Hepatitis-C-Virus - Viruskinetik und Resistenzmechanismen

Zusammenfassung

Während der ersten Wochen einer auf Interferon basierenden Behandlung der chronischen Hepatitis-C-Virusinfektion kann üblicherweise ein biphasischer Abfall der Viruslast beobachtet werden. Die mathematisch-statistische Auswertung der Viruskinetik ermöglicht die Schätzung von individuellen kinetischen Raten, insbesondere der Verlustrate infizierter Zellen, der Abbaurate von freiem Virus sowie von einem Effizienzfaktor zur Hemmung der Virusproduktion. Die Analyse mathematischer Viruskinetikmodelle erlaubt Rückschlüsse auf die einer Therapie zugrunde liegenden Mechanismen. Ein effizientes bzw. fehlendes virologisches Therapieansprechen spiegelt sich außerdem typischerweise in guten bzw. schlechten kinetischen Parametern wider. Dies gilt für einzelne Patienten, aber auch für generelle Unterschiede im Rahmen der bekannten Genotypabhängigkeit des Therapieansprechens. Die Ursachen für ein vorhandenes oder fehlendes virologisches Therapieansprechen auf eine interferonbasierte Therapie bei einzelnen Patienten sind jedoch nicht bekannt. Neben wirts- und therapiespezifischen Ursachen wird vermutet, dass das HCV über spezifische Interferonresistenzmechanismen verfügt. Bisher wurden drei HCV-Proteine durch In-vitro-Untersuchungen in einen direkten Zusammenhang mit solchen Interferonresistenzmechanismen gebracht: das Hüllprotein (E)2 sowie die nichtstrukturellen Proteine (NS)3/4A und 5A. Spezifische Mutationen im Bereich der vermuteten Interaktionsstellen zur Vermittlung von Resistenzmechanismen in Korrelation mit dem virologischen Ansprechen auf eine interferonbasierte Therapie konnten dabei auf HCV-Isolaten von Patienten für das E2- (HVR2, CD81-Bindungsregion, PePHD) und NS3/4A-Protein nicht nachgewiesen werden. Im Bereich des NS5A-Proteins gibt es Hinweise für eine Bedeutung von Mutationen im Bereich einer Interferonsensitivität determinierenden Region (ISDR) bzw. des gesamten NS5A-Proteins bei HCV-1a/b-Isolaten.

Abstract

Typically, a biphasic decay of viremia can be observed during the first few weeks of interferon-based treatment in patients with chronic hepatitis C. The mathematical and statistical analysis of viral kinetics enables the estimation of individual kinetic parameters. Especially, the infected cell loss, the degradation rate of free virus, and an efficiency factor on blocking viral production can be estimated. Furthermore, mathematical models of viral kinetics have the potential to reveal mechanisms of antiviral therapy. The lower sustained virologic response rates in several patient populations are reflected by impaired kinetic parameters. Besides host-specific and treatment-related differences, especially hepatitis C virus genotype strongly correlates with initial and long-term virologic responses. Reasons for virologic response or non-response to interferon-based therapy for individual patients are unknown. Beside host- and treatment-related causes it is assumed that HCV is able to specifically evade the antiviral actions of interferon. So far, three HCV proteins [envelope (E)2, non-structural (NS) protein 3/4A, and NS5A protein] have been associated with interferon resistance mechanisms. However, within the E2 (HVR2, CD81 binding domains, PePHD) and NS3/4A proteins no specific mutations in correlation with virologic response to interferon-based antiviral therapy were observed. For the NS5A protein, mutations within the interferon sensitivity determining region (ISDR) and the complete NS5A protein may be of importance for virologic treatment response in patients infected with genotype HCV-1a/b isolates.

