Molecular targeting of antiviral drugs used against hepatitis C virus infection

Abstract

Present study reports an update on the molecular interaction of antiviral drugs with viral and host cell components during hepatitis C virus (HCV) infection. In addition to the traditional therapeutic drug regimen, termed as standard of care, some recent drugs have been added in the existing regimen used for HCV infection. These drugs were categorized as direct-acting antivirals (DAAs) agents and “other agents”, with their efficacious impact in the control of HCV infection. They target both viral proteases and host cell receptor proteins/enzymes involved in HCV entry into the cell, replication, and assembly to check their propagation both in situ as well as in cell to cell transmission. Recent studies have reported a significant rise in sustained virological response after the use of these drugs both alone and in combination with pegylated interferon-α (PegIFN-α) plus ribavirin. Recently, DAAs have been reported to be highly effective in eradication of HCV infection, especially liver cirrhosis, reducing but not avoiding the occurrence of liver cancer. Some studies have demonstrated that the presence of resistant HCV variants, arising during viral replication, may be controlled by the new drug regimen. It is important to note here that all these drugs are influenced by viral as well as host factors including basic viral load, HCV genotypes, IFN action, interleukin 28B polymorphism and some liver and metabolic diseases, etc. This is an area with on-going investigations to explore more antiviral agents that may address new challenges in HCV therapy.

Keywords

Hepatitis C virus / interferon / pegylated interferon / direct-acting antivirals / sustained virological response / drug-resistance

References

[1] Mohd Hanafiah K,Flaxman AD.Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence.Hepatology2013;57:1333-42

[2] Alter MJ.Epidemiology of hepatitis C virus infection.World J Gastroenterol2007;13:2436-41 PMCID:PMC4146761

[3] Lavanchy D.The global burden of hepatitis C.Liver Int2009;29 Suppl1:74-81

[4] McHutchison JG.Chronic hepatitis C: an age wave of disease burden..Am J Manag Care2005;11:S286-95; quiz S307-11

[5] Irshad M,Irshad K.Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection.World J Hepatol2017;9:1305-14 PMCID:PMC5756719

[6] Chevaliez S.HCV Genome and Life Cycle.In: Tan SL, editor. Hepatitis C Viruses: Genomes and Molecular Biology. UK: Norfolk; 2006 PMCID:PMC1415842

[7] Khaliq S,Pervaiz A.Sequence variability of HCV core region: important predictors of HCV induced pathogenesis and viral production.Infect Genet Evol2011;11:543-56

[8] Drummer HE,Poumbourios P.Cell surface expression of functional hepatitis C virus E1 and E2 glycoproteins.FEBS Lett2003;546:385-90

[9] Steinmann E,Kallis S,Bartenschlager R.Hepatitis C virus p7 protein is crucial for assembly and release of infectious virions.PLoS Pathog2007;3:e103 PMCID:PMC1924870

[10] Steinmann E.Hepatitis C virus p7-a viroporin crucial for virus assembly and an emerging target for antiviral therapy.Viruses2010;2:2078-95 PMCID:PMC3185753

[11] Gallinari P,Nardi C,Tomei L,De Francesco R.Multiple enzymatic activities associated with recombinant NS3 protein of hepatitis C virus.J Virol1998;72:6758-69 PMCID:PMC109884

[12] Stapleford KA.Hepatitis C virus NS2 coordinates virus particle assembly through physical interactions with the E1-E2 glycoprotein and NS3- NS4A enzyme complexes.J Virol2011;85:1706-17 PMCID:PMC3028914

[13] Morikawa K,Gouttenoire J,Brass V,Moradpour A.Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus.J Viral Hepat2011;18:305-15

[14] Gouttenoire J,Moradpour D.Hepatitis C virus nonstructural protein 4B:a journey into unexplored territory.Rev Med Virol2010;20:117-29

[15] Macdonald A,Street A,Harris M.The hepatitis C virus NS5A protein binds to members of the Src family of tyrosine kinases and regulates kinase activity.J Gen Virol2004;85:721-9

[16] Reed KE,Rice CM.Phosphorylation of the hepatitis C virus NS5A protein in vitro and in vivo: properties of the NS5A-associated kinase.J Virol1997;71:7187-97 PMCID:PMC192058

[17] Moradpour D,Rice CM.Replication of hepatitis C virus.Nat Rev Microbiol2007;5:453-63

[18] Ghany MG,Thomas DL,American Association for the Study of Liver Disease..Diagnosis, management, and treatment of hepatitis C: an update.Hepatology2009;49:1335-74

