Hepatitis c virus: Molecular biology & current therapeutic options

Indian Journal of Medical Research

Volumn 131, Issue 1, 2010, Pages 17-34

  Sharma, Suresh D ^a  

^a PENNSYLVANIA STATE UNIVERSITY   (United States)

Author keywords

HCV; Hepatocellular carcinoma (HCC); Novel HCV therapeutics; Pegylated interferon; Ribavirin; Structural and nonstructural proteins

Indexed keywords

4 (1 AMINOETHYL) N (4 PYRIDYL)CYCLOHEXANECARBOXAMIDE; ALPHA INTERFERON; ALTERNATE READING FRAME PROTEIN; ANTIVIRUS AGENT; BMS 824; CASTANOSPERMINE 6 BUTYRATE; CORE PROTEIN; CYANOVIRIN N; FASUDIL; IDX 184; LOGANIN; MESOPORPHYRIN; MK 0608; NONSTRUCTURAL PROTEIN 2; NONSTRUCTURAL PROTEIN 3; NONSTRUCTURAL PROTEIN 4A; NONSTRUCTURAL PROTEIN 4B; NONSTRUCTURAL PROTEIN 5A; NONSTRUCTURAL PROTEIN 5B; P7 PROTEIN; PEGINTERFERON ALPHA; PEGINTERFERON ALPHA2A; PF 00868554; RIBAVIRIN; TELAPREVIR; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALOPICITABINE; VERBENALIN; VIRUS ENVELOPE PROTEIN; VIRUS PROTEIN;

ANEMIA; ANTIVIRAL ACTIVITY; ARTHRALGIA; CANCER RISK; CLINICAL TRIAL; DEPRESSION; DRUG COST; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG RESPONSE; DRUG TARGETING; DRUG WITHDRAWAL; FATTY LIVER; FEVER; HEADACHE; HEMOLYTIC ANEMIA; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; IMMUNE RESPONSE; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; MYALGIA; NONHUMAN; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; PRURITUS; RASH; REVIEW; VIRUS CELL INTERACTION; VIRUS CORE; VIRUS GENOME; VIRUS INHIBITION; VIRUS PARTICLE; VIRUS REPLICATION; VIRUS TRANSMISSION;

CELL LINE; HEPACIVIRUS; HEPATITIS C; HUMANS; INTERFERON ALFA-2A; INTERFERON ALFA-2B; POLYETHYLENE GLYCOLS; VIRAL PROTEINS; VIRUS REPLICATION;

EID: 76149141825     PISSN: 09715916     EISSN: 09715916     Source Type: Journal    
DOI: None     Document Type: Review

References (165)

1. 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 1999; 6: 35-47.
2. Alter, MJ, Epidemiology of hepatitis C virus infection. World J Gastroenterol 2007; 13: 2436-41.
3. Gottwein JM, Scheel TK, Jensen TB, Lademann JB, Prentoe JC, Knudsen ML, et al, Development and characterization of hepatitis C virus genotype 1-7 cell culture systems: Role of cd81 and scavenger receptor class b type i and effect of antiviral drugs. Hepatol 2009; 49: 364-77.
4. Kuiken C, Simmonds P, Nomenclature and numbering of the hepatitis C virus. Methods Mol Biol (Clifton) NJ 2009; 510: 33-53.
5. von Hahn T, Yoon JC, Alter H, Rice CM, Rehermann B, Balfe P, et al. Hepatitis C virus continuously escapes from neutralizing antibody and t-cell responses during chronic infection in vivo. Gastroenterology 2007; 132: 667-78.
6. Akeno N, Blackard JT, Tomer Y. HCV E2 protein binds directly to thyroid cells and induces IL-8 production: A new mechanism for HCV induced thyroid autoimmunity. J Autoimmun 2008; 31: 339-44.
7. Zhong J, Gastaminza P, Cheng G, Kapadia S, Kato T, Burton DR, et al. Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci USA 2005; 102: 9294-9.
8. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 2005; 11: 791-6.
9. Kaito M, Watanabe S, Tanaka H, Fujita N, Konishi M, Iwasa M, et al. Morphological identification of hepatitis C virus e1 and E2 envelope glycoproteins on the virion surface using immunogold electron microscopy. Int J Mol Med 2006; 18: 673-8.
10. Diviney S, Tuplin A, Struthers M, Armstrong V, Elliott RM, Simmonds P, et al. A hepatitis C virus cis-acting replication element forms a long-range RNA-RNA interaction with upstream rna sequences in ns5b. J Virol 2008; 82: 9008-22.
11. Lukavsky PJ, Otto GA, Lancaster AM, Sarnow P, Puglisi JD. Structures of two RNA domains essential for hepatitis C virus internal ribosome entry site function. Nat Struct Biol 2000; 7: 1105-10.
