Impact of hepatitis C virus heterogeneity on interferon sensitivity: An overview

World Journal of Gastroenterology

Volumn 20, Issue 24, 2014, Pages 7555-7569

  El Shamy, Ahmed ^a,b   Hotta, Hak ^a  

^a KOBE UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b Department of Virology ^*  (Egypt)

Author keywords

Core protein; Genotype; Hepatitis C virus; Interferon; Interferon sensitivity determining region; Interferon ribavirin resistance determining region; Nonstructural proteins 5A

Indexed keywords

AMINO ACID; CORE PROTEIN; GLYCOPROTEIN E2; INTERFERON; INTERLEUKIN 28; INTERLEUKIN 8; MESSENGER RNA; NONSTRUCTURAL PROTEIN 3; NONSTRUCTURAL PROTEIN 5A; PEGINTERFERON; PROTEIN KINASE R; RIBAVIRIN; STAT1 PROTEIN; VIRUS PROTEIN; VIRUS RNA; ANTIVIRUS AGENT; GLYCOPROTEIN E2, HEPATITIS C VIRUS; NS-5 PROTEIN, HEPATITIS C VIRUS; NS3 PROTEIN, HEPATITIS C VIRUS; VIRUS ENVELOPE PROTEIN;

ANTIVIRAL RESISTANCE; ANTIVIRAL SUSCEPTIBILITY; ARTICLE; GENE MUTATION; GENE SEQUENCE; GENETIC HETEROGENEITY; GENETIC POLYMORPHISM; GENETIC VARIABILITY; GENOTYPE; GLUCOSE METABOLISM; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; IMMUNE RESPONSE; LIPID METABOLISM; LIVER CELL CARCINOMA; META ANALYSIS (TOPIC); NONHUMAN; PHYLOGENY; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SEQUENCE ALIGNMENT; TREATMENT OUTCOME; TREATMENT RESPONSE; VIRUS GENOME; VIRUS VIRULENCE; ANIMAL; DRUG EFFECTS; GENETICS; HEPACIVIRUS; MUTATION; PATHOGENICITY; PHENOTYPE; VIROLOGY;

ANIMALS; ANTIVIRAL AGENTS; DRUG RESISTANCE, VIRAL; GENOTYPE; HEPACIVIRUS; HEPATITIS C; HUMANS; INTERFERONS; MUTATION; PHENOTYPE; TREATMENT OUTCOME; VIRAL CORE PROTEINS; VIRAL ENVELOPE PROTEINS; VIRAL NONSTRUCTURAL PROTEINS; VIRAL PROTEINS;

EID: 84903197643     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v20.i24.7555     Document Type: Article

References (172)

1. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244: 359-362 [PMID: 2523562 DOI: 10.1126/science.2523562]
2. Kuo G, Choo QL, Alter HJ, Gitnick GL, Redeker AG, Pur-cell RH, Miyamura T, Dienstag JL, Alter MJ, Stevens CE. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244: 362-364 [PMID: 2496467 DOI: 10.1126/science.2496467]
3. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology 1997; 26: 15S-20S [PMID: 9305658 DOI: 10.1002/ hep.510260703]
4. Di Bisceglie AM. Hepatitis C. Lancet 1998; 351: 351-355 [PMID: 9652633 DOI: 10.1016/S0140-6736(97)07361-3]
5. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specifc antibody to HCV seroprevalence. Hepatology 2013; 57: 1333-1342 [PMID: 23172780 DOI: 10.1002/hep.26141]
6. Arzumanyan A, Reis HM, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 2013; 13: 123-135 [PMID: 23344543 DOI: 10.1038/nrc3449]
7. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across fve continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006; 24: 2137-2150 [PMID: 16682732 DOI: 10.1200/JCO.2005.05.2308]
8. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gas-troenterology 2004; 127: 1372-1380 [PMID: 15521006 DOI: 10.1053/j.gastro.2004.07.020]
9. El-Serag HB. Epidemiology of viral hepatitis and hepato-cellular carcinoma. Gastroenterology 2012; 142: 1264-1273e1 [PMID: 22537432 DOI: 10.1053/j.gastro.2011.12.061]
10. Thomas DL. Global control of hepatitis C: where challenge meets opportunity. Nat Med 2013; 19: 850-858 [PMID: 23836235 DOI: 10.1038/nm.3184]
11. Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med 2013; 19: 837-849 [PMID: 23836234 DOI: 10.1038/ nm.3248]
12. Okamoto H, Okada S, Sugiyama Y, Yotsumoto S, Tanaka T, Yoshizawa H, Tsuda F, Miyakawa Y, Mayumi M. The 5'-ter-minal sequence of the hepatitis C virus genome. Jpn J Exp Med 1990; 60: 167-177 [PMID: 2170712]
13. Tanaka T, Kato N, Cho MJ, Sugiyama K, Shimotohno K. Structure of the 3' terminus of the hepatitis C virus genome. J Virol 1996; 70: 3307-3312 [PMID: 8627816]
14. Honda M, Ping LH, Rijnbrand RC, Amphlett E, Clarke B, Rowlands D, Lemon SM. Structural requirements for initiation of translation by internal ribosome entry within genome-length hepatitis C virus RNA. Virology 1996; 222: 31-42 [PMID: 8806485 DOI: 10.1006/viro.1996.0395]
15. Kieft JS, Zhou K, Jubin R, Doudna JA. Mechanism of ribo-some recruitment by hepatitis C IRES RNA. RNA 2001; 7: 194-206 [PMID: 11233977 DOI: 10.1017/S1355838201001790]
16. Spahn CM, Kieft JS, Grassucci RA, Penczek PA, Zhou K, Doudna JA, Frank J. Hepatitis C virus IRES RNA-induced changes in the conformation of the 40s ribosomal subunit. Science 2001; 291: 1959-1962 [PMID: 11239155]
17. Otto GA, Puglisi JD. The pathway of HCV IRES-mediated translation initiation. Cell 2004; 119: 369-380 [PMID: 15507208 DOI: 10.1016/j.cell.2004.09.038]
18. Okamoto H, Kojima M, Okada S, Yoshizawa H, Iizuka H, Tanaka T, Muchmore EE, Peterson DA, Ito Y, Mishiro S. Genetic drift of hepatitis C virus during an 8.2-year infection in a chimpanzee: variability and stability. Virology 1992; 190: 894-899 [PMID: 1325713 DOI: 10.1016/0042-6822(92)90933-G]
19. Smith DB, Pathirana S, Davidson F, Lawlor E, Power J, Yap PL, Simmonds P. The origin of hepatitis C virus genotypes. J Gen Virol 1997; 78 (Pt 2): 321-328 [PMID: 9018053]
20. Chayama K, Hayes CN. Hepatitis C virus: How genetic variability affects pathobiology of disease. J Gastroenterol Hepatol 2011; 26 Suppl 1: 83-95 [PMID: 21199518 DOI: 10.1111/ j.1440-1746.2010.06550.x]
21. Schweitzer CJ, Liang TJ. Impact of host and virus genome variability on HCV replication and response to interferon. Curr Opin Virol 2013; 3: 501-507 [PMID: 23835049]
22. Simmonds P, Bukh J, Combet C, Deléage G, Enomoto N, Feinstone S, Halfon P, Inchauspé G, Kuiken C, Maertens G, Mizokami M, Murphy DG, Okamoto H, Pawlotsky JM, Penin F, Sablon E, Shin I T, Stuyver LJ, Thiel HJ, Viazov S, Weiner AJ, Widell A. Consensus proposals for a unifed system of nomenclature of hepatitis C virus genotypes. Hepatology 2005; 42: 962-973 [PMID: 16149085 DOI: 10.1002/ hep.20819]
