberger, G. Teuber, M. von Wagner, W. P. Hofmann, M. Albrecht, T. Lengauer, S. Zeuzem, and C. Sarrazin. 2006. Mutations in the HCV-p7 protein and sensitivity to antiviral therapy with amantadine in chronic hepatitis C. Antivir. Ther. 11:507-519.
93. Mihm, U., W. P. Hofmann, B. Kronenberger, M. von Wagner, S. Zeuzem, and C. Sarrazin. 2004. Correlation of serum interleukin 8 with virologic response to antiviral therapy in patients with chronic hepatitis C. J. Hepatol. 40:845-852.
94. Moradpour, D., P. Kary, C. M. Rice, and H. E. Blum. 1998. Continuous human cell lines inducibly expressing hepatitis C virus structural and non-structural proteins. Hepatology 28:192-201.
95. Moribe, T., N. Hayashi, Y. Kanazawa, E. Mita, H. Fusamoto, M. Negi, T. Kaneshige, H. Igimi, T. Kamada, and K. Uchida. 1995. Hepatitis C viral complexity detected by single-strand conformation polymorphism and response to interferon therapy. Gastroenterology 108:789-795.
96. Murakami, T., N. Enomoto, M. Kurosaki, N. Izumi, F. Marumo, and C. Sato. 1999. Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection. Hepatology 30:1045-1053.
97. Murashima, S., R. Kumashiro, T. Ide, I. Miyajima, T. Hino, Y. Koga, K. Ishii, T. Ueno, S. Sakisaka, and M. Sata. 2000. Effect of interferon treatment on serum 2′,5′-oligoadenylate synthetase levels in hepatitis C-infected patients. J. Med. Virol. 62:185-190.
98. Murphy, M. D., H. R. Rosen, G. I. Marousek, and S. Chou. 2002. Analysis of sequence configurations of the ISDR, PKR-binding domain, and V3 region as predictors of response to induction interferon-alpha and ribavirin therapy in chronic hepatitis C infection. Dig. Dis. Sci. 47:1195-1205.
99. Myers, R. P., K. Patel, S. Pianko, T. Poynard, and J. G. McHutchison. 2003. The rate of fibrosis progression is an independent predictor of the response to antiviral therapy in chronic hepatitis C. J. Viral Hepat. 10:16-22.
100. Naganuma, A., A. Nozaki, T. Tanaka, K. Sugiyama, H. Takagi, M. Mori, K. Shimotohno, and N. Kato. 2000. Activation of the interferon-inducible 2′-5′-oligoadenylate synthetase gene by hepatitis C virus core protein. J. Virol. 74:8744-8750.
101. Nagasaka, A., S. Hige, I. Tsunematsu, J. Yoshida, Y. Sasaki, T. Matsushima, and M. Asaka. 1996. Changes in hepatitis C virus quasispecies and density populations in patients before and after interferon therapy. J. Med. Virol. 50:214-220.
102. Nakazawa, T., N. Kato, S. Ohkoshi, A. Shibuya, and K. Shimotohno. 1994. Characterization of the 5′ noncoding and structural region of the hepatitis C virus genome from patients with non-A, non-B hepatitis responding differently to interferon treatment. J. Hepatol. 20:623-629.
103. Nousbaum, J., S. J. Polyak, S. C. Ray, D. G. Sullivan, A. M. Larson, R. L. Carithers, Jr., and D. R. Gretch. 2000. Prospective characterization of full-length hepatitis C virus NS5A quasispecies during induction and combination antiviral therapy. J. Virol. 74:9028-9038.
104. O'Brien, C., E. Godofsky, M. Rodriguez-Torres, N. Afdhal, S. C. Pappas, P. Pockros, E. Lawitz, N. Bzowej, V. Rustgi, M. Sulkowski, K. Sherman, I. Jacobson, G. Chao, S. Knox, K. Pietropaolo, and N. A. Brown. 2005. Abstr. 56th Am. Assoc. Study Liver Dis., abstr. 95.
105. Odeberg, J., Z. Yun, A. Sonnerborg, O. Weiland, and J. Lundeberg. 1998. Variation in the hepatitis C virus NS5A region in relation to hypervariable region 1 heterogeneity during interferon treatment. J. Med. Virol. 56:33-38.
106. Okada, S., Y. Akahane, H. Suzuki, H. Okamoto, and S. Mishiro. 1992. The degree of variability in the amino terminal region of the E2/NS1 protein of hepatitis C virus correlates with responsiveness to interferon therapy in viremic patients. Hepatology 16:619-624.