[19] Chhatwal J,Hur C.Direct-acting antiviral agents for patients with hepatitis C virus genotype 1 infection are cost-saving.Clin Gastroenterol Hepatol2017;15:827-37.e8

[20] Buhler S.New targets for antiviral therapy of chronic hepatitis C.Liver Int2012;32:9-16

[21] Aghemo A.New horizons in hepatitis C antiviral therapy with direct acting antivirals.Hepatology2013;58:428-38

[22] Temesgen Z.Daclatasvir for the treatment of chronic hepatitis C virus infection.Drugs Today (Barc)2015;51:277-88

[23] Kowdley KV,Crespo I,Davis MN,Bernstein DE,Vierling JM,Anderson JK,Dvory-Sobol H,Hindes RG,Symonds WT,Nelson DR.Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment- naïve patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial.Lancet2013;381:2100-7

[24] Lawitz E,Hassanein T,Poordad FF,Afdhal NH,Dejesus E,Nelson DR,Jacobson IM,Abrams GA,Rodriguez-Torres M,Sulkowski MS,Hyland RH,Lin M,Hindes R,Symonds WT,Muir A.Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial.Lancet Infect Dis2013;13:401-8

[25] Issur M.Resistance patterns associated with HCV NS5A inhibitors provide limited insight into drug binding.Viruses2014;6:4227-41 PMCID:PMC4246218

[26] Nelson DR,Chuang WL,Rodriguez- Torres M,Rasenack JW,Lee CM,Pianko S,Cronin PW,Subramanian GM.Albinterferon Alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 2 or 3.Gastroenterology2010;139:1267-76 PMCID:PMC3175757

[27] Zeuzem S,Lawitz EJ,Rodriguez- Torres M,Grigorescu M,Lurie Y,Muir AJ,Pulkstenis E,McHutchison JG.Albinterferon alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 1.Gastroenterology2010;139:1257-66

[28] Muir AJ,Zaman A,de la Torre A,Gordon SC,Vierling JM,Byrnes-Blake K,Freeman J,Hausman D,Lawitz E.Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection.Hepatology2010;52:822-32

[29] Zhu Y.Antiviral treatment of hepatitis C virus infection and factors affecting efficacy.World J Gastroenterol2013;19:8963-73 PMCID:PMC3870549

[30] Cummings MD,Lin TI,Lenz O,Felländer S,Nyström S,Vrang L,Rosenquist A,Raboisson P.Induced-fit binding of the macrocyclic noncovalent inhibitor TMC435 to its HCV NS3/NS4A protease target.Angew Chem Int Ed Engl2010;49:1652-5

[31] Sato K,Yamazaki Y,Horiguchi N,Kusano M.Spontaneous remission of hepatitis B virus reactivation during direct-acting antiviral agent-based therapy for chronic hepatitis C.Hepatol Res2017;47:1346-53

[32] Guidelines for the Screening Care and Treatment of Persons with Chronic Hepatitis Infection: Updated Version C. Geneva: World Health Organization; 2016

[33] Hopkins S.Cyclophilin inhibitors: an emerging class of therapeutics for the treatment of chronic hepatitis C infection.Viruses2012;4:2558-77 PMCID:PMC3509662

[34] Hopkins S,Chatterji U,Lim P.The cyclophilin inhibitor SCY-635 disrupts hepatitis C virus NS5A-cyclophilin A complexes.Antimicrob Agents Chemother2012;56:3888-97 PMCID:PMC3393457

[35] Rocco A,Coccoli P,Di Spirito A,Strazzullo P.Vitamin B12 supplementation improves rates of sustained viral response in patients chronically infected with hepatitis C virus.Gut2013;62:766-73

[36] Abu-Mouch S,Jarchovsky J,Assy N.Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients.World J Gastroenterol2011;17:5184-90 PMCID:PMC3243885

[37] Nimer A.Vitamin D improves viral response in hepatitis C genotype 2-3 naïve patients.World J Gastroenterol2012;18:800-5 PMCID:PMC3286143

[38] Malaguarnera M,Giordano M,Bertino G,Neri S,Li Volti G.L-carnitine supplementation improves hematological pattern in patients affected by HCV treated with Peg interferon-α 2b plus ribavirin.World J Gastroenterol2011;17:4414-20 PMCID:PMC3218156

[39] Qian XJ,Zhao P.Entry inhibitors: new advances in HCV treatment.Emerg Microbes Infect2016;5:e3 PMCID:PMC4735057