23. Simmonds P. Genetic diversity and evolution of hepatitis C virus--15 years on. J Gen Virol 2004; 85: 3173-3188 [PMID: 15483230 DOI: 10.1099/vir.0.80401-0]
24. Sy T, Jamal MM. Epidemiology of hepatitis C virus (HCV) infection. Int J Med Sci 2006; 3: 41-46 [PMID: 16614741 DOI: 10.7150/ijms.3.41]
25. Mihm S, Fayyazi A, Hartmann H, Ramadori G. Analysis of histopathological manifestations of chronic hepatitis C virus infection with respect to virus genotype. Hepatology 1997; 25: 735-739 [PMID: 9049227 DOI: 10.1002/hep.510250340]
26. Rubbia-Brandt L, Leandro G, Spahr L, Giostra E, Quadri R, Malé PJ, Negro F. Liver steatosis in chronic hepatitis C: a morphological sign suggesting infection with HCV genotype 3. Histopathology 2001; 39: 119-124 [PMID: 11493327 DOI: 10.1046/j.1365-2559.2001.01208.x]
27. Sharma P, Balan V, Hernandez J, Rosati M, Williams J, Rodriguez-Luna H, Schwartz J, Harrison E, Anderson M, Byrne T, Vargas HE, Douglas DD, Rakela J. Hepatic steato-sis in hepatitis C virus genotype 3 infection: does it correlate with body mass index, fbrosis, and HCV risk factors? Dig Dis Sci 2004; 49: 25-29 [PMID: 14992430]
28. Bruno S, Crosignani A, Maisonneuve P, Rossi S, Silini E, Mondelli MU. Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: a seventeen-year prospective cohort study. Hepatology 2007; 46: 1350-1356 [PMID: 17680653 DOI: 10.1002/hep.21826]
29. Lee MH, Yang HI, Lu SN, Jen CL, Yeh SH, Liu CJ, Chen PJ, You SL, Wang LY, Chen WJ, Chen CJ. Hepatitis C virus se-romarkers and subsequent risk of hepatocellular carcinoma: long-term predictors from a community-based cohort study. J Clin Oncol 2010; 28: 4587-4593 [PMID: 20855826 DOI: 10.1200/JCO.2010.29.1500]
30. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-982 [PMID: 12324553 DOI: 10.1056/ NEJMoa020047]
31. McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER, Galati JS, Bacon BR, Davis MN, Mukhopadhyay P, Koury K, Noviello S, Pedicone LD, Brass CA, Albrecht JK, Sulkowski MS. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580-593 [PMID: 19625712 DOI: 10.1056/NEJMoa0808010]
32. Rumi MG, Aghemo A, Prati GM, D'Ambrosio R, Donato MF, Soffredini R, Del Ninno E, Russo A, Colombo M. Randomized study of peginterferon-alpha2a plus ribavirin vs peginterferon-alpha2b plus ribavirin in chronic hepatitis C. Gastroenterology 2010; 138: 108-115 [PMID: 19766645 DOI: 10.1053/j.gastro.2009.08.071]
33. Zeuzem S, Berg T, Moeller B, Hinrichsen H, Mauss S, Wedemeyer H, Sarrazin C, Hueppe D, Zehnter E, Manns MP. Expert opinion on the treatment of patients with chronic hepatitis C. J Viral Hepat 2009; 16: 75-90 [PMID: 18761607 DOI: 10.1111/j.1365-2893.2008.01012.x]
34. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepa-tology 2009; 49: 1335-1374 [PMID: 19330875 DOI: 10.1002/ hep.22759]
35. Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, Fried MW, Adler M, Reesink HW, Martin M, Sankoh AJ, Adda N, Kauffman RS, George S, Wright CI, Poordad F. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011; 365: 1014-1024 [PMID: 21916639 DOI: 10.1056/NEJMoa1014463]
36. Limaye AR, Draganov PV, Cabrera R. Boceprevir for chronic HCV genotype 1 infection. N Engl J Med 2011; 365: 176; author reply 177-178 [PMID: 21751914 DOI: 10.1056/ NEJMc1105515]
37. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiff-man M, Reindollar R, Goodman ZD, Koury K, Ling M, Al-brecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958-965 [PMID: 11583749 DOI: 10.1016/S0140-6736(01)06102-5]
38. Alfaleh FZ, Hadad Q, Khuroo MS, Aljumah A, Algamedi A, Alashgar H, Al-Ahdal MN, Mayet I, Khan MQ, Kessie G. Peginterferon alpha-2b plus ribavirin compared with inter-feron alpha-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4. Liver Int 2004; 24: 568-574 [PMID: 15566506 DOI: 10.1111/j.1478-3231.2004.0976.x]
39. Kamal SM, El Tawil AA, Nakano T, He Q, Rasenack J, Hakam SA, Saleh WA, Ismail A, Aziz AA, Madwar MA. Peginterferon {alpha}-2b and ribavirin therapy in chronic hepatitis C genotype 4: impact of treatment duration and viral kinetics on sustained virological response. Gut 2005; 54: 858-866 [PMID: 15888797 DOI: 10.1136/gut.2004.057182]
40. Derbala M, Amer A, Bener A, Lopez AC, Omar M, El Ghannam M. Pegylated interferon-alpha 2b-ribavirin combination in Egyptian patients with genotype 4 chronic hepatitis. J Viral Hepat 2005; 12: 380-385 [PMID: 15985008 DOI: 10.1111/j.1365-2893.2005.00604.x]
41. El-Zayadi AR, Attia M, Barakat EM, Badran HM, Hamdy H, El-Tawil A, El-Nakeeb A, Selim O, Saied A. Response of hepatitis C genotype-4 naïve patients to 24 weeks of Peg-interferon-alpha2b/ribavirin or induction-dose interferon-alpha2b/ribavirin/amantadine: a non-randomized controlled study. Am J Gastroenterol 2005; 100: 2447-2452 [PMID: 16279899 DOI: 10.1111/j.1572-0241.2005.00253.x]
42. Pang PS, Planet PJ, Glenn JS. The evolution of the major hepatitis C genotypes correlates with clinical response to in-terferon therapy. PLoS One 2009; 4: e6579 [PMID: 19668364 DOI: 10.1371/journal.pone.0006579]
43. McMullan LK, Grakoui A, Evans MJ, Mihalik K, Puig M, Branch AD, Feinstone SM, Rice CM. Evidence for a functional RNA element in the hepatitis C virus core gene. Proc Natl Acad Sci USA 2007; 104: 2879-2884 [PMID: 17299041 DOI: 10.1073/pnas.0611267104]
44. Kountouras J, Zavos C, Chatzopoulos D. Apoptosis in hepatitis C. J Viral Hepat 2003; 10: 335-342 [PMID: 12969183 DOI: 10.1046/j.1365-2893.2003.00452.x]
45. Hahn YS. Subversion of immune responses by hepatitis C virus: immunomodulatory strategies beyond evasion? Curr Opin Immunol 2003; 15: 443-449 [PMID: 12900277 DOI: 10.1016/S0952-7915(03)00076-1]
46. Mori Y, Moriishi K, Matsuura Y. Hepatitis C virus core protein: its coordinate roles with PA28gamma in metabolic abnormality and carcinogenicity in the liver. Int J Biochem Cell Biol 2008; 40: 1437-1442 [PMID: 18321762 DOI: 10.1016/ j.biocel.2008.01.027]
47. Pazienza V, Clément S, Pugnale P, Conzelman S, Foti M, Mangia A, Negro F. The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specifc mechanisms. Hepatology 2007; 45: 1164-1171 [PMID: 17465001 DOI: 10.1002/hep.21634]