12. Shimoike T, McKenna SA, Lindhout DA, and Puglisi JD. Translational insensitivity to potent activation of pkr by HCV IRES RNA. Antiviral Res 2009.
13. Fan Z, Yang QR, Twu JS, Sherker AH. Specific in vitro association between the hepatitis C viral genome and core protein. J Med Virol 1999; 59: 131-4.
14. Friebe P, Bartenschlager R. Role of rna structures in genome terminal sequences of the hepatitis C virus for replication and assembly. J Virol 2009; 83: 11989-95.
15. Song Y, Friebe P, Tzima E, Junemann C, Bartenschlager R, Niepmann M. The hepatitis C virus RNA 3'-untranslated region strongly enhances translation directed by the internal ribosome entry site. J Virol 2006; 80: 11579-88.
16. Ye L, Timani KA, Kong L, Yang X, Liao Q, Wu J. Two cisacting elements in negative RNA strand of hepatitis C virus involved in synthesis of positive RNA strand in vitro. Acta Virol 2005; 49: 83-90.
17. Zhang Z, Harris D, Pandey VN. The fuse binding protein is a cellular factor required for efficient replication of hepatitis C virus. J Virol 2008; 82: 5761-73.
18. You S, Stump DD, Branch AD, Rice CM. A cis-acting replication element in the sequence encoding the ns5b RNA-dependent RNA polymerase is required for hepatitis C virus RNA replication. J Virol 2004; 78: 1352-66.
19. Friebe P, Boudet J, Simorre JP, Bartenschlager R. Kissing-loop interaction in the 3' end of the hepatitis C virus genome essential for RNA replication. J Virol 2005; 79: 380-92.
20. Jopling CL. Regulation of hepatitis C virus by microrna-122. Biochem Soc Trans 2008; 36: 1220-3.
21. Henke JI, Goergen D, Zheng J, Song Y, Schuttler CG, Fehr C, et al. Microrna-122 stimulates translation of hepatitis C virus RNA. EMBO J 2008; 27: 3300-10.
22. Kruger M, Beger C, Welch PJ, Barber JR, Manns MP, Wong- Staal F. Involvement of proteasome alpha-subunit psma7 in hepatitis C virus internal ribosome entry site-mediated translation. Mol Cell Biol 2001; 21: 8357-64.
23. Santolini E, Migliaccio G, La Monica N. Biosynthesis and biochemical properties of the hepatitis C virus core protein. J Virol 1994; 68: 3631-41.
24. Targett-Adams P, Hope G, Boulant S, McLauchlan J, Maturation of hepatitis C virus core protein by signal peptide peptidase is required for virus production. J Biol Chem 2008; 283: 16850-9.
25. Ait-Goughoulte M, Hourioux C, Patient R, Trassard S, Brand D, Roingeard P. Core protein cleavage by signal peptide peptidase is required for hepatitis C virus-like particle assembly. J Gen Virol 2006; 87: 855-60.
26. Suzuki R, Sakamoto S, Tsutsumi T, Rikimaru A, Tanaka K, Shimoike T, et al. Molecular determinants for subcellular localization of hepatitis C virus core protein. J Virol 2005; 79: 1271-81.
27. Williamson CD, Colberg-Poley AM. Access of viral proteins to mitochondria via mitochondria-associated membranes. Rev Med Virol 2009; 19: 147-64.
28. Tsutsumi T, Matsuda M, Aizaki H, Moriya K, Miyoshi H, Fujie H, et al. Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein. Heptatol 2009; 50: 378-86.
29. Miyanari Y, Atsuzawa K, usuda N, Watashi K, Hishiki T, Zayas M, et al. The lipid droplet is an important organelle for hepatitis C virus production. Nat Cell Biol 2007; 9: 1089-97.
30. Roingeard P. Hourioux C. Hepatitis C virus core protein, lipid droplets and steatosis. J Viral Hepat 2008; 15: 157-64.
31. McLauchlan J. Lipid droplets and hepatitis C virus infection. Biochim Biophys Acta 2009; 1791: 552-9.
32. Hourioux C, Patient R, Morin A, Blanchard E, Moreau A, Trassard S, et al. The genotype 3-specific hepatitis C virus core protein residue phenylalanine 164 increases steatosis in an in vitro cellular model. Gut 2007; 56: 1302-8.
33. Piodi A, Chouteau P, Lerat H, Hezode C, Pawlotsky JM. Morphological changes in intracellular lipid droplets induced by different hepatitis C virus genotype core sequences and relationship with steatosis. Heptatol 2008; 48: 16-27.
34. Barba G, Harper F, Harada T, Kohara M, Goulinet S, Matsuura Y, et al. Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. Proc Nat Acad Sci USA 1997; 94: 1200-5.
35. Lo SY, Masiarz F, Hwang SB, Lai MM, Ou JH. Differential subcellular localization of hepatitis C virus core gene products. Virology 1995; 213: 455-61.