[40] Jiang J,Wu X,Tang H.Hepatitis C virus attachment mediated by apolipoprotein E binding to cell surface heparan sulfate.J Virol2012;86:7256-67 PMCID:PMC3416335

[41] Helle F,Vu-Dac N,Voisset C.Cyanovirin-N inhibits hepatitis C virus entry by binding to envelope protein glycans.J Biol Chem2006;281:25177-83

[42] Holmskov U,Jensenius JC.Collections and ficolins: humoral lectins of the innate immune defense.Annu Rev Immunol2003;21:547-78

[43] Ciesek S,Colpitts CC,Friesland M,Manns MP,Wedemeyer H,Pietschmann T.The green tea polyphenol, epigallocatechin-3- gallate, inhibits hepatitis C virus entry.Hepatology2011;54:1947-55

[44] Calland N,Belouzard S,Duverlie G,Hober D,Rouillé Y.(-)-Epigallocatechin-3-gallate is a new inhibitor of hepatitis C virus entry.Hepatology2012;55:720-9

[45] Calland N,Belouzard S,Bonnafous P,Deloison G,Sahpaz S,Lambert O,Duverlie G,Rosenberg AR,Rouillé Y.Polyphenols inhibit hepatitis C virus entry by a new mechanism of action.J Virol2015;89:10053-63 PMCID:PMC4577911

[46] Redwan EM,El-Fakharany EM.Potential lactoferrin activity against pathogenic viruses.C R Biol2014;337:581-95

[47] Hong W,Li T,Song Y,Li W.A p7 ion channel- derived peptide inhibits hepatitis C virus infection in vitro.J Biol Chem2015;290:23254-63 PMCID:PMC4645583

[48] Brimacombe CL,Meredith LW,Syder AJ,Timpe JM,Baumert TF,Wong-Staal F,McKeating JA.Neutralizing antibody-resistant hepatitis C virus cell-to-cell transmission.J Virol2011;85:596-605 PMCID:PMC3014195

[49] Lavillette D,Voisset C,Bartosch B,Patel AH,Ball JK.Characterization of host-range and cell entry properties of the major genotypes and subtypes of hepatitis C virus.Hepatology2005;41:265-74

[50] Gottwein JM,Jensen TB,Prentoe JC,Hoegh AM.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.Hepatology2009;49:364-77

[51] Vanwolleghem T,Meuleman Vanwolleghem T P,Meuleman P,Meunier JC,Purcell RH.Polyclonal immunoglobulins from a chronic hepatitis C virus patient protect human liver- chimeric mice from infection with a homologous hepatitis C virus strain.Hepatology2008;47:1846-55

[52] Meuleman P,Paulson M,Desombere I,Leroux-Roels G.Anti-CD81 antibodies can prevent a hepatitis C virus infection in vivo.Hepatology2008;48:1761-8

[53] Ji C,Pamulapati C,Fertig G,Rubas W,Ries S,Klumpp K.Prevention of hepatitis C virus infection and spread in human liver chimeric mice by an anti-CD81 monoclonal antibody.Hepatology2015;61:1136-44

[54] Zeisel MB,Schnober EK,Blum HE,Wakita T,Doffoel M,Soulier E,Schuster C,Bartenschlager R,Barth H.Scavenger receptor class B type I is a key host factor for hepatitis C virus infection required for an entry step closely linked to CD81.Hepatology2007;46:1722-31

[55] Lavie M,Vu-Dac N,Duverlie G,Dubuisson J.Serum amyloid A has antiviral activity against hepatitis C virus by inhibiting virus entry in a cell culture system.Hepatology2006;44:1626-34

[56] Masson D,Ishibashi M,Miller SG,Tall AR.Increased HDL cholesterol and apoA-I in humans and mice treated with a novel SR-BI inhibitor.Arterioscler Thromb Vasc Biol2009;29:2054-60 PMCID:PMC2783626

[57] Syder AJ,Zeisel MB,Soulier E,Chow S,Baumert TF,McKelvy J.Small molecule scavenger receptor BI antagonists are potent HCV entry inhibitors.J Hepatol2011;54:48-55

[58] Krieger SE,Davis C,Harris HJ,Mee C,Royer C,Grunert F,Dreux M,McKeating JA,Baumert TF.Inhibition of hepatitis C virus infection by anticlaudin- 1 antibodies is mediated by neutralization of E2-CD81-claudin-1 associations.Hepatology2010;51:1144-57