48. Ray RB, Lagging LM, Meyer K, Ray R. Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fbroblasts to tumorigenic phenotype. J Virol 1996; 70: 4438-4443 [PMID: 8676467]
49. Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K, Matsuura Y, Kimura S, Miyamura T, Koike K. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 1998; 4: 1065-1067 [PMID: 9734402 DOI: 10.1038/2053]
50. Akuta N, Suzuki F, Sezaki H, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Watahiki S, Sato J, Matsuda M, Ko-bayashi M, Arase Y, Ikeda K, Kumada H. Association of ami-no acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy. Intervirology 2005; 48: 372-380 [PMID: 16024941 DOI: 10.1159/000086064]
51. El-Shamy A, Kim SR, Ide YH, Sasase N, Imoto S, Deng L, Shoji I, Hotta H. Polymorphisms of hepatitis C virus non-structural protein 5A and core protein and clinical outcome of pegylated-interferon/ribavirin combination therapy. Intervi-rology 2012; 55: 1-11 [PMID: 21293098 DOI: 10.1159/000322219]
52. El-Shamy A, Shoji I, Saito T, Watanabe H, Ide YH, Deng L, Kawata S, Hotta H. Sequence heterogeneity of NS5A and core proteins of hepatitis C virus and virological responses to pegylated-interferon/ribavirin combination therapy. Microbiol Immunol 2011; 55: 418-426 [PMID: 21371092 DOI: 10.1111/j.1348-0421.2011.00331.x]
53. Kim SR, El-Shamy A, Imoto S, Kim KI, Ide YH, Deng L, Shoji I, Tanaka Y, Hasegawa Y, Ota M, Hotta H. Prediction of response to pegylated interferon/ribavirin combination therapy for chronic hepatitis C genotype 1b and high viral load. J Gastroenterol 2012; 47: 1143-1151 [PMID: 22441534 DOI: 10.1007/s00535-012-0578-z]
54. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ike-da K, Kumada H. Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels. J Hepatol 2007; 46: 403-410 [PMID: 17126448 DOI: 10.1016/j.jhep.2006.09.019]
55. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H. Predictors of viral kinetics to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b. J Med Virol 2007; 79: 1686-1695 [PMID: 17854035 DOI: 10.1002/jmv.20979]
56. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Miyakawa Y, Kumada H. Prediction of response to pegylated interferon and ribavirin in hepatitis C by polymorphisms in the viral core protein and very early dynamics of viremia. Intervirology 2007; 50: 361-368 [PMID: 17728547 DOI: 10.1159/000107707]
57. Okanoue T, Itoh Y, Hashimoto H, Yasui K, Minami M, Takehara T, Tanaka E, Onji M, Toyota J, Chayama K, Yosh-ioka K, Izumi N, Akuta N, Kumada H. Predictive values of amino acid sequences of the core and NS5A regions in antiviral therapy for hepatitis C: a Japanese multi-center study. J Gastroenterol 2009; 44: 952-963 [PMID: 19517057 DOI: 10.1007/s00535-009-0087-x]
58. Hayashi K, Katano Y, Ishigami M, Itoh A, Hirooka Y, Na-kano I, Urano F, Yoshioka K, Toyoda H, Kumada T, Goto H. Mutations in the core and NS5A region of hepatitis C virus genotype 1b and correlation with response to pegylated-interferon-alpha 2b and ribavirin combination therapy. J Viral Hepat 2011; 18: 280-286 [PMID: 20367792]
59. Mori N, Imamura M, Kawakami Y, Saneto H, Kawaoka T, Takaki S, Aikata H, Takahashi S, Chayama K. Randomized trial of high-dose interferon-alpha-2b combined with ribavi-rin in patients with chronic hepatitis C: Correlation between amino acid substitutions in the core/NS5A region and viro-logical response to interferon therapy. J Med Virol 2009; 81: 640-649 [PMID: 19235866 DOI: 10.1002/jmv.21438]
60. Enomoto N, Maekawa S. HCV genetic elements determining the early response to peginterferon and ribavirin therapy. Intervirology 2010; 53: 66-69 [PMID: 20068344 DOI: 10.1159/000252787]
61. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H. A matched case-controlled study of 48 and 72 weeks of peginterferon plus ribavirin combination therapy in patients infected with HCV genotype 1b in Japan: amino acid substitutions in HCV core region as predictor of sustained virological response. J Med Virol 2009; 81: 452-458 [PMID: 19152407 DOI: 10.1002/jmv.21400]
62. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H. Amino acid substitutions in the hepatitis C virus core region of genotype 1b are the important predictor of severe insulin resistance in patients without cirrhosis and diabetes mellitus. J Med Virol 2009; 81: 1032-1039 [PMID: 19382270 DOI: 10.1002/ jmv.21473]
63. Kobayashi M, Akuta N, Suzuki F, Hosaka T, Sezaki H, Ko-bayashi M, Suzuki Y, Arase Y, Ikeda K, Watahiki S, Mineta R, Iwasaki S, Miyakawa Y, Kumada H. Infuence of amino-acid polymorphism in the core protein on progression of liver disease in patients infected with hepatitis C virus genotype 1b. J Med Virol 2010; 82: 41-48 [PMID: 19950230 DOI: 10.1002/jmv.21629]
64. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H. Amino acid substitutions in the hepatitis C virus core region are the important predictor of hepatocarcinogenesis. Hepatology 2007; 46: 1357-1364 [PMID: 17657816 DOI: 10.1002/hep.21836]
65. Akuta N, Suzuki F, Seko Y, Kawamura Y, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Hara T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H. Complicated relationships of amino acid substitution in hepatitis C virus core region and IL28B genotype infuencing hepatocarcinogenesis. Hepatol-ogy 2012; 56: 2134-2141 [PMID: 22806754 DOI: 10.1002/ hep.25949]
66. Nakamoto S, Imazeki F, Fukai K, Fujiwara K, Arai M, Kanda T, Yonemitsu Y, Yokosuka O. Association between mutations in the core region of hepatitis C virus genotype 1 and hepatocellular carcinoma development. J Hepatol 2010; 52: 72-78 [PMID: 19910070 DOI: 10.1016/j.jhep.2009.10.001]
67. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H. Amino acid substitutions in hepatitis C virus core region predict hepatocarcinogenesis following eradication of HCV RNA by antiviral therapy. J Med Virol 2011; 83: 1016-1022 [PMID: 21503914 DOI: 10.1002/jmv.22094]