107. Olsen, D. B., A. B. Eldrup, L. Bartholomew, B. Bhat, M. R. Bosserman, A. Ceccacci, L. F. Colwell, J. F. Fay, O. A. Flores, K. L. Getty, J. A. Grobler, R. L. LaFemina, E. J. Markel, G. Migliaccio, M. Prhavc, M. W. Stahlhut, J. E. Tomassini, M. MacCoss, D. J. Hazuda, and S. S. Carroll. 2004. A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties. Antimicrob. Agents Chemother. 48:3944-3953.
108. Pascu, M., P. Martus, M. Hohne, B. Wiedenmann, U. Hopf, E. Schreier, and T. Berg. 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.
109. Pawlotsky, J. M., H. Dahari, A. U. Neumann, C. Hezode, G. Germanidis, I. Lonjon, L. Castera, and D. Dhumeaux. 2004. Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology 126:703-714.
110. Pawlotsky, J. M., G. Germanidis, A. U. Neumann, M. Pellerin, P. O. Frainais, and D. Dhumeaux. 1998. Interferon resistance of hepatitis C virus genotype 1b: relationship to nonstructural 5A gene quasispecies mutations. J. Virol. 72:2795-2805.
111. Pawlotsky, J. M., M. Pellerin, M. Bouvier, F. Roudot-Thoraval, G. Germanidis, A. Bastie, F. Darthuy, J. Remire, C. J. Soussy, and D. Dhumeaux. 1998. Genetic complexity of the hypervariable region 1 (HVR1) of hepatitis C virus (HCV): influence on the characteristics of the infection and responses to Interferon alfa therapy in patients with chronic hepatitis C. J. Med. Virol. 54:256-264.
112. Pawlotsky, J. M., R. Brillet, C. Hezode, and D. Dhumeaux. 2004. Abstr. 39th Eur. Assoc. Study Liver, abstr. 62.
113. Pfeiffer, J. K., and K. Kirkegaard. 2003. A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity. Proc. Natl. Acad. Sci. USA 100:7289-7294.
114. Pfeiffer, J. K., and K. Kirkegaard. 2005. Ribavirin resistance in hepatitis C virus replicon-containing cell lines conferred by changes in the cell line or mutations in the replicon RNA. J. Virol. 79:2346-2355.
115. Pileri, P., Y. Uematsu, S. Campagnoli, G. Galli, F. Falugi, R. Petracca, A. J. Weiner, M. Houghton, D. Rosa, G. Grandi, and S. Abrignani. 1998. Binding of hepatitis C virus to CD81. Science 282:938-941.
116. Polyak, S. J., K. S. Khabar, D. M. Paschal, H. J. Ezelle, G. Duverlie, G. N. Barber, D. E. Levy, N. Mukaida, and D. R. Gretch. 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.
117. Polyak, S. J., K. S. Khabar, M. Rezeiq, and D. R. Gretch. 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.
118. Polyak, S. J., D. M. Paschal, S. McArdle, M. J. Gale, Jr., D. Moradpour, and D. R. Gretch. 1999. Characterization of the effects of hepatitis C virus nonstructural 5A protein expression in human cell lines and on interferon-sensitive virus replication. Hepatology 29:1262-1271.
119. Querenghi, F., Q. Yu, G. Billaud, G. Maertens, C. Trepo, and F. Zoulim. 2001. Evolution of hepatitis C virus genome in chronically infected patients receiving ribavirin monotherapy. J. Viral Hepat. 8:120-131.
120. Reesink, H. W., N. Forestier, C. W. Weegink, S. Zeuzem, L. McNair, S. Purdy, H. M. Chu, and P. L. M. Jansen. 2006. Abstr. 41st Eur. Assoc. Study Liver, abstr. 737.
121. Reesink, H. W., S. Zeuzem, C. J. Weegink, N. Forestier, A. van Vliet, J. van de Wetering de Rooij, L. McNair, S. Purdy, R. Kauffman, J. Adam, and P. L. M. Jansen. 2006. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase 1b, placebo-controlled, randomized study. Gastroenterology 131:997-1002.
122. Rehermann, B., and F. V. Chisari. 2000. Cell mediated immune response to the hepatitis C virus. Curr. Top. Microbiol. Immunol. 242:299-325.
123. Reichard, O., J. Andersson, R. Schvarcz, and O. Weiland. 1991. Ribavirin treatment for chronic hepatitis C. Lancet 337:1058-1061.
124. Reiser, M., H. Hinrichsen, J. P. Benhamou, H. W. Reesink, H. Wedemeyer, C. Avendano, N. Riba, C. L. Yong, G. Nehmiz, and G. Steinmann. 2005. Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C. Hepatology 41:832-835.