E2 - Hepatitis C - Interferon-α - ISDR - Mutationen - NS3 - NS4A - NS5A - Resistenzmechanismen - Viruskinetik

E2 - hepatitis C - interferon-α - ISDR - Mutations - NS3 - NS4A - NS5A - resistance mechanism - viral kinetics

Literatur

• 1 McHutchison J G, Gordon S C, Schiff E R. et al . Interferon alfa-2 b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group.  N Engl J Med. 1998;  339 1485-1492
• 2 Manns M P, McHutchison J G, Gordon S C. et al . Peginterferon alfa-2 b plus ribavirin compared with interferon alfa-2 b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.  Lancet. 2001;  358 958-965
• 3 Poynard T, Marcellin P, Lee S S. et al . Randomised trial of interferon alpha2 b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2 b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT).  Lancet. 1998;  352 1426-1432
• 4 Fried M W, Shiffman M L, Reddy K R. et al . Peginterferon alfa-2 a plus ribavirin for chronic hepatitis C virus infection.  N Engl J Med. 2002;  347 975-982
• 5 Hadziyannis S J, Dunant H, Sette H J. et al . Peginterferon alfa2 a (40 kD) and ribavirin combination therapy in chronic hepatitis C: a randomized study of the effect of treatment duration and ribavirin dose.  Ann Intern Med. 2004;  140 346-355
• 6 Simmonds P. Variability of hepatitis C virus.  Hepatology. 1995;  21 570-583
• 7 Zeuzem S, Schmidt J M, Lee J H. et al . Effect of interferon alfa on the dynamics of hepatitis C virus turnover in vivo.  Hepatology. 1996;  23 366-371
• 8 Lam N P, Neumann A U, Gretch D R. et al . Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa.  Hepatology. 1997;  26 226-231
• 9 Zeuzem S, Schmidt J M, Lee J H. et al . Hepatitis C virus dynamics in vivo: effect of ribavirin and interferon alfa on viral turnover.  Hepatology. 1998;  28 245-252
• 10 Neumann A U, Lam N P, Dahari H. et al . Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.  Science. 1998;  282 103-107
• 11 Nguyen T T, Sedghi-Vaziri A, Wilkes L B. et al . Fluctuations in viral load (HCV RNA) are relatively insignificant in untreated patients with chronic HCV infection.  J Viral Hepat. 1996;  3 75-78
• 12 Herrmann E, Lee J H, Marinos G. et al . Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon.  Hepatology. 2003;  37 1351-1358
• 13 Bergmann C, Layden J E, Levy-Drummer R S. et al . Clinical implications of a new triphasic model of hepatitis C viral kinetics during IFN-alpha therapy.  Hepatology. 2001;  33 (Suppl) 345A
• 14 Ribeiro R M, Layden-Almer J, Powers K A. et al . Dynamics of alanine aminotransferase during hepatitis C virus treatment.  Hepatology. 2003;  38 509-517
• 15 Powers K A, Dixit N M, Ribeiro R M. et al . Modeling viral and drug kinetics: hepatitis C virus treatment with pegylated interferon alfa-2 b.  Semin Liver Dis. 2003;  23 (Suppl 1) 13-18
• 16 Zhu H, Zhao H, Collins C D. et al . Gene expression associated with interferon alfa antiviral activity in an HCV replicon cell line.  Hepatology. 2003;  37 1180-1188
• 17 Chung R T, He W, Saquib A. et al . Hepatitis C virus replication is directly inhibited by IFN-alpha in a full-length binary expression system.  Proc Natl Acad Sci U S A. 2001;  98 9847-9852
• 18 Neumann A U, Lam N P, Dahari H. et al . Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus.  J Infect Dis. 2000;  182 28-35
• 19 Layden T J, Layden J E, Reddy K R. et al . Induction therapy with consensus interferon (CIFN) does not improve sustained virologic response in chronic hepatitis C.  J Viral Hepat. 2002;  9 334-339
• 20 Layden J E, Layden T J, Reddy K R. et al . First phase viral kinetic parameters as predictors of treatment response and their influence on the second phase viral decline.  J Viral Hepat. 2002;  9 340-345
• 21 Jessner W, Stauber R, Hackl F. et al . Early viral kinetics on treatment with pegylated interferon-alpha-2 a in chronic hepatitis C virus genotype 1 infection.  J Viral Hepat. 2003;  10 37-42
• 22 Zeuzem S, Herrmann E, Lee J H. et al . Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha2 a.  Gastroenterology. 2001;  120 1438-1447