68. Seko Y, Akuta N, Suzuki F, Kawamura Y, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H. Amino acid substitutions in the hepatitis C Virus core region and lipid metabolism are associated with hepatocarcinogenesis in nonresponders to interferon plus ribavirin combination therapy. Intervirology 2013; 56: 13-21 [PMID: 22907167 DOI: 10.1159/000339993]
69. El-Shamy A, Shindo M, Shoji I, Deng L, Okuno T, Hotta H. Polymorphisms of the core, NS3, and NS5A proteins of hepatitis C virus genotype 1b associate with development of hepatocellular carcinoma. Hepatology 2013; 58: 555-563 [PMID: 23281009 DOI: 10.1002/hep.26205]
70. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H. Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 2a high viral load and virological response to interferon-ribavirin combination therapy. Intervirology 2009; 52: 301-309 [PMID: 19729953 DOI: 10.1159/000235909]
71. Kadokura M, Maekawa S, Sueki R, Miura M, Komase K, Shindo H, Amemiya F, Uetake T, Inoue T, Sakamoto M, Na-kagawa M, Sakamoto N, Watanabe M, Enomoto N. Analysis of the complete open reading frame of hepatitis C virus in genotype 2a infection reveals critical sites infuencing the response to peginterferon and ribavirin therapy. Hepatol Int 2011; 5: 789-799 [PMID: 21484117 DOI: 10.1007/s12072-011-9267-x]
72. Kadokura M, Maekawa S, Sueki R, Miura M, Komase K, Shindo H, Amemiya F, Uetake T, Inoue T, Sakamoto M, Na-kagawa M, Sakamoto N, Watanabe M, Enomoto N. Analysis of the complete open reading frame of genotype 2b hepatitis C virus in association with the response to peginterferon and ribavirin therapy. PLoS One 2011; 6: e24514 [PMID: 21935415 DOI: 10.1371/journal.pone.0024514]
73. El-Shamy A, Shoji I, El-Akel W, Bilasy SE, Deng L, El-Raziky M, Jiang DP, Esmat G, Hotta H. NS5A sequence heterogeneity of hepatitis C virus genotype 4a predicts clinical outcome of pegylated-interferon-ribavirin therapy in Egyptian patients. J Clin Microbiol 2012; 50: 3886-3892 [PMID: 22993188 DOI: 10.1128/JCM.02109-12]
74. El-Shamy A, Shoji I, Kim SR, Ide Y, Imoto S, Deng L, Yoon S, Fujisawa T, Tani S, Yano Y, Seo Y, Azuma T, Hotta H. Sequence heterogeneity in NS5A of hepatitis C virus genotypes 2a and 2b and clinical outcome of pegylated-inter-feron/ribavirin therapy. PLoS One 2012; 7: e30513 [PMID: 22319571 DOI: 10.1371/journal.pone.0030513]
75. Alhamlan FS, Al-Ahdal MN, Khalaf NZ, Abdo AA, Sanai FM, Al-Ashgar HI, Elhefnawi M, Zaid A, Al-Qahtani AA. Hepatitis C virus genotype 1: how genetic variability of the core protein affects the response to pegylated-interferon and ribavirin therapy. J Med Virol 2014; 86: 224-234 [PMID: 24166351 DOI: 10.1002/jmv.23823]
76. Alestig E, Arnholm B, Eilard A, Lagging M, Nilsson S, Nor-krans G, Wahlberg T, Wejstål R, Westin J, Lindh M. Core mutations, IL28B polymorphisms and response to peginter-feron/ribavirin treatment in Swedish patients with hepatitis C virus genotype 1 infection. BMC Infect Dis 2011; 11: 124 [PMID: 21569441 DOI: 10.1186/1471-2334-11-124]
77. Donlin MJ, Cannon NA, Yao E, Li J, Wahed A, Taylor MW, Belle SH, Di Bisceglie AM, Aurora R, Tavis JE. Pretreatment sequence diversity differences in the full-length hepatitis C virus open reading frame correlate with early response to therapy. J Virol 2007; 81: 8211-8224 [PMID: 17522222 DOI: 10.1128/JVI.00487-07]
78. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Ku-mada H. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology 2010; 52: 421-429 [PMID: 20648473 DOI: 10.1002/hep.23690]
79. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H. Amino acid substitutions in the hepatitis C virus core region of genotype 1b affect very early viral dynamics during treatment with telaprevir, peginterferon, and ribavirin. J Med Virol 2010; 82: 575-582 [PMID: 20166188 DOI: 10.1002/jmv.21741]
80. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Kumada H. Amino acid substitution in HCV core region and genetic variation near the IL28B gene affect viral dynamics during telaprevir, peginterferon and ribavirin treatment. Intervirology 2012; 55: 417-425 [PMID: 21325786 DOI: 10.1159/000323526]
81. Akuta N, Suzuki F, Fukushima T, Kawamura Y, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Hara T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H. Prediction of treatment efficacy and telaprevir-resistant variants after triple therapy in patients infected with hepatitis C virus genotype 1. J Clin Microbiol 2013; 51: 2862-2868 [PMID: 23784126 DOI: 10.1128/JCM.01129-13]
82. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Kumada H. Amino acid substitution in HCV core/NS5A region and genetic variation near IL28B gene affect treatment effcacy to interferon plus ribavirin combination therapy. Intervirology 2012; 55: 231-241 [PMID: 21734353 DOI: 10.1159/000328327]
83. Ikeda F, Dansako H, Nishimura G, Mori K, Kawai Y, Ariumi Y, Miyake Y, Takaki A, Nouso K, Iwasaki Y, Ikeda M, Kato N, Yamamoto K. Amino acid substitutions of hepatitis C virus core protein are not associated with intracellular antiviral response to interferon-α in vitro. Liver Int 2010; 30: 1324-1331 [PMID: 20602680 DOI: 10.1111/j.1478-3231.2010.02299.x]
84. Hiraga N, Abe H, Imamura M, Tsuge M, Takahashi S, Hayes CN, Ochi H, Tateno C, Yoshizato K, Nakamura Y, Kamatani N, Chayama K. Impact of viral amino acid substitutions and host interleukin-28b polymorphism on replication and susceptibility to interferon of hepatitis C virus. Hepatology 2011; 54: 764-771 [PMID: 21618576 DOI: 10.1002/hep.24453]
85. Funaoka Y, Sakamoto N, Suda G, Itsui Y, Nakagawa M, Kakinuma S, Watanabe T, Mishima K, Ueyama M, Onozuka I, Nitta S, Kitazume A, Kiyohashi K, Murakawa M, Azuma S, Tsuchiya K, Watanabe M. Analysis of interferon signaling by infectious hepatitis C virus clones with substitutions of core amino acids 70 and 91. J Virol 2011; 85: 5986-5994 [PMID: 21490101 DOI: 10.1128/JVI.02583-10]