36. Sansonno D, Lauletta G, Nisi L, Gatti P, Pesola F, Pansini N, et al. Non-enveloped HCV core rotein as constitutive antigen of cold-precipitable immune complexes in type ii mixed cryoglobulinaemia. Clin Exp Immunol 2003; 133: 275-82.
37. Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K, et al. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 1998; 4: 1065-7.
38. Fishman SL, Factor SH, Balestrieri C, Fan X, Dibisceglie AM, Desai SM, et al. Mutations in the hepatitis C virus core gene are associated with advanced liver disease and hepatocellular carcinoma. Clin Cancer Res 2009; 15: 3205-13.
39. Pazienza V, Clement S, Pugnale P, Conzelmann S, Pascarella S, Mangia A, et al. Gene expression profile of huh-7 cells expressing hepatitis C virus genotype 1b or 3a core proteins. Liver Int 2009; 29: 661-9.
40. Herzer K, Weyer S, Krammer PH, Galle PR, Hofmann TG, Hepatitis C virus core protein inhibits tumor suppressor protein promyelocytic leukemia function in human hepatoma cells. Cancer Res 2005; 65: 10830-7.
41. Shesheer Kumar M, Venkateswara Rao K, Mohammed Habeebullah C, Dashavantha Reddy V. Expression of alternate reading frame protein (f1) of hepatitis C virus in Escherichia coli and detection of antibodies for f1 in indian patients. Infect Genet Evol 2008; 8: 374-7.
42. Varaklioti A, Vassilaki N, Georgopoulou u, Mavromara P. Alternate translation occurs within the core coding region of the hepatitis C viral genome. J Biol Chem 2002; 277: 17713-21.
43. Vassilaki N, Mavromara P. Two alternative translation mechanisms are responsible for the expression of the HCV arfp/f/core+1 coding open reading frame. J Biol Chem 2003; 278: 40503-13.
44. Yuksek K, Chen WL, Chien D, Ou JH. ubiquitin-independent degradation of hepatitis C virus f protein. J Virol 2009; 83: 612-21.
45. Pileri P, uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, et al. Binding of hepatitis C virus to cd81. Science 1998; 282: 938-41.
46. Ploss A, Evans MJ, Gaysinskaya VA, Panis M, You H, de Jong YP, et al. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 2009; 457: 882-6.
47. Owsianka AM, Timms JM, Tarr AW, Brown RJ, Hickling TP, Szwejk A, et al. Identification of conserved residues in the E2 envelope glycoprotein of the hepatitis C virus that are critical for cd81 binding. J Virol 2006; 80: 8695-704.
48. Voisset C, Callens N, Blanchard E, Op De Beeck A, Dubuisson J, Vu-Dac N. High density lipoproteins facilitate hepatitis C virus entry through the scavenger receptor class b type i. J Biol Chem 2005; 280: 7793-9.
49. Cocquerel L, Voisset C, Dubuisson J. Hepatitis C virus entry: Potential receptors and their biological functions. J Gen Virol 2006; 87: 1075-84.
50. Voisset C, Dubuisson J. Functional hepatitis C virus envelope glycoproteins. Biol Cell 2004; 96: 413-20.
51. Yu X, Qiao M, Atanasov I, Hu Z, Kato T, Liang TJ, et al. Cryoelectron microscopy and three-dimensional reconstructions of hepatitis C virus particles. Virology 2007; 367: 126-34.
52. Voisset C, Op de Beeck A, Horellou P, Dreux M, Gustot T, Duverlie G, et al. High-density lipoproteins reduce the neutralizing effect of hepatitis C virus (HCV)-infected patient antibodies by promoting HCV entry. J Gen Virol 2006; 87: 2577-81.
53. Bartosch B, Verney G, Dreux M, Donot P, Morice Y, Penin F, et al. An interplay between hypervariable region 1 of the hepatitis C virus E2 glycoprotein, the scavenger receptor bi, and high-density lipoprotein promotes both enhancement of infection and protection against neutralizing antibodies. J Virol 2005; 79: 8217-29.
54. Pietschmann T, Zayas M, Meuleman P, Long G, Appel N, Koutsoudakis G, et al. Production of infectious genotype 1b virus particles in cell culture and impairment by replication enhancing mutations. Pub Libr Sci Pathog 2009; 5: e1000475.
55. Lin C, Lindenbach BD, Pragai BM, McCourt DW, Rice CM. Processing in the hepatitis C virus E2-NS2 region: Identification of p7 and two distinct E2-specific products with different c termini. J Virol 1994; 68: 5063-73.
56. Carrere-Kremer S, Montpellier C, Lorenzo L, Brulin B, Cocquerel L, Belouzard S, et al. Regulation of hepatitis C virus polyprotein processing by signal peptidase involves structural determinants at the p7 sequence junctions. J Biol Chem 2004; 279: 41384-92.