125. Roberts, S., G. Cookdley, G. Dore, R. Robson, D. Shaw, H. Berns, M. Brandi, S. Fettner, G. Hill, D. Ipe, K. Klumpp, M. Mannino, E. O'Mara, Y. Tu, and C. Washington. 2006. Abstr. 57th Am. Assoc. Study Liver Dis., abstr. LB2.
126. Saito, T., T. Ito, H. Ishiko, M. Yonaha, K. Morikawa, A. Miyokawa, and K. Mitamura. 2003. Sequence analysis of PePHD within HCV E2 region and correlation with resistance of interferon therapy in Japanese patients infected with HCV genotypes 2a and 2b. Am. J. Gastroenterol. 98:1377-1383.
127. Saiz, J. C., F. X. Lopez-Labrador, S. Ampurdanes, J. Dopazo, X. Forns, J. M. Sanchez-Tapias, and J. Rodes. 1998. The prognostic relevance of the nonstructural 5A gene interferon sensitivity determining region is different in
128. Samuel, C. E. 2001. Antiviral actions of interferons. Clin. Microbiol. Rev. 14:778-809, table.
129. Sandres, K., M. Dubois, C. Pasquier, J. L. Payen, L. Alric, M. Duffaut, J. P. Vinel, J. P. Pascal, J. Puel, and J. Izopet. 2000. Genetic heterogeneity of hypervariable region 1 of the hepatitis C virus (HCV) genome and sensitivity of HCV to alpha interferon therapy. J. Virol. 74:661-668.
130. Sarrazin, C., U. Mihm, E. Herrmann, C. Welsch, M. Albrecht, U. Sarrazin, S. Traver, T. Lengauer, and S. Zeuzem. 2005. Clinical significance of in vitro replication enhancing mutations of the hepatitis C virus replicon in patients with chronic hepatitis C. J. Infect. Dis. 192:1710-1719.
131. Sarrazin, C., R. Rouzier, F. Wagner, N. Forestier, D. Larry, S. K. Gupta, M. Hussain, A. Shah, D. Cutler, J. Zhang, and S. Zeuzem. SCH503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alfa-2b for genotype 1 non-responders. Gastroenterology, in press.
132. Sarrazin, C., T. Berg, J. H. Lee, B. Rüster, B. Kronenberger, W. K. Roth, and S. Zeuzem. 2000. Mutations in the protein kinase-binding domain of the NS5A protein in patients infected with hepatitis C virus type 1a are associated with treatment response. J. Infect. Dis. 181:432-441.
133. Sarrazin, C., T. Berg, J. H. Lee, G. Teuber, C. F. Dietrich, W. K. Roth, and S. Zeuzem. 1999. Improved correlation between multiple mutations within the NS5A region and virological response in European patients chronically infected with hepatitis C virus type 1b undergoing combination therapy. J. Hepatol. 30:1004-1013.
134. Sarrazin, C., M. Bruckner, E. Herrmann, B. Rüster, K. Bruch, W. K. Roth, and S. Zeuzem. 2001. Quasispecies heterogeneity of the carboxy-terminal part of the E2 gene including the PePHD and sensitivity of hepatitis C virus 1b isolates to antiviral therapy. Virology 289:150-163.
135. Sarrazin, C., E. Herrmann, K. Bruch, and S. Zeuzem. 2002. Hepatitis C virus nonstructural 5A protein and interferon resistance: a new model for testing the reliability of mutational analyses. J. Virol. 76:11079-1090.
136. Sarrazin, C., I. Kornetzky, B. Rüster, J. H. Lee, B. Kronenberger, K. Bruch, W. K. Roth, and S. Zeuzem. 2000. Mutations within the E2 and NS5A protein in patients infected with hepatitis C virus type 3a and correlation with treatment response. Hepatology 31:1360-1370.
137. Sarrazin, C., T. Kieffer, D. Bartels, B. Hanzelka, U. Mueh, M. Welker, D. Wincheringer, L. Chao, T. Grossmann, S. Purdy, C. Weegink, H. Reesink, S. Zeuzem, and A. Kwong. 2005. Abstr. 56th Am. Assoc. Study Liver Dis., abstr. LB06.
138. Schinkel, J., M. D. de Jong, B. Bruning, B. van Hoek, W. J. Spaan, and A. C. Kroes. 2003. The potentiating effect of ribavirin on interferon in the treatment of hepatitis C: lack of evidence for ribaviriri-induced viral mutagenesis. Antivir. Ther. 8:535-540.