86. Eng FJ, Walewski JL, Klepper AL, Fishman SL, Desai SM, McMullan LK, Evans MJ, Rice CM, Branch AD. Internal initiation stimulates production of p8 minicore, a member of a newly discovered family of hepatitis C virus core protein isoforms. J Virol 2009; 83: 3104-3114 [PMID: 19129450 DOI: 10.1128/JVI.01679-08]
87. Macdonald A, Harris M. Hepatitis C virus NS5A: tales of a promiscuous protein. J Gen Virol 2004; 85: 2485-2502 [PMID: 15302943 DOI: 10.1099/vir.0.80204-0]
88. Tanji Y, Kaneko T, Satoh S, Shimotohno K. Phosphorylation of hepatitis C virus-encoded nonstructural protein NS5A. J Virol 1995; 69: 3980-3986 [PMID: 7769656]
89. Polyak SJ, Paschal DM, McArdle S, Gale MJ, Moradpour D, Gretch DR. Characterization of the effects of hepatitis C virus nonstructural 5A protein expression in human cell lines and on interferon-sensitive virus replication. Hepatol-ogy 1999; 29: 1262-1271 [PMID: 10094974 DOI: 10.1002/ hep.510290438]
90. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Izumi N, Marumo F, Sato C. 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 Invest 1995; 96: 224-230 [PMID: 7542279 DOI: 10.1172/JCI118025]
91. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Ogura Y, Izumi N, Marumo F, Sato C. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996; 334: 77-81 [PMID: 8531962 DOI: 10.1056/NEJM199601113340203]
92. Kurosaki M, Enomoto N, Murakami T, Sakuma I, Asahina Y, Yamamoto C, Ikeda T, Tozuka S, Izumi N, Marumo F, Sato C. 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 1997; 25: 750-753 [PMID: 9049230 DOI: 10.1002/hep.510250343]
93. Chayama K, Tsubota A, Kobayashi M, Okamoto K, Hashimoto M, Miyano Y, Koike H, Kobayashi M, Koida I, Arase Y, Saitoh S, Suzuki Y, Murashima N, Ikeda K, Kumada H. 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 1997; 25: 745-749 [PMID: 9049229 DOI: 10.1002/hep.510250342]
94. Shen C, Hu T, Shen L, Gao L, Xie W, Zhang J. Mutations in ISDR of NS5A gene infuence interferon effcacy in Chinese patients with chronic hepatitis C virus genotype 1b infection. J Gastroenterol Hepatol 2007; 22: 1898-1903 [PMID: 17914967 DOI: 10.1111/j.1440-1746.2006.04566.x]
95. Hayashi K, Katano Y, Honda T, Ishigami M, Itoh A, Hiroo-ka Y, Nakano I, Urano F, Yoshioka K, Toyoda H, Kumada T, Goto H. Mutations in the interferon sensitivity-determining region of hepatitis C virus genotype 2a correlate with response to pegylated-interferon-alpha 2a monotherapy. J Med Virol 2009; 81: 459-466 [PMID: 19152412 DOI: 10.1002/ jmv.21407]
96. Hofgärtner WT, Polyak SJ, Sullivan DG, Carithers RL, Gretch DR. Mutations in the NS5A gene of hepatitis C virus in North American patients infected with HCV genotype 1a or 1b. J Med Virol 1997; 53: 118-126 [PMID: 9334922]
97. Frangeul L, Cresta P, Perrin M, Lunel F, Opolon P, Agut H, Huraux JM. Mutations in NS5A region of hepatitis C virus genome correlate with presence of NS5A antibodies and response to interferon therapy for most common European hepatitis C virus genotypes. Hepatology 1998; 28: 1674-1679 [PMID: 9828234 DOI: 10.1002/hep.510280630]
98. Squadrito G, Orlando ME, Cacciola I, Rumi MG, Artini M, Pic-ciotto A, Loiacono O, Siciliano R, Levrero M, Raimondo G. Long-term response to interferon alpha is unrelated to "interferon sensitivity determining region" variability in patients with chronic hepatitis C virus-1b infection. J Hepatol 1999; 30: 1023-1027 [PMID: 10406179 DOI: 10.1016/S0168-8278(99)80255-4]
99. Berg T, Mas Marques A, Höhne M, Wiedenmann B, Hopf U, Schreier E. 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. Hepatol-ogy 2000; 32: 1386-1395 [PMID: 11093746 DOI: 10.1053/ jhep.2000.20527]
100. Pascu M, Martus P, Höhne M, Wiedenmann B, Hopf U, Sch-reier E, Berg T. 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 2004; 53: 1345-1351 [PMID: 15306598 DOI: 10.1136/gut.2003.031336]
101. Yen YH, Hung CH, Hu TH, Chen CH, Wu CM, Wang JH, Lu SN, Lee CM. Mutations in the interferon sensitivity-determining region (nonstructural 5A amino acid 2209-2248) in patients with hepatitis C-1b infection and correlating response to combined therapy of pegylated interferon and ribavirin. Aliment Pharmacol Ther 2008; 27: 72-79 [PMID: 17973647 DOI: 10.1111/j.1365-2036.2007.03560.x]
102. Shirakawa H, Matsumoto A, Joshita S, Komatsu M, Tanaka N, Umemura T, Ichijo T, Yoshizawa K, Kiyosawa K, Tanaka E. Pretreatment prediction of virological response to pe-ginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors. Hepatology 2008; 48: 1753-1760 [PMID: 18925643 DOI: 10.1002/hep.22543]
103. Muñoz de Rueda P, Casado J, Patón R, Quintero D, Palacios A, Gila A, Quiles R, León J, Ruiz-Extremera A, Salmerón J. Mutations in E2-PePHD, NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 of hepatitis C virus genotype 1 and their relationships to pegylated interferon-ribavirin treatment responses. J Virol 2008; 82: 6644-6653 [PMID: 18448540 DOI: 10.1128/ JVI.02231-07]
104. Murakami T, Enomoto N, Kurosaki M, Izumi N, Marumo F, Sato C. Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection. Hepatology 1999; 30: 1045-1053 [PMID: 10498658 DOI: 10.1002/hep.510300405]
105. Akuta N, Suzuki F, Tsubota A, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H. Association of amino acid substitution pattern in nonstructural protein 5A of hepatitis C virus genotype2a low viral load and response to interferon monotherapy. J Med Virol 2003; 69: 376-383 [PMID: 12526048 DOI: 10.1002/jmv.10299]
106. Bagaglio S, Bruno R, Lodrini S, De Mitri MS, Andreone P, Loggi E, Galli L, Lazzarin A, Morsica G. Genetic heterogeneity of hepatitis C virus (HCV) in clinical strains of HIV positive and HIV negative patients chronically infected with HCV genotype 3a. J Biol Regul Homeost Agents 2003; 17: 153-161 [PMID: 14518715]
107. Gale MJ, Korth MJ, Tang NM, Tan SL, Hopkins DA, Dever TE, Polyak SJ, Gretch DR, Katze MG. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 1997; 230: 217-227 [PMID: 9143277 DOI: 10.1006/viro.1997.8493]