57. Haqshenas G, Mackenzie JM, Dong X, Gowans EJ, Hepatitis C virus p7 protein is localized in the endoplasmic reticulum when it is encoded by a replication-competent genome. J Gen Virol 2007; 88: 134-42.
58. Carrere-Kremer S, Montpellier-Pala C, Cocquerel L, Wychowski C, Penin F, Dubuisson J, Subcellular localization and topology of the p7 polypeptide of hepatitis C virus. J Virol 2002; 76: 3720-30.
59. Luik P, Chew C, Aittoniemi J, Chang J, Wentworth P, Jr., Dwek RA, et al. The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy. Proc Nat Acad Sci USA 2009; 106: 12712-6
60. Sakai A, Claire MS, Faulk K, Govindarajan S, Emerson Su, Purcell RH, et al. The p7 polypeptide of hepatitis C virus is critical for infectivity and contains functionally important genotype-specific sequences. Proc Nat Acad Sci USA 2003; 100: 11646-51.
61. Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R. Replication of subgenomic hepatitis C virus rnas in a hepatoma cell line. Science 1999; 285: 110-3.
62. Blight KJ, Kolykhalov AA, Rice CM. Efficient initiation of HCV RNA replication in cell culture. Science 2000; 290: 1972-4.
63. Griffin SD, Beales LP, Clarke DS, Worsfold O, Evans SD, Jaeger J, et al. The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, amantadine. FEBS Lett 2003; 535: 34-8.
64. Steinmann E, Whitfield T, Kallis S, Dwek RA, Zitzmann N, Pietschmann T, et al. Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus. Heptatol 2007; 46: 330-8.
65. Steinmann E, Penin F, Kallis S, Patel AH, Bartenschlager R, Pietschmann T. Hepatitis C virus p7 protein is crucial for assembly and release of infectious virions. Pub Libr Sci Pathog 2007; 3: e103.
66. Pavlovic D, Fischer W, Hussey M, Durantel D, Durantel S, Branza-Nichita N, et al. Long alkylchain iminosugars block the HCV p7 ion channel. Adv Exp Med Biol 2005; 564: 3-4.
67. Santolini E, Pacini L, Fipaldini C, Migliaccio G, Monica N. The NS2 protein of hepatitis C virus is a transmembrane polypeptide. J Virol 1995; 69: 7461-71.
68. Yamaga AK, Ou JH. Membrane topology of the hepatitis C virus NS2 protein. J Biol Chem 2002; 277: 33228-34.
69. Grakoui A, McCourt DW, Wychowski C, Feinstone SM, Rice CM. Characterization of the hepatitis C virus-encoded serine proteinase: Determination of proteinase-dependent polyprotein cleavage sites. J Virol 1993; 67: 2832-43.
70. Grakoui A, McCourt DW, Wychowski C, Feinstone SM, Rice CM. A second hepatitis c virus-encoded proteinase. Proc Natl Acad Sci USA 1993; 90: 10583-7.
71. Jones CT, Murray CL, Eastman DK, Tassello J, Rice CM. Hepatitis C virus p7 and NS2 proteins are essential for production of infectious virus. J Virol 2007; 81: 8374-83.
72. Welbourn S, Pause A. The hepatitis C virus NS2/3 protease. Curr Issu Mol Biol 2007; 9: 63-9.
73. Schregel V, Jacobi S, Penin F, Tautz N. Hepatitis C virus NS2 is a protease stimulated by cofactor domains in NS3. Proc Natl Acad Sci uSA 2009; 106: 5342-7.
74. Dimitrova M, Imbert I, Kieny MP, Schuster C. Protein-protein interactions between hepatitis C virus nonstructural proteins. J Virol 2003; 77: 5401-14.
75. Yi M, Ma Y, Yates J, Lemon SM. Trans-complementation of an NS2 defect in a late step in hepatitis C virus (HCV) particle assembly and maturation. Pub Libr Sci Pathog 2009; 5: e1000403.
76. Hahm B, Han DS, Back SH, Song OK, Cho MJ, Kim CJ, et al. NS3-4A of hepatitis C virus is a chymotrypsin-like protease. J Virol 1995; 69: 2534-9.
77. Mottola G, Cardinali G, Ceccacci A, Trozzi C, Bartholomew L, Torrisi MR, et al. Hepatitis C virus nonstructural proteins are localized in a modified endoplasmic reticulum of cells expressing viral subgenomic replicons. Virology 2002; 293: 31-43.
78. Jennings TA, Chen Y, Sikora D, Harrison MK, Sikora B, Huang L, et al. RNA unwinding activity of the hepatitis C virus NS3 helicase is modulated by the ns5b polymerase. Biochemistry 2008; 47: 1126-35.
79. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, et al. IPS-1, an adaptor triggering rig-i- and mda5-mediated type i interferon induction. Nat Immunol 2005; 6: 981-8.
80. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, et al. Cardif is an adaptor protein in the rig-I antiviral pathway and is targeted by hepatitis C virus. Nature 2005; 437: 1167-72.
81. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Nat Acad Sci USA 2005; 102: 17717-22.
82. Ahlen G, Derk E, Weiland M, Jiao J, Rahbin N, Aleman S, et al. Cleavage of the ips-1/cardif/mavs/visa does not inhibit t cell-mediated elimination of hepatitis C virus non-structural 3/4A-expressing hepatocytes. Gut 2009; 58: 560-9.
83. Liefhebber JM, Hensbergen PJ, Deelder AM, Spaan WJ, van Leeuwen H. Characterization of hepatitis C virus NS3 modifications in the context of replication. J Gen Virol 2009.
84. Selimovic D, Hassan M. Inhibition of hepatitis C virus (HCV) core protein- induced cell growth by non-structural protein 4A (ns4A) is mediated by mitochondrial dysregulation. Bosn J Basic Med Sci 2008; 8: 4-11.
85. Nomura-Takigawa Y, Nagano-Fujii M, Deng L, Kitazawa S, Ishido S, Sada K, et al. Non-structural protein 4A of hepatitis C virus accumulates on mitochondria and renders the cells prone to undergoing mitochondria-mediated apoptosis. J Gen Virol 2006; 87: 1935-45.
86. Hugle T, Fehrmann F, Bieck E, Kohara M, Krausslich HG, Rice CM, et al. The hepatitis C virus nonstructural protein 4b is an integral endoplasmic reticulum membrane protein. Virology 2001; 284: 70-81.
87. Welsch C, Albrecht M, Maydt J, Herrmann E, Welker MW, Sarrazin C, et al. Structural and functional comparison of the non-structural protein 4b in flaviviridae. J Mol graphics Modelling 2007; 26: 546-57.
88. Yu GY, Lee KJ, Gao L, Lai MM. Palmitoylation and polymerization of hepatitis C virus ns4b protein. J Virol 2006; 80: 6013-23.
89. Liefhebber JM, Brandt BW, Broer R, Spaan WJ, van Leeuwen HC. Hepatitis C virus ns4b carboxy terminal domain is a membrane binding domain. J Virol 2009; 6: 62-73.
90. Blight KJ, Allelic variation in the hepatitis C virus ns4b protein dramatically influences RNA replication. J Virol 2007; 81: 5724-36.
91. Pfeifer U, Thomssen R, Legler K, Bottcher U, Gerlich W, Weinmann E, et al. Experimental non-a, non-b hepatitis: Four types of cytoplasmic alteration in hepatocytes of infected chimpanzees. Virchows Archiv 1980; 33: 233-43.
92. Egger D, Wolk B, Gosert R, Bianchi L, Blum HE, Moradpour D, et al. Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex. J Virol 2002; 76: 5974-84.
93. El-Hage N, Luo G. Replication of hepatitis C virus RNA occurs in a membrane-bound replication complex containing nonstructural viral proteins and RNA. J Gen Virol 2003; 84: 2761-9.
94. Lundin M, Lindstrom H, Gronwall C, Persson MA. Dual topology of the processed hepatitis C virus protein ns4b is influenced by the NS5A protein. J Gen Virol 2006; 87: 3263-72.
95. Park JS, Yang JM, Min MK. Hepatitis C virus nonstructural protein ns4b transforms NIH3T3 cells in cooperation with the ha-ras oncogene. Biochem Biophys Res Commu 2000; 267: 581-7.
96. Huang L, Hwang J, Sharma SD, Hargittai MR, Chen Y, Arnold JJ, et al. Hepatitis C virus nonstructural protein 5a (NS5A) is an RNA-binding protein. J Bio Chem 2005; 280: 36417-28.
97. Quintavalle M, Sambucini S, Di Pietro C, De Francesco R, Neddermann P. The alpha isoform of protein kinase CKI is responsible for hepatitis C virus NS5A hyperphosphorylation. J Virol 2006; 80: 11305-12.
98. Quintavalle M, Sambucini S, Summa V, Orsatti L, Talamo F, De Francesco R, et al. Hepatitis C virus NS5A is a direct substrate of casein kinase i-alpha, a cellular kinase identified by inhibitor affinity chromatography using specific NS5A hyperphosphorylation inhibitors. J Biol Chem 2007; 282: 5536-44.
99. Evans MJ, Rice CM, Goff SP. Phosphorylation of hepatitis C virus nonstructural protein 5a modulates its protein interactions and viral RNA replication. Proc Natl Acad Sci USA 2004; 101: 13038-43.