139. Senturk, H., A. Mert, M. Akdogan, F. Tabak, G. Basaran, S. Turkoglu, G. Ozbay, and S. Badur. 2000. Amantadine monotherapy of chronic hepatitis C patients infected with genotype 1b. Scand. J. Infect. Dis. 32:575-576.
140. Shindo, M., K. Hamada, S. Koya, K. Arai, Y. Sokswa, and T. Okuno. 1996. The clinical significance of changes in genetic heterogeneity of the hypervariable region 1 in chronic hepatitis C with interferon therapy. Hepatology 24:1018-1023.
141. Sidwell, R. W., J. H. Huffman, G. P. Khare, L. B. Allen, J. T. Witkowski, and R. K. Robins. 1972. Broad-spectrum antiviral activity of Virazole: 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science 177:705-706.
142. Simmonds, P., J. Bukh, C. Combet, G. Deleage, N. Enomoto, S. Feinstone, P. Halfen, G. Inchauspe, C. Kuiken, G. Maertens, M. Mizokami, D. G. Murphy, H. Okamoto, J. M. Pawlotsky, F. Penin, E. Sablon, I. Shin, L. J. Stuyver, H. J. Thiel, S. Viazov, A. J. Weiner, and A. Widell. 2005. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 42:962-973.
143. Simmonds, P., E. C. Holmes, T. A. Cha, F. McOmish, B. Irvine, E. Beall, P. L. Yap, J. Kolberg, and M. S. Urdea. 1993. Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. J. Gen. Virol. 74:2391-2399.
144. Song, J., M. Fujii, F. Wang, M. Itoh, and H. Hotta, 1999. The NS5A protein of hepatitis C virus partially inhibits the antiviral activity of interferon. J. Gen. Virol. 80:879-886.
145. Squadrito, G., F. Leone, M. Sartori, B. Nalpas, P. Berthelot, G. Raimondo, S. Pol, and C. Brechet. 1997. Mutations in the nonstructural 5A region of hepatitis C virus and response of chronic hepatitis C to interferon alfa. Gastroenterology 113:567-572.
146. Stark, G. R., I. M. Kerr, B. R. G. Williams, R. H. Silverman, and R. D. Schreiber. 1998. How cells respond to interferons. Annu. Rev. Biochem. 67:227-264.
147. Steinmann, E., G. Koutsoudakis, S. Kallis, F. Penin, R. Bartenschlage, and T. Pietschmann. 2005. Abstr. 12th Int. Symp. Hepat. C Virus Relat. Viruses, abstr. 31.
148. Sumpter, R., Jr., C. Wang, E. Foy, Y. M. Loo, and M. Gale, Jr. 2004. Viral evolution and interferon resistance of hepatitis C virus RNA replication in a cell culture model. J. Virol. 78:11591-11604.
149. Taguchi, T., M. Nagano-Fujii, M. Akutsu, H. Kadoya, S. Ohgimoto, S. Ishido, and H. Hotta. 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.
150. Tam, R. C., B. Pai, J. Bard, C. Lim, D. R. Averett, U. T. Phan, and T. Milovanovic. 1999. Ribavirin polarizes human T cell responses towards a type 1 cytokine profile. J. Hepatol. 30:376-382.
151. Tanabe, Y., N. Sakamoto, N. Enomoto, M. Kurosaki, E. Ueda, S. Maekawa, T. Yamashiro, M. Nakagawa, C. H. Chen, N. Kanazawa, S. Kakinuma, and M. Watanabe. 2004. Synergistic inhibition of intracellular hepatitis C virus replication by combination of ribavirin and interferon-alpha. J. Infect. Dis. 189:1129-1139.
152. Taylor, D. R., S. T. Shi, P. R. Romano, G. N. Barber, and M. M. C. Lai. 1999. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science 285:107-110.
153. Taylor, D. R., B. Tian, P. R. Romano, A. G. Hinnebusch, M. M. Lai, and M. B. Mathews. 2001. Hepatitis C virus envelope protein E2 does not inhibit PKR by simple competition with autophosphorylation sites in the RNA-binding domain. J. Virol. 75:1265-1273.
154. Tellinghuisen, T. L., J. Marcotrigiano, and C. M. Rice. 2005. Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase. Nature 435:374-379.
155. Teuber, G., T. Berg, U. Naumann, J. Raedle, S. Brinkmann, U. Hopf, and S. Zeuzem. 2001. Randomized, placebo-controlled, double-blind trial with interferon-alpha with and without amantadine sulphate in primary interferon-alpha nonresponders with chronic hepatitis C. J. Viral Hepat. 8:276-283.