[59] Fofana I,Grunert F,Xiao F,Soulier E,Thumann C,McKeating JA,Pessaux P,Schuster C,Baumert TF.Monoclonal anti-claudin 1 antibodies prevent hepatitis C virus infection of primary human hepatocytes.Gastroenterology2010;139:953-64

[60] Mailly L,Lupberger J,Aubert P,Calabrese D,Fofana I,Bandiera S,Volz T,Harris HJ,Girardi E,Ericsson M,Bartenschlager R,Vercauteren K,Villa P,Pfeffer S,Neunlist M,Dandri M,Robinet E.Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody.Nat Biotechnol2015;5:549-54 PMCID:PMC4430301

[61] Lupberger J,Xiao F,Fofana I,Davis C,Turek M,Royer C,Zahid MN,Fresquet J,Rothenberg SM,Patel AH,Doffoël M,Poch O,Brino L.EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy.Nat Med2011;17:589-95 PMCID:PMC3938446

[62] Blanchard E,Goueslain L,Dubuisson J,Rouillé Y.Hepatitis C virus entry depends on clathrin-mediated endocytosis.J Virol2006;80:6964-72 PMCID:PMC1489042

[63] Blanchard AA,Shiu RP,Nistor A,Myal Y.Differential expression of claudin 1, 3, and 4 during normal mammary gland development in the mouse.DNA Cell Biol2006;25:79-86

[64] Blaising J,Polyak SJ,Boulant S.Arbidol inhibits viral entry by interfering with clathrin-dependent trafficking.Antiviral Res2013;100:215-9

[65] Meertens L,Dragic T.Hepatitis C virus entry requires a critical postinternalization step and delivery to early endosomes via clathrin-coated vesicles.J Virol2006;80:11571-8 PMCID:PMC1642584

[66] Polyak SJ,Shuhart MC,Liu Y.Inhibition of T- cell inflammatory cytokines, hepatocyte NF-kB signaling, and HCV infection by standardized Silymarin.Gastroenterology2007;132:1925-36

[67] Behrens SE,De Francesco R.Identification and properties of the RNA- dependent RNA polymerase of hepatitis C virus.EMBO J1996;15:12-22 PMCID:PMC449913

[68] Lohmann V,Herian U.Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity.J Virol1997;71:8416-28 PMCID:PMC192304

[69] Morikawa K,Gouttenoire J,Brass V,Moradpour A.Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus.J Viral Hepat2011;18:305-15

[70] Lamarre D,Bailey M,Bolger G,Bös M,Cartier M,Faucher AM,Kawai SH,Lagacé L,Narjes H,Rancourt J,St George R,Steinmann G,Tsantrizos YS,Yong CL.An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.Nature2003;426:186-9

[71] Delang L,Vliegen I,Neddermann P.Hepatitis C virus-specific directly acting antiviral drugs.Curr Top Microbiol Immunol2013;369:289-320

[72] Summa V,McCauley JA,Burlein C,Coleman PJ,Ferrara M,Gates AT,Harper S,Huang Q,Monteagudo E,Rowley M,Soriano A,Vacca JP,Liverton NJ.MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants.Antimicrob Agents Chemother2012;56:4161-7 PMCID:PMC3421554

[73] Pawlotsky JM.NS5A inhibitors in the treatment of hepatitis C.J Hepatol2013;59:375-82

[74] Kaneko T,Satoh S,Asabe S,Shimotohno K.Production of two phosphoproteins from the NS5A region of the hepatitis C viral genome.Biochem Biophys Res Commun1994;205:320-6

[75] Quintavalle M,Summa V,Talamo F,Neddermann P.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 Chem2007;282:5536-44

[76] Chen YC,Huang JY,Jeng KS,Lai MM.Polo-like kinase 1 is involved in hepatitis C virus replication by hyperphosphorylating NS5A.J Virol2010;84:7983-93 PMCID:PMC2916529

[77] Bartenschlager R,Penin F.The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection.Nat Rev Microbiol2013;11:482-96

[78] Paul D,Gouttenoire J,Krijnse-Locker J,Bartenschlager R.NS4B self-interaction through conserved C-terminal elements is required for the establishment of functional hepatitis C virus replication complexes.J Virol2011;85:6963-76 PMCID:PMC3126587

[79] Rehman S,Javed T.Antiviral drugs against hepatitis C virus.Genet Vaccines Ther2011;9:11 PMCID:PMC3136400