• 23 Halfon P, Neumann A U, Bourliere M. et al . Slow viral dynamics of hepatitis C virus genotype 4.  J Viral Hepat. 2003;  10 351-353
• 24 Buti M, Sanchez-Avila F, Lurie Y. et al . Viral kinetics in genotype 1 chronic hepatitis C patients during therapy with 2 different doses of peginterferon alfa-2 b plus ribavirin.  Hepatology. 2002;  35 930-936
• 25 Zeuzem S, Welsch C, Herrmann E. Pharmacokinetics of peginterferons.  Semin Liver Dis. 2003;  23 (Suppl 1) 23-28
• 26 Pawlotsky J M, Dahari H, Conrad A. et al . Effect of intermittent interferon (IFN), daily IFN and IFN plus ribavirin induction therapy on hepatitis C virus (HCV) genotype 1 b replication kinetics and clearance.  Hepatology. 1998;  28 288A
• 27 Neumann A U, Dahari H, Conrad A. et al . Early prediction and mechanismen of the ribavirin/IFN-a dual therapy effect on chronic hepatitis C virus (HCV).  Hepatology. 1999;  30 309A
• 28 Lake-Bakaar G, Ruffini L, Kuzmic P. Effect of ribavirin and amantadine on early hepatitis C virus RNA rebound and clearance in serum during daily high-dose interferon.  Dig Dis Sci. 2003;  48 126-139
• 29 Layden-Almer J E, Ribeiro R M, Wiley T. et al . Viral dynamics and response differences in HCV-infected African American and white patients treated with IFN and ribavirin.  Hepatology. 2003;  37 1343-1350
• 30 Berg T, Kaul T, Naumann U. et al . Einfluss von Ribavirin auf die Dynamik der Hepatitis-C-Virämie bei Interferon-(-behandelten Patienten mit Response oder Nonresponse.  Z Gastroenterol. 2000;  38 881-886
• 31 Torre F, Giusto R, Grasso A. et al . Clearance kinetics of hepatitis C virus under different antiviral therapies.  J Med Virol. 2001;  64 455-459
• 32 Benhamou Y, Hinrichsen H, Sentjens R. et al . Safety, tolerability and antiviral effect of BILN 2061, a novel HCV serine protease inhibitor, after oral treatment over 2 days in patients with chronic hepatitis C genotype 1, with advanced liver fibrosis.  Hepatology. 2002;  36 304A
• 33 Hinrichsen H, Benhamou Y, Wedemeyer H. et al . First report on the antiviral efficacy of BILN 2061, a novel oral serine protease inhibitor, in patients with chronic hepatitis C genotype 1.  Gastroenterology. 2004;  126 (in press)
• 34 Lamarre D, Anderson P C, Bailey M. et al . An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.  Nature. 2003;  426 186-189
• 35 De Francesco R, Rice C M. New therapies on the horizon for hepatitis C: are we close?.  Clin Liver Dis. 2003;  7 211-242, xi
• 36 Reddy K R, Hoofnagle J H, Tong M J. et al . Racial differences in responses to therapy with interferon in chronic hepatitis C. Consensus Interferon Study Group.  Hepatology. 1999;  30 787-793
• 37 McHutchison J G, Poynard T, Pianko S. et al . The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. The International Hepatitis Interventional Therapy Group.  Gastroenterology. 2000;  119 1317-1323
• 38 Layden-Almer J E, Layden T J. Viral kinetics in hepatitis C virus: special patient populations.  Semin Liver Dis. 2003;  23 (Suppl 1) 29-33
• 39 Neumann A U, Reddy K R, Levy-Drummer R S. et al . Interferon pharmacokinetics and host factors: Effects on hepatitis C genotype 1 viral kinetics during treatment with consensus interferon.  Hepatology. 2001;  34 428A
• 40 Cotler S J, Layden J E, Neumann A U. et al . First phase hepatitis c viral kinetics in previous nonresponders patients.  J Viral Hepat. 2003;  10 43-49
• 41 Karino Y, Toyota J, Sugawara M. et al . Hepatitis C virus genotypes and hepatic fibrosis regulate 24-h decline of serum hepatitis C virus RNA during interferon therapy in patients with chronic hepatitis C.  J Gastroenterol Hepatol. 2003;  18 404-410
• 42 Torriani F J, Ribeiro R M, Gilbert T L. et al . Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) dynamics during HCV treatment in HCV/HIV coinfection.  J Infect Dis. 2003;  188 1498-1507
• 43 Talal A H, Shata M T, Markatou M. et al . Virus Dynamics and Immune Responses During Treatment in Patients Coinfected With Hepatitis C and HIV.  J Acquir Immune Defic Syndr. 2004;  35 103-113