156. Teuber, G., M. Pascu, T. Berg, M. Lafrenz, J. Pausch, F. Kullmann, G. Ramadori, R. Arnold, H. Weidenbach, E. Musch, U. Junge, K. H. Wiedmann, E. Herrmann, M. Zankel, and S. Zeuzem. 2003. Randomized, controlled trial with IFN-alpha combined with ribavirin with and without amantadine sulphate in non-responders with chronic hepatitis C. J. Hepatol. 39:606-613.
157. Tong, X., R. Chase, A. Skelton, T. Chen, J. Wright-Minogue, and B. A. Malcolm. 2006. Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034. Antivir. Res. 70:28-38.
158. Villano, S., A. Howe, D. Raible, D. Harper, J. Speth, and G. Bichier. 2006. Abstr. 57th Am. Assoc. Study Liver Dis., abstr. 1127.
159. Wakita, T., T. Pietschmann, T. Kato, T. Date, M. Miyamoto, Z. Zhao, K. Murthy, A. Habermann, H. G. Krausslich, M. Mizokami, R. Barten-schlager, and T. J. Liang. 2005. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat. Med. 11:791-796.
160. Wang, C., J. Pflughiber, R. Sumpter, Jr., O. L. Sodora, D. Hul, G. C. Sen, and M. Gale, Jr. 2003. Alpha interferon induces distinct translational control programs to suppress hepatitis C virus RNA replication. J. Virol. 77:3898-3912.
161. Watanabe, H., K. Nagayama, N. Enomoto, J. Itakura, Y. Tanabe, C. Sato, N. Izumi, and M. Watanabe. 2003. Amino acid substitutions in PKR-eIF2 phosphorylation homology domain (PePHD) of hepatitis C virus E2 protein in genotype 2a/2b and 1b in Japan and interferon efficacy. Hepatol. Res. 26:268-274.
162. Weich, V., E. Herrmann, C. Sarrazin, H. Hinrichsen, P. Buggisch, T. Gerlach, H. Klinker, U. Spengler, A. Bergk, B. Wiedenmann, S. Zeuzem, and T. Berg. 2004. Abstr. 55th Am. Assoc. Study Liver Dis., abstr. 389.
163. World Health Organization. 1999. Global surveillance and control of hepatitis C. Report of a WHO consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J. Viral Hepat. 6:35-47.
164. Xu, Z., J. Clioi, T. S. B. Yen, W. Lu, A. Strohecker, S. Govindarajan, D. Chien, M. J. Selby, and J. Ou. 2001. Synthesis of a novel hepatitis C virus protein by ribosomal frameshift. EMBO J. 20:3840-3848.
165. Yang, S. S., M. Y. Lai, D. S. Chen, G. H. Chen, and J. H. Kao. 2003. Mutations in the NS5A and E2-PePHD regions of hepatitis C virus genotype 1b and response to combination therapy of interferon plus ribavirin. Liver Int. 23:426-433.
166. Yoneyama, M., M. Kikuchi, T. Natsukawa, N. Shinobu, T. Imaizumi, M. Miyagishi, K. Taira, S. Akira, and T. Fujita. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5:730-737.
167. Young, K. C., K. L. Lindsay, K. J. Lee, W. C. Liu, J. W. He, S. L. Milstein, and M. M. Lai. 2003. Identification of a ribavirin-resistant NS5B mutation of hepatitis C virus during ribavirin monotherapy. Hepatology 38:869-878.
168. Zeuzem, S., R. Hultcrantz, M. Bourliere, T. Goeser, P. Marcellin, J. Sanchez-Tapias, C. Sarrazin, J. Harvey, C. Brass, and J. Albrecht. 2004. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J. Hepatol. 40:993-999.
169. Zeuzem, S., J. H. Lee, and W. K. Roth. 1997. Mutations in the nonstructural 5A gene of European hepatitis C virus isolates and response to interferon alfa. Hepatology 25:740-744.
170. Zeuzem, S., G. Teuber, U. Naumann, T. Berg, J. Raedle, S. Hartmann, and U. Hopf. 2000. Randomized, double-blind, placebo-controlled trial of interferon alfa2a with and without amantadine as initial treatment for chronic hepatitis C. Hepatology 32:835-841.
171. Zeuzem, S., C. Sarrazin, and J. Zhang. 2005. Abstr. 56th Am. Assoc. Study Liver Dis., abstr. 233.
172. Zhou, S., R. Liu, B. M. Baroudy, B. A. Malcolm, and G. R. Reyes. 2003. The effect of ribavirin and IMPDH inhibitors on hepatitis C virus subgenomic replicon RNA. Virology 310:333-342.