108. Gale M, Blakely CM, Kwieciszewski B, Tan SL, Dossett M, Tang NM, Korth MJ, Polyak SJ, Gretch DR, Katze MG. Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol Cell Biol 1998; 18: 5208-5218 [PMID: 9710605]
109. Gale MJ, Korth MJ, Katze MG. Repression of the PKR protein kinase by the hepatitis C virus NS5A protein: a potential mechanism of interferon resistance. Clin Diagn Virol 1998; 10: 157-162 [PMID: 9741641 DOI: 10.1016/S0928-0197(98)00034-8]
110. Sarrazin C, Herrmann E, Bruch K, Zeuzem S. Hepatitis C virus nonstructural 5A protein and interferon resistance: a new model for testing the reliability of mutational analyses. J Virol 2002; 76: 11079-11090 [PMID: 12368350 DOI: 10.1128/ JVI.76.21.11079-11090.2002]
111. Macquillan GC, Niu X, Speers D, English S, Garas G, Har-nett GB, Reed WD, Allan JE, Jeffrey GP. Does sequencing the PKRBD of hepatitis C virus NS5A predict therapeutic response to combination therapy in an Australian population? J Gastroenterol Hepatol 2004; 19: 551-557 [PMID: 15086599 DOI: 10.1111/j.1440-1746.2003.03319.x]
112. Nousbaum J, Polyak SJ, Ray SC, Sullivan DG, Larson AM, Carithers RL, Gretch DR. Prospective characterization of full-length hepatitis C virus NS5A quasispecies during induction and combination antiviral therapy. J Virol 2000; 74: 9028-9038 [PMID: 10982347 DOI: 10.1128/JVI.74.19.9028-903 8.2000]
113. Taguchi T, Nagano-Fujii M, Akutsu M, Kadoya H, Ohgi-moto S, Ishido S, Hotta H. 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 2004; 85: 959-969 [PMID: 15039538 DOI: 10.1099/vir.0.19513-0]
114. Polyak SJ, Khabar KS, Paschal DM, Ezelle HJ, Duverlie G, Barber GN, Levy DE, Mukaida N, Gretch DR. Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J Virol 2001; 75: 6095-6106 [PMID: 11390611 DOI: 10.1128/JVI.75.13.6095-6106.2001]
115. Polyak SJ, Khabar KS, Rezeiq M, Gretch DR. Elevated levels of interleukin-8 in serum are associated with hepatitis C virus infection and resistance to interferon therapy. J Virol 2001; 75: 6209-6211 [PMID: 11390624 DOI: 10.1128/JVI.75.13.6209-6211.2001]
116. Duverlie G, Khorsi H, Castelain S, Jaillon O, Izopet J, Lunel F, Eb F, Penin F, Wychowski C. Sequence analysis of the NS5A protein of European hepatitis C virus 1b isolates and relation to interferon sensitivity. J Gen Virol 1998; 79 (Pt 6): 1373-1381 [PMID: 9634077]
117. Layden-Almer JE, Kuiken C, Ribeiro RM, Kunstman KJ, Perelson AS, Layden TJ, Wolinsky SM. Hepatitis C virus genotype 1a NS5A pretreatment sequence variation and viral kinetics in African American and white patients. J Infect Dis 2005; 192: 1078-1087 [PMID: 16107963 DOI: 10.1086/432760]
118. Vuillermoz I, Khattab E, Sablon E, Ottevaere I, Durantel D, Vieux C, Trepo C, Zoulim F. Genetic variability of hepatitis C virus in chronically infected patients with viral breakthrough during interferon-ribavirin therapy. J Med Virol 2004; 74: 41-53 [PMID: 15258967 DOI: 10.1002/jmv.20144]
119. Puig-Basagoiti F, Forns X, Furcić I, Ampurdanés S, Gi-ménez-Barcons M, Franco S, Sánchez-Tapias JM, Saiz JC. Dynamics of hepatitis C virus NS5A quasispecies during interferon and ribavirin therapy in responder and non-re-sponder patients with genotype 1b chronic hepatitis C. J Gen Virol 2005; 86: 1067-1075 [PMID: 15784900 DOI: 10.1099/ vir.0.80526-0]
120. Murphy MD, Rosen HR, Marousek GI, Chou S. Analysis of sequence configurations of the ISDR, PKR-binding do- main, and V3 region as predictors of response to induction interferon-alpha and ribavirin therapy in chronic hepatitis C infection. Dig Dis Sci 2002; 47: 1195-1205 [PMID: 12064791]
121. El-Shamy A, Sasayama M, Nagano-Fujii M, Sasase N, Imoto S, Kim SR, Hotta H. Prediction of efficient virological response to pegylated interferon/ribavirin combination therapy by NS5A sequences of hepatitis C virus and anti-NS5A antibodies in pre-treatment sera. Microbiol Immunol 2007; 51: 471-482 [PMID: 17446688 DOI: 10.1111/j.1348-0421.2007. tb03922.x]
122. El-Shamy A, Nagano-Fujii M, Sasase N, Imoto S, Kim SR, Hotta H. Sequence variation in hepatitis C virus nonstruc-tural protein 5A predicts clinical outcome of pegylated in-terferon/ribavirin combination therapy. Hepatology 2008; 48: 38-47 [PMID: 18537193 DOI: 10.1002/hep.22339]
123. Sasase N, Kim SR, Kudo M, Kim KI, Taniguchi M, Imoto S, Mita K, Hayashi Y, Shoji I, El-Shamy A, Hotta H. Outcome and early viral dynamics with viral mutation in PEG-IFN/ RBV therapy for chronic hepatitis in patients with high viral loads of serum HCV RNA genotype 1b. Intervirology 2010; 53: 49-54 [PMID: 20068341 DOI: 10.1159/000252784]
124. Fukuhara T, Taketomi A, Okano S, Ikegami T, Soejima Y, Shirabe K, Maehara Y. Mutations in hepatitis C virus genotype 1b and the sensitivity of interferon-ribavirin therapy after liver transplantation. J Hepatol 2010; 52: 672-680 [PMID: 20346532 DOI: 10.1016/j.jhep.2009.10.034]
125. Maekawa S, Sakamoto M, Miura M, Kadokura M, Sueki R, Komase K, Shindo H, Komatsu N, Shindo K, Kanayama A, Ohmori T, Amemiya F, Takano S, Yamaguchi T, Nakayama Y, Kitamura T, Inoue T, Okada S, Enomoto N. Comprehensive analysis for viral elements and interleukin-28B polymorphisms in response to pegylated interferon plus ribavi-rin therapy in hepatitis C virus 1B infection. Hepatology 2012; 56: 1611-1621 [PMID: 22577043 DOI: 10.1002/hep.25826]
126. Tsai YH, Kuang WF, Lu TY, Kao JH, Lai MY, Liu CJ, Chen PJ, Hwang LH. The non-structural 5A protein of hepatitis C virus exhibits genotypic differences in interferon antagonism. J Hepatol 2008; 49: 899-907 [PMID: 18842320 DOI: 10.1016/j.jhep.2008.06.030]
127. Kumthip K, Chusri P, Jilg N, Zhao L, Fusco DN, Zhao H, Goto K, Cheng D, Schaefer EA, Zhang L, Pantip C, Thong-sawat S, O'Brien A, Peng LF, Maneekarn N, Chung RT, Lin W. Hepatitis C virus NS5A disrupts STAT1 phosphoryla-tion and suppresses type I interferon signaling. J Virol 2012; 86: 8581-8591 [PMID: 22674974 DOI: 10.1128/JVI.00533-12]
128. Hughes M, Gretton S, Shelton H, Brown DD, McCormick CJ, Angus AG, Patel AH, Griffn S, Harris M. A conserved proline between domains II and III of hepatitis C virus NS5A infuences both RNA replication and virus assembly. J Virol 2009; 83: 10788-10796 [PMID: 19656877 DOI: 10.1128/ JVI.02406-08]