100. Lemm JA, O'Boyle D, Liu M, Nower PT, Colonno R, Deshpande MS, et al. Identification of hepatitis C virus NS5A inhibitors. J Virol 2009; 84: 482-91.
101. Tellinghuisen TL, Foss KL, Treadaway J. Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. Pub Libr Sci Pathog 2008; 4: e1000032.
102. Hughes M, Griffin S, Harris M. Domain iii of NS5A contributes to both RNA replication and assembly of hepatitis C virus particles. J Gen Virol 2009; 90: 1329-34.
103. Burckstummer T, Kriegs M, Lupberger J, Pauli EK, Schmittel S, Hildt E. Raf-1 kinase associates with hepatitis C virus NS5A and regulates viral replication. FEBS Lett 2006; 580: 575-80.
104. Sauter D, Himmelsbach K, Kriegs M, Carvajal Yepes M, Hildt E, Localization determines function: N-terminally truncated NS5A fragments accumulate in the nucleus and impair HCV replication. J Hepatol 2009; 50: 861-71.
105. Amako Y, Sarkeshik A, Hotta H, Yates J, 3rd, Siddiqui A. Role of oxysterol binding protein in hepatitis C virus infection. J Virol 2009; 83: 9237-46.
106. Kanda T, Steele R, Ray R, Ray RB. Inhibition of intrahepatic IFN-(gamma) production by hepatitis C virus non-structural protein 5a in transgenic mice. J Virol 2009; 83: 8463-9.
107. Kriegs M, Burckstummer T, Himmelsbach K, Bruns M, Frelin L, Ahlen G, et al. The hepatitis C virus non-structural NS5A protein impairs both the innate and adaptive hepatic immune response in vivo. J Biol Chem 2009; 284: 28343-51.
108. Lesburg CA, Cable MB, Ferrari E, Hong Z, Mannarino AF, Weber PC. Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat Struct Biol 1999; 6: 937-43.
109. Schmidt-Mende J, Bieck E, Hugle T, Penin F, Rice CM, Blum HE, et al. Determinants for membrane association of the hepatitis C virus RNA-dependent RNA polymerase. J Biol Chem 2001; 276: 44052-63.
110. Moradpour D, Brass V, Bieck E, Friebe P, Gosert R, Blum HE, et al. Membrane association of the RNA-dependent RNA polymerase is essential for hepatitis C virus RNA replication. J Virol 2004; 78: 13278-84.
111. Shirota Y, Luo H, Qin W, Kaneko S, Yamashita T, Kobayashi K, et al. Hepatitis C virus (HCV) NS5A binds RNA-dependent RNA polymerase (RDRP) ns5b and modulates RNA-dependent RNA polymerase activity. J Biol Chem 2002; 277: 11149-55.
112. Quezada EM, Kane CM. The hepatitis C virus NS5A stimulates ns5b during in vitro RNA synthesis in a template specific manner. Open Biochem J 2009; 3: 39-48.
113. Simister P, Schmitt M, Geitmann M, Wicht O, Danielson uH, Klein R, et al. Structural and functional analysis of hepatitis C virus strain jfh1 polymerase. J Virol 2009; 83: 11926-39.
114. Burton JR, Jr., Everson GT. HCV NS5B polymerase inhibitors. Clin Liver Dis 2009; 13: 453-65.
115. Wang M, Ng KK, Cherney MM, Chan L, Yannopoulos CG, Bedard J, et al. Non-nucleoside analogue inhibitors bind to an allosteric site on HCV ns5b polymerase. Crystal structures and mechanism of inhibition. J Biol Chem 2003; 278: 9489-95.
116. Chatterji U, Bobardt M, Selvarajah S, Yang F, Tang H, Sakamoto N, et al. The isomerase active site of cyclophilin a is critical for hepatitis C virus replication. J Biol Chem 2009; 284: 16998-7005.
117. Kim SJ, Kim JH, Kim YG, Lim HS, Oh JW. Protein kinase C-related kinase 2 regulates hepatitis C virus RNA polymerase function by phosphorylation. J Biol Chem 2004; 279: 50031-41.
118. Kim, SJ, Kim JH, Sun JM, Kim MG, Oh JW. Suppression of hepatitis C virus replication by protein kinase C-related kinase 2 inhibitors that block phosphorylation of viral RNA polymerase. J Viral Hepat 2009; 16: 697-704.
119. Young KC, Lindsay KL, Lee KJ, Liu WC, He JW, Milstein SL, et al. Identification of a ribavirin-resistant ns5b mutation of hepatitis C virus during ribavirin monotherapy. Heptatol 2003; 38: 869-78.
120. Sentandreu V, Jimenez-Hernandez N, Torres-Puente M, Bracho MA, Valero A, Gosalbes MJ, et al. Evidence of recombination in intrapatient populations of hepatitis C virus. Pub Libr Sci ONE 2008; 3: e3239.