[80] Yang F,Nelson HB,Kenworthy R.Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro.J Virol2008;82:5269-78 PMCID:PMC2395199

[81] Kaul A,Berger C,Schmitt J,Zayas M,Luban J.Essential role of cyclophilin A for hepatitis C virus replication and virus production and possible link to polyprotein cleavage kinetics.PLoS Pathog2009;5:e1000546 PMCID:PMC2718831

[82] Watashi K,Hosaka M,Shimotohno K.Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes.Hepatology2003;38:1282-8

[83] Jopling CL,Lancaster AM,Sarnow P.Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA.Science2005;309:1577-81

[84] Shimakami T,Jangra RK,Spaniel C,Lemon SM.Stabilization of hepatitis C virus RNA by an Ago2-miR-122 complex.Proc Natl Acad Sci U S A2012;109:941-6 PMCID:PMC3271899

[85] Henke JI,Zheng J,Schüttler CG,Jünemann C.microRNA-122 stimulates translation of hepatitis C virus RNA.EMBO J2008;27:3300-10 PMCID:PMC2586803

[86] Lanford RE,Petri A,Lindow M,Kauppinen S.Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection.Science2010;327:198-201 PMCID:PMC3436126

[87] Janssen HL,Lawitz EJ,Rodriguez-Torres M,van der Meer AJ,Chen A,Persson R,Kauppinen S,Hodges MR.Treatment of HCV infection by targeting microRNA.N Engl J Med2013;368:1685-94

[88] Qu X,Weidner J,Alonzi D,Butters T,Guo JT.Inhibitors of endoplasmic reticulum alpha-glucosidases potently suppress hepatitis C virus virion assembly and release.Antimicrob Agents Chemother2011;55:1036-44 PMCID:PMC3067080

[89] Ouzounov S,Dwek RA,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 Res2002;55:425-35

[90] Pawlotsky JM,McHutchison JG.The hepatitis C virus life cycle as a target for new antiviral therapies.Gastroenterology2007;132:1979-98

[91] Takkenberg B,Weegink C,Reesink H.Novel therapies in hepatitis B and C.Curr Gastroenterol Rep2008;10:81-90

[92] Herker E,Hernandez C,Kaehlcke K,Farese RVJr.Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1.Nat Med2010;16:1295-8 PMCID:PMC3431199

[93] Yen CL,Koliwad S,Farese RVJr.Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis..J Lipid Res2008;49:2283-301 PMCID:PMC3837458

[94] Jacobson IM,Freilich B,Kwo PY,Becker S,Pound D,Strauss R,Flamm S,Mukhopadhyay P,Brass CA.Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients:a randomized trial.Hepatology2007;46:971-81

[95] Zeuzem S,Ferenci P,Horsmans Y,Ibranyi E,Noviello S,Albrecht J.Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia.J Hepatol2006;44:97-103

[96] Shiffman ML,Bacon BR,Harley H,Shafran SD,Lin A,Zeuzem S.Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3.N Engl J Med2007;357:124-34

[97] Buskila D.Hepatitis C-associated rheumatic disorders.Rheum Dis Clin North Am2009;35:111-23

[98] Kamal SM,Mahmoud S,El Gohary I,Hafez T,Aziz AA.Enhanced efficacy of pegylated interferon alpha-2a over pegylated interferon and ribavirin in chronic hepatitis C genotype 4A randomized trial and quality of life analysis.Liver Int2011;31:401-11

[99] Stetson DB.Type I interferons in host defense.Immunity2006;25:373-81

[100] Gale MJr.Effector genes of interferon action against hepatitis C virus.Hepatology2003;37:975-8

[101] Gilmour KC.Signal transduction and activation of gene transcription by interferons.Gene Expr1995;5:1-18

[102] Taylor DR,Lai MM.Hepatitis C virus and interferon resistance.Microbes Infect2000;2:1743-56

[103] Hoofnagle JH,Jones DB,Di Bisceglie A,Waggoner JG,Jones EA.Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report..N Engl J Med1986;315:1575-8

[104] Cavalcante LN.Predictive factors associated with hepatitis C antiviral therapy response.World J Hepatol2015;7:1617-31 PMCID:PMC4483544

[105] Gale MJr.Evasion of intracellular host defence by hepatitis C virus.Nature2005;436:939-45

[106] Irshad M,Irshad K.An insight into the diagnosis and pathogenesis of hepatitis C virus infection.World J Gastroenterol2013;19:7896-909 PMCID:PMC3848138