129. Tellinghuisen TL, Foss KL, Treadaway J. Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLoS Pathog 2008; 4: e1000032 [PMID: 18369478 DOI: 10.1371/journal.ppat.1000032]
130. Masaki T, Suzuki R, Murakami K, Aizaki H, Ishii K, Mu-rayama A, Date T, Matsuura Y, Miyamura T, Wakita T, Suzuki T. Interaction of hepatitis C virus nonstructural protein 5A with core protein is critical for the production of infectious virus particles. J Virol 2008; 82: 7964-7976 [PMID: 18524832 DOI: 10.1128/JVI.00826-08]
131. Yuan HJ, Jain M, Snow KK, Gale M, Lee WM. Evolution of hepatitis C virus NS5A region in breakthrough patients during pegylated interferon and ribavirin therapy*. J Viral Hepat 2010; 17: 208-216 [PMID: 19656286 DOI: 10.1111/ j.1365-2893.2009.01169.x]
132. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Pe-tracca R, Weiner AJ, Houghton M, Rosa D, Grandi G, Abri-gnani S. Binding of hepatitis C virus to CD81. Science 1998; 282: 938-941 [PMID: 9794763]
133. Gale M, Foy EM. Evasion of intracellular host defence by hepatitis C virus. Nature 2005; 436: 939-945 [PMID: 16107833 DOI: 10.1038/nature04078]
134. Smith DB. Evolution of the hypervariable region of hepatitis C virus. J Viral Hepat 1999; 6 Suppl 1: 41-46 [PMID: 10760034 DOI: 10.1046/j.1365-2893.1999.00010.x]
135. Alfonso V, Flichman DM, Sookoian S, Mbayed VA, Campos RH. Evolutionary study of HVR1 of E2 in chronic hepatitis C virus infection. J Gen Virol 2004; 85: 39-46 [PMID: 14718618 DOI: 10.1099/vir.0.19403-0]
136. Taylor DR, Shi ST, Romano PR, Barber GN, Lai MM. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science 1999; 285: 107-110 [PMID: 10390359]
137. Taylor DR, Tian B, Romano PR, Hinnebusch AG, Lai MM, Mathews MB. Hepatitis C virus envelope protein E2 does not inhibit PKR by simple competition with autophosphorylation sites in the RNA-binding domain. J Virol 2001; 75: 1265-1273 [PMID: 11152499 DOI: 10.1128/JVI.75.3.1265-1273.2001]
138. Gupta R, Subramani M, Khaja MN, Madhavi C, Roy S, Habibullah CM, Das S. Analysis of mutations within the 5' untranslated region, interferon sensitivity region, and PePHD region as a function of response to interferon therapy in hepatitis C virus-infected patients in India. J Clin Microbiol 2006; 44: 709-715 [PMID: 16517843 DOI: 10.1128/JCM.44.3.709-715.2006]
139. Saito T, Ito T, Ishiko H, Yonaha M, Morikawa K, Miyo-kawa A, Mitamura K. 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 2003; 98: 1377-1383 [PMID: 12818284 DOI: 10.1111/j.1572-0241.2003.07469.x]
140. Sarrazin C, Bruckner M, Herrmann E, Rüster B, Bruch K, Roth WK, Zeuzem S. 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 2001; 289: 150-163 [PMID: 11601926]
141. Gaudy C, Lambelé M, Moreau A, Veillon P, Lunel F, Goudeau A. Mutations within the hepatitis C virus genotype 1b E2-PePHD domain do not correlate with treatment outcome. J Clin Microbiol 2005; 43: 750-754 [PMID: 15695675 DOI: 10.1128/JCM.43.2.750-754.2005]
142. Hung CH, Lee CM, Lu SN, Lee JF, Wang JH, Tung HD, Chen TM, Hu TH, Chen WJ, Changchien CS. Mutations in the NS5A and E2-PePHD region of hepatitis C virus type 1b and correlation with the response to combination therapy with interferon and ribavirin. J Viral Hepat 2003; 10: 87-94 [PMID: 12614464 DOI: 10.1046/j.1365-2893.2003.00414.x]
143. Farci P, Purcell RH. Clinical signifcance of hepatitis C virus genotypes and quasispecies. Semin Liver Dis 2000; 20: 103-126 [PMID: 10895435]
144. Sanjo M, Saito T, Ishii R, Nishise Y, Haga H, Okumoto K, Ito J, Watanabe H, Saito K, Togashi H, Fukuda K, Imai Y, El-Shamy A, Deng L, Shoji I, Hotta H, Kawata S. Secondary structure of the amino-terminal region of HCV NS3 and virological response to pegylated interferon plus riba-virin therapy for chronic hepatitis C. J Med Virol 2010; 82: 1364-1370 [PMID: 20572079 DOI: 10.1002/jmv.21818]
145. Tong X, Chase R, Skelton A, Chen T, Wright-Minogue J, Malcolm BA. Identifcation and analysis of ftness of resistance mutations against the HCV protease inhibitor SCH 503034. Antiviral Res 2006; 70: 28-38 [PMID: 16448708 DOI: 10.1016/j.antiviral.2005.12.003]
146. Lin C, Gates CA, Rao BG, Brennan DL, Fulghum JR, Lu-ong YP, Frantz JD, Lin K, Ma S, Wei YY, Perni RB, Kwong AD. In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061. J Biol Chem 2005; 280: 36784-36791 [PMID: 16087668 DOI: 10.1074/jbc.M506462200]
147. Courcambeck J, Bouzidi M, Perbost R, Jouirou B, Amrani N, Cacoub P, Pèpe G, Sabatier JM, Halfon P. Resistance of hepatitis C virus to NS3-4A protease inhibitors: mechanisms of drug resistance induced by R155Q, A156T, D168A and D168V mutations. Antivir Ther 2006; 11: 847-855 [PMID: 17302247]
148. Hiraga N, Imamura M, Abe H, Hayes CN, Kono T, Onishi M, Tsuge M, Takahashi S, Ochi H, Iwao E, Kamiya N, Yamada I, Tateno C, Yoshizato K, Matsui H, Kanai A, Inaba T, Tanaka S, Chayama K. Rapid emergence of telaprevir resistant hepatitis C virus strain from wildtype clone in vivo. Hepatology 2011; 54: 781-788 [PMID: 21626527 DOI: 10.1002/hep.24460]
149. Yi M, Tong X, Skelton A, Chase R, Chen T, Prongay A, Bo-gen SL, Saksena AK, Njoroge FG, Veselenak RL, Pyles RB, Bourne N, Malcolm BA, Lemon SM. Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor. Reduced RNA replication ftness and partial rescue by second-site mutations. J Biol Chem 2006; 281: 8205-8215 [PMID: 16352601 DOI: 10.1074/jbc.M510246200]
150. Adiwijaya BS, Herrmann E, Hare B, Kieffer T, Lin C, Kwong AD, Garg V, Randle JC, Sarrazin C, Zeuzem S, Caron PR. A multi-variant, viral dynamic model of genotype 1 HCV to assess the in vivo evolution of protease-in-hibitor resistant variants. PLoS Comput Biol 2010; 6: e1000745 [PMID: 20419154 DOI: 10.1371/journal.pcbi.1000745]