121. Lindenmann J, Burke DC, Isaacs A. Studies on the production, mode of action and properties of interferon. Br J Exp Pathol 1957; 38: 551-62.
122. Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 2005; 436: 967-72.
123. Potter CW, Phair JP, Vodinelich L, Fenton R, Jennings R. Antiviral, immunosuppressive and antitumour effects of ribavirin. Nature 1976; 259: 496-7.
124. NIH consensus statement on management of hepatitis C: 2002. NIH Consens State Sci Statements 2002; 19: 1-46.
125. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis interventional therapy group. N Engl J Med 1998; 339: 1485-92.
126. Hong Z, Cameron CE. Pleiotropic mechanisms of ribavirin antiviral activities. Prog Drug Res 2002; 59: 41-69.
127. Crotty S, Maag D, Arnold JJ, Zhong W, Lau JY, Hong Z, et al. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med 2000; 6: 1375-9.
128. Lee JH, von Wagner M, Roth WK, Teuber G, Sarrazin C, Zeuzem S. Effect of ribavirin on virus load and quasispecies distribution in patients infected with hepatitis C virus. J Hepatol 1998; 29: 29-35.
129. Welzel TM, Morgan TR, Bonkovsky HL, Naishadham D, Pfeiffer RM, Wright EC, et al. Variants in interferon-alpha pathway genes and response to pegylated interferon-alpha2a plus ribavirin for treatment of chronic hepatitis C virus infection in the hepatitis Cantiviral long-term treatment against cirrhosis trial. Heptatol 2009; 49: 1847-58.
130. Helle F, Wychowski C, Vu-Dac N, Gustafson KR, Voisset C, Dubuisson J. Cyanovirin-n inhibits hepatitis C virus entry by binding to envelope protein glycans. J Biol Chem 2006; 281: 25177-83.
131. Ouzounov S, Mehta A, Dwek RA, Block TM, Jordan R. The combination of interferon alpha-2b and n-butyl deoxynojirimycin has a greater than additive antiviral effect upon production of infectious bovine viral diarrhea virus (BVDV) in vitro: Implications for hepatitis C virus (HCV) therapy. Antiviral Research 2002; 55: 425-35.
132. Durantel D. Celgosivir, an alpha-glucosidase i inhibitor for the potential treatment of HCV infection. Curr Opin Investig Drugs 2009; 10: 860-70.
133. Zitzmann N, Mehta AS, Carrouee S, Butters TD, Platt FM, McCauley J, et al. Imino sugars inhibit the formation and secretion of bovine viral diarrhea virus, a pestivirus model of hepatitis C virus: Implications for the development of broad spectrum anti-hepatitis virus agents. Proc Natl Acad Sci USA 1999; 96: 11878-82.
134. Chapel C, Garcia C, Roingeard P, Zitzmann N, Dubuisson J, Dwek RA, et al. Antiviral effect of alpha-glucosidase inhibitors on viral morphogenesis and binding properties of hepatitis C virus-like particles. J Gen Virol 2006; 87: 861-71.
135. Trotard M, Lepere-Douard C, Regeard M, Piquet-Pellorce C, Lavillette D, Cosset FL, et al. Kinases required in hepatitis C virus entry and replication highlighted by small interference RNA screening. FASEB J 2009; 23: 3780-9.
136. Berger KL, Cooper JD, Heaton NS, Yoon R, Oakland TE, Jordan TX, et al. Roles for endocytic trafficking and phosphatidylinositol 4-kinase iii alpha in hepatitis C virus replication. Proc Natl Acad Sci USA 2009; 106: 7577-82.
137. Zhang H, Rothwangl K, Mesecar AD, Sabahi A, Rong L, Fong HH. Lamiridosins, hepatitis C virus entry inhibitors from lamium album. J Nat Prod 2009; (PMID: 19904996).
138. Witteveldt J, Evans MJ, Bitzegeio J, Koutsoudakis G, Owsianka AM, Angus AG, et al. Cd81 is dispensable for hepatitis C virus cell-to-cell transmission in hepatoma cells. J Gen Virol 2009; 90: 48-58.
139. Ferreon JC, Ferreon AC, Li K, Lemon SM. Molecular determinants of TRIF proteolysis mediated by the hepatitis C virus NS3/4A protease. J Biol Chem 2005; 280: 20483-92.
140. McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827-38.
141. Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839-50.
142. Moriyama K, Suzuki T, Negishi K, Graci JD, Thompson CN, Cameron CE, et al. Effects of introduction of hydrophobic group on ribavirin base on mutation induction and anti-RNA viral activity. J Medicinal Chem 2008; 51: 159-66.
143. Hou W, Tian Q, Zheng J, Bonkovsky HL. Zinc mesoporphyrin induces rapid proteasomal degradation of hepatitis c nonstructural 5a protein in human hepatoma cells. Gastroenterology, 2009.