[107] Shao RX,Peng LF,Chung WJ,Tsai WL,Chung RT.Suppressor of cytokine signaling 3 suppresses hepatitis C virus replication in an mTORdependent manner.J Virol2010;84:6060-9 PMCID:PMC2876663

[108] Lin W,Hiasa Y,Blackard JT,Chung RT.Hepatitis C virus expression suppresses interferon signaling by degrading STAT1.Gastroenterology2005;128:1034-41

[109] Lin W,Yeung E,Blackard JT,Holtzman MJ.Hepatitis C virus core protein blocks interferon signaling by interaction with the STAT1 SH2 domain.J Virol2006;80:9226-35 PMCID:PMC1563912

[110] Taylor DR,Romano PR,Lai MM.Inhibition of the interferon- inducible protein kinase PKR by HCV E2 protein.Science1999;285:107-10

[111] Li XD,Seth RB,Chen ZJ.Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity.Proc Natl Acad Sci U S A2005;102:17717-22 PMCID:PMC1308909

[112] Meylan E,Hofmann K,Binder M,Tschopp J.Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus.Nature2005;437:1167-72

[113] Li K,Ferreon JC,Ferreon AC,Ray SC,Lemon SM.Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF.Proc Natl Acad Sci U S A2005;102:2992-7 PMCID:PMC548795

[114] Foy E,Sumpter RJr,Johnson CL,Fish PM,Fujita T,Gale MJr.Control of antiviral defenses through hepatitis C virus disruption of retinoic acid inducible gene-I signaling.Proc Natl Acad Sci U S A2005;102:2986-91 PMCID:PMC549461

[115] Foy E,Wang C,Ikeda M,Gale MJr.Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease.Science2003;300:1145-8

[116] Xu J,Xu Y,Gao G.Identification of the nonstructural protein 4B of hepatitis C virus as a factor that inhibits the antiviral activity of interferon-alpha.Virus Res2009;141:55-62

[117] Gale MJJr,Katze MG.Repression of the PKR protein kinase by the hepatitis C virus NS5A protein: a potential mechanism of interferon resistance.Clin Diagn Virol1998;10:157-62

[118] Gale MJJr,Tang NM,Hopkins DA,Polyak SJ,Katze MG.Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein.Virology1997;230:217-27

[119] Gong GZ,Jiang YF,Liu B.Hepatitis C virus non-structural 5A abrogates signal transducer and activator of transcription-1 nuclear translocation induced by IFN-alpha through dephosphorylation.World J Gastroenterol2007;13:4080-4 PMCID:PMC4205308

[120] Lan KH,Lee WP,Chen MY,Yen SH,Lee SD.HCV NS5A inhibits interferon-alpha signaling through suppression of STAT1 phosphorylation in hepatocyte-derived cell lines.J Hepatol2007;46:759-67

[121] Kumthip K.The role of HCV proteins on treatment outcomes.Virol J2015;12:217 PMCID:PMC4678629

[122] Ge D,Thompson AJ,Shianna KV,Heinzen EL,Bertelsen AH,Sulkowski M,Goldstein DB.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature2009;461:399-401

[123] Guss D,Rosen P.Diagnosis and management of hepatitis C infection in primary care settings.J Gen Intern Med2018;33:551-7

[124] Veldt BJ,Wedemeyer H,Hofmann WP,Manns MP,Schalm SW.Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis.Ann Intern Med2007;147:677-84

[125] Morgan TR,Kim HY,Shiffman ML,Lee WM,Bonkovsky HL,Morishima C,Lok AS.Outcome of sustained virological responders with histologically advanced chronic hepatitis C.Hepatology2010;52:833-44 PMCID:PMC2932862

[126] Chen Yi Mei SLG,Christensen B,McDonald L,Iser D,Desmond PV.Sustained virological response halts fibrosis progression: a long-term follow-up study of people with chronic hepatitis C infection.PLoS One2017;12:e0185609 PMCID:PMC5655473

[127] Terrault NA.Management of the patient with SVR.J Hepatol2016;65 Suppl 1:S120-9

[128] Ahmed A.Mechanisms of hepatitis C viral resistance to direct acting antivirals.Viruses2015;7:6716-29 PMCID:PMC4690891

[129] Sesmero E.Using the hepatitis C virus RNA-dependent RNA polymerase as a model to understand viral polymerase structure, function and dynamics.Viruses2015;7:3974-94 PMCID:PMC4517137

[130] Pawlotsky JM.Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus.Hepatology2011;53:1742-51