151. Bartolini B, Giombini E, Zaccaro P, Selleri M, Rozera G, Ab-bate I, Comandini UV, Ippolito G, Solmone M, Capobianchi MR. Extent of HCV NS3 protease variability and resistance-associated mutations assessed by next generation sequencing in HCV monoinfected and HIV/HCV coinfected patients. Virus Res 2013; 177: 205-208 [PMID: 23954579 DOI: 10.1016/j.virusres.2013.08.001]
152. Bruno S, Cammà C, Di Marco V, Rumi M, Vinci M, Camozzi M, Rebucci C, Di Bona D, Colombo M, Craxì A, Mondelli MU, Pinzello G. Peginterferon alfa-2b plus ribavirin for naïve patients with genotype 1 chronic hepatitis C: a randomized controlled trial. J Hepatol 2004; 41: 474-481 [PMID: 15336451 DOI: 10.1016/j.jhep.2004.05.012]
153. Hadziyannis SJ, Sette H, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H, Bernstein D, Rizzetto M, Zeuzem S, Pockros PJ, Lin A, Ackrill AM. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346-355 [PMID: 14996676 DOI: 10.7326/0003-4819-140-5-200403020-00010]
154. Kuboki M, Iino S, Okuno T, Omata M, Kiyosawa K, Ku-mada H, Hayashi N, Sakai T. Peginterferon alpha-2a (40 KD) plus ribavirin for the treatment of chronic hepatitis C in Japanese patients. J Gastroenterol Hepatol 2007; 22: 645-652 [PMID: 17444850]
155. Zeuzem S, Hultcrantz R, Bourliere M, Goeser T, Marcellin P, Sanchez-Tapias J, Sarrazin C, Harvey J, Brass C, Albrecht J. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004; 40: 993-999 [PMID: 15158341 DOI: 10.1016/j.jhep.2004.02.007]
156. Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, Vinelli F, Scotto G, Bacca D, Annese M, Romano M, Zechini F, Sogari F, Spirito F, Andriulli A. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005; 352: 2609-2617 [PMID: 15972867 DOI: 10.1056/NEJMoa042608]
157. von Wagner M, Huber M, Berg T, Hinrichsen H, Rasenack J, Heintges T, Bergk A, Bernsmeier C, Häussinger D, Herrmann E, Zeuzem S. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005; 129: 522-527 [PMID: 16083709 DOI: 10.1053/j.gastro.2005.05.008]
158. Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Solá R, Shafran SD, Barange K, Lin A, Soman A, Zeuzem S. Pe-ginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007; 357: 124-134 [PMID: 17625124 DOI: 10.1056/NEJMoa066403]
159. Yu ML, Dai CY, Huang JF, Hou NJ, Lee LP, Hsieh MY, Chiu CF, Lin ZY, Chen SC, Hsieh MY, Wang LY, Chang WY, Chuang WL. A randomised study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C. Gut 2007; 56: 553-559 [PMID: 16956917 DOI: 10.1136/gut.2006.102558]
160. Dalgard O, Bjøro K, Ring-Larsen H, Bjornsson E, Holberg-Petersen M, Skovlund E, Reichard O, Myrvang B, Sundelöf B, Ritland S, Hellum K, Frydén A, Florholmen J, Verbaan H. Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response. Hepatology 2008; 47: 35-42 [PMID: 17975791 DOI: 10.1002/hep.21975]
161. Hasan F, Asker H, Al-Khaldi J, Siddique I, Al-Ajmi M, Owaid S, Varghese R, Al-Nakib B. Peginterferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4. Am J Gastroenterol 2004; 99: 1733-1737 [PMID: 15330911 DOI: 10.1111/j.1572-0241.2004.40077.x]
162. Kamal SM, El Kamary SS, Shardell MD, Hashem M, Ahmed IN, Muhammadi M, Sayed K, Moustafa A, Hakem SA, Ibra-hiem A, Moniem M, Mansour H, Abdelaziz M. Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: The role of rapid and early virologic response. Hepatology 2007; 46: 1732-1740 [PMID: 17943989 DOI: 10.1002/hep.21917]
163. El Makhzangy H, Esmat G, Said M, Elraziky M, Shouman S, Refai R, Rekacewicz C, Gad RR, Vignier N, Abdel-Hamid M, Zalata K, Bedossa P, Pol S, Fontanet A, Mohamed MK. Response to pegylated interferon alfa-2a and ribavirin in chronic hepatitis C genotype 4. J Med Virol 2009; 81: 1576-1583 [PMID: 19626613 DOI: 10.1002/jmv.21570]
164. Bonny CRC, Randl K. Treatment of interferon-naive patients with HCV genotype 5 with interferon (or PEG-interferon) plus ribavirin results in a very high sustained virological response. J Hepatol 2003; 38: 738A [DOI: 10.1016/S0270-9139(03)81241-7]
165. Legrand-Abravanel F, Sandres-Sauné K, Barange K, Alric L, Moreau J, Desmorat P, Vinel JP, Izopet J. Hepatitis C virus genotype 5: epidemiological characteristics and sensitivity to combination therapy with interferon-alpha plus ribavi-rin. J Infect Dis 2004; 189: 1397-1400 [PMID: 15073676 DOI: 10.1086/382544]
166. Dev AT, McCaw R, Sundararajan V, Bowden S, Sievert W. Southeast Asian patients with chronic hepatitis C: the impact of novel genotypes and race on treatment outcome. Hepatology 2002; 36: 1259-1265 [PMID: 12395338 DOI: 10.1053/jhep.2002.36781]
167. Hui CK, Yuen MF, Sablon E, Chan AO, Wong BC, Lai CL. Interferon and ribavirin therapy for chronic hepatitis C virus genotype 6: a comparison with genotype 1. J Infect Dis 2003; 187: 1071-1074 [PMID: 12660921 DOI: 10.1086/368217]
168. Fung J, Lai CL, Hung I, Young J, Cheng C, Wong D, Yuen MF. Chronic hepatitis C virus genotype 6 infection: response to pegylated interferon and ribavirin. J Infect Dis 2008; 198: 808-812 [PMID: 18657036 DOI: 10.1086/591252]
169. Nguyen NH, VuTien P, Garcia RT, Trinh H, Nguyen H, Nguyen K, Levitt B, Nguyen MH. Response to pegylated in-terferon and ribavirin in Asian American patients with chronic hepatitis C genotypes 1 vs 2/3 vs 6. J Viral Hepat 2010; 17: 691-697 [PMID: 20002562 DOI: 10.1111/j.1365-2893.2009.01226. x]
170. Tsang OT, Zee JS, Chan JM, Li RS, Kan YM, Li FT, Lo FH, Chow DA, Cheung KW, Chan KH, Yeung YW, Ng FH, Li MK, Kwan WK, Lai TS. Chronic hepatitis C genotype 6 responds better to pegylated interferon and ribavirin combination therapy than genotype 1. J Gastroenterol Hepatol 2010; 25: 766-771 [PMID: 20492332 DOI: 10.1111/j.1440-1746.2009.06163. x]
171. Zhou YQ, Wang XH, Hong GH, Zhu Y, Zhang XQ, Hu YJ, Mao Q. Twenty-four weeks of pegylated interferon plus ribavirin effectively treat patients with HCV genotype 6a. J Viral Hepat 2011; 18: 595-600 [PMID: 21105968 DOI: 10.1111/ j.1365-2893.2010.01373.x]
172. Tangkijvanich P, Komolmit P, Mahachai V, Poovorawan K, Akkarathamrongsin S, Poovorawan Y. Response-guided therapy for patients with hepatitis C virus genotype 6 infection: a pilot study. J Viral Hepat 2012; 19: 423-430 [PMID: 22571904]