144. Gardelli C, Attenni B, Donghi M, Meppen M, Pacini B, Harper S, et al. Phosphoramidate prodrugs of 2'-c-methylcytidine for therapy of hepatitis C virus infection. J Medicinal Chem 2009; 52: 5394-407.
145. Mathy JE, Ma S, Compton T, Lin K. Combinations of cyclophilin inhibitor nim811 with hepatitis C virus NS3-4A protease or ns5b polymerase inhibitors enhance antiviral activity and suppress the emergence of resistance. Antimicrob Agents Chemother 2008; 52: 3267-75.
146. Coelmont L, Kaptein S, Paeshuyse J, Vliegen I, Dumont JM, Vuagniaux G, et al. Debio 025, a cyclophilin binding molecule, is highly efficient in clearing hepatitis C virus (HCV) replicon-containing cells when used alone or in combination with specifically targeted antiviral therapy for HCV (stat-c) inhibitors. Antimicrob Agents Chemother 2009; 53: 967-76.
147. Bader T, Fazili J, Madhoun M, Aston C, Hughes D, Rizvi S, et al. Fluvastatin inhibits hepatitis c replication in humans. Am J Gastroenterol 2008; 103: 1383-9.
148. Ikeda M, Kato N. Life style-related diseases of the digestive system: Cell culture system for the screening of anti-hepatitis C virus (HCV) reagents: Suppression of HCV replication by statins and synergistic action with interferon. J Pharmacol Sci 2007; 105: 145-50.
149. Delang L, Paeshuyse J, Vliegen I, Leyssen P, Obeid S, Durantel D, et al. Statins potentiate the in vitro anti-hepatitis C virus activity of selective hepatitis C virus inhibitors and delay or prevent resistance development. Heptatol 2009; 50: 6-16.
150. Makeyev EV, Zhang J, Carrasco MA, Maniatis T. The microrna mir-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mrna splicing. Mol Cell 2007; 27: 435-48.
151. Fabbri M, Ivan M, Cimmino A, Negrini M, Calin GA. Regulatory mechanisms of micrornas involvement in cancer. Expert Opin Biol Ther 2007; 7: 1009-19.
152. Nathans R, Chu CY, Serquina AK, Lu CC, Cao H, Rana TM. Cellular microrna and p bodies modulate host-hiv-1 interactions. Mol Cell 2009; 34: 696-709.
153. Mamiya N, Worman HJ. Hepatitis C virus core protein binds to a dead box RNA helicase. J Biol Chem 1999; 274: 15751-6.
154. Ariumi Y, Kuroki M, Abe K, Dansako H, Ikeda M, Wakita T, et al, Ddx3 dead-box rna helicase is required for hepatitis C virus rna replication. J Virol 2007; 81: 13922-6.
155. Owsianka AM, Patel AH. Hepatitis C virus core protein interacts with a human dead box protein ddx3. Virology 1999; 257: 330-40.
156. Klade CS, Wedemeyer H, Berg T, Hinrichsen H, Cholewinska G, Zeuzem S, et al. Therapeutic vaccination of chronic hepatitis C nonresponder patients with the peptide vaccine IC41. Gastroenterol 2008; 134: 1385-95.
157. Law M, Maruyama T, Lewis J, Giang E, Tarr AW, Stamataki Z, et al. Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nat Med 2008; 14: 25-7.
158. Fytili P, Dalekos GN, Schlaphoff V, Suneetha PV, Sarrazin C, Zauner W, et al. Cross-genotype-reactivity of the immunodominant HCV cd8 t-cell epitope NS3-1073. Vaccine 2008; 26: 3818-26.
159. van der Meer-Janssen YP, van Galen J, Batenburg JJ, Helms JB. Lipids in host-pathogen interactions: Pathogens exploit the complexity of the host cell lipidome. Prog Lipid Res 2009.
160. Meyer MF, Lehmann M, Cornberg M, Wiegand J, Manns MP, Klade C, et al. Clearance of low levels of HCV viremia in the absence of a strong adaptive immune response. Virology J 2007; 4: 58.
161. Smith RE. Hepatitis C virus therapies. Nat Rev Drug Discov 2006; 5: 715-6.
162. Rudolf KFB, Anna MP. Hepatitis C Viral NS3-4A protease activity is enhanced by the NS3 helicase. J Biol Chem 2008; 283: 29929-37.
163. Frick DN. The hepatitis C virus NS3 protein: a model RNA helicase and potential drug target. Curr Issues Mol Biol 2007; 9: 1-20.
164. Shimoike TS, Mimori HT, Matsuura Y, Miyamura T. Interaction of hepatitis C virus core protein with viral sense RNA and suppression of its translation. J Virol 1999; 73: 9718-25.
165. http://www.tacerebio.com/Technology/technology.html, accessed in June 2009.