• 44 Gale M J Jr, Korth M J, Tang N M. et al . 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
• 45 Taylor D R, Shi S T, Romano P R. et al . Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein.  Science. 1999;  285 107-110
• 46 Foy E, Li K, Wang C. et al . Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease.  Science. 2003;  300 1145-1148
• 47 Taylor D R, Tian B, Romano P R. et al . 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
• 48 Gale M Jr, Blakely C M, Kwieciszewski B. et al . Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation.  Mol Cell Biol. 1998;  18 5208-5218
• 49 Enomoto N, Sakuma I, Asahina Y. et al . Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1 b infection.  N Engl J Med. 1996;  334 77-81
• 50 Enomoto N, Sakuma I, Asahina Y. et al . Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1 b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region.  J Clin Invest. 1995;  96 224-230
• 51 Kurosaki M, Enomoto N, Murakami T. et al . 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
• 52 Komatsu H, Fujisawa T, Inui A. et al . Mutations in the nonstructural protein 5A gene and response to interferon therapy in young patients with chronic hepatitis C virus 1 b infection.  J Med Virol. 1997;  53 361-365
• 53 Chayama K, Tsubota A, Kobayashi M. et al . 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 1 b hepatitis C virus infection.  Hepatology. 1997;  25 745-749
• 54 Zeuzem S, Lee J H, Roth W K. Mutations in the nonstructural 5A gene of European hepatitis C virus isolates and response to interferon alfa.  Hepatology. 1997;  25 740-744
• 55 Khorsi H, Castelain S, Wyseur A. et al . Mutations of hepatitis C virus 1 b NS5A 2209 - 2248 amino acid sequence do not predict the response to recombinant interferon-alfa therapy in French patients.  J Hepatol. 1997;  27 72-77
• 56 Squadrito G, Leone F, Sartori M. et al . Mutations in the nonstructural 5A region of hepatitis C virus and response of chronic hepatitis C to interferon alfa.  Gastroenterology. 1997;  113 567-572
• 57 Odeberg J, Yun Z, Sonnerborg A. et al . Variation in the hepatitis C virus NS5 a region in relation to hypervariable region 1 heterogeneity during interferon treatment.  J Med Virol. 1998;  56 33-38
• 58 Chung R T, Monto A, Dienstag J L. et al . Mutations in the NS5A region do not predict interferon-responsiveness in american patients infected with genotype 1 b hepatitis C virus.  J Med Virol. 1999;  58 353-358
• 59 Hofgärtner W T, Polyak S J, Sullivan D G. et al . Mutations in the NS5A gene of hepatitis C virus in North American patients infected with HCV genotype 1 a or 1 b.  J Med Virol. 1997;  53 118-126
• 60 McKechnie V M, Mills P R, McCruden E A. The NS5 a gene of hepatitis C virus in patients treated with interferon-alpha.  J Med Virol. 2000;  60 367-378
• 61 Pawlotsky J M, Germanidis G, Neumann A U. et al . Interferon resistance of hepatitis C virus genotype 1 b: relationship to nonstructural 5A gene quasispecies mutations.  J Virol. 1998;  72 2795-2805
• 62 Witherell G W, Beineke P. Statistical analysis of combined substitutions in nonstructural 5A region of hepatitis C virus and interferon response.  J Med Virol. 2001;  63 8-16
• 63 Sarrazin C, Berg T, Lee J H. et al . Improved correlation between multiple mutations within the NS5A region and virological response in European patients chronically infected with hepatitis C virus type 1 b undergoing combination therapy.  J Hepatol. 1999;  30 1004-1013
• 64 Sarrazin C, Berg T, Lee J H. et al . Mutations in the protein kinase-binding domain of the NS5A protein in patients infected with hepatitis C virus type 1 a are associated with treatment response.  J Infect Dis. 2000;  181 432-441
• 65 Saiz J C, Lopez-Labrador F X, Ampurdanes S. et al . The prognostic relevance of the nonstructural 5A gene interferon sensitivity determining region is different in infections with genotype 1 b and 3 a isolates of hepatitis C virus.  J Infect Dis. 1998;  177 839-847
• 66 Duverlie G, Khorsi H, Castelain S. et al . Sequence analysis of the NS5A protein of European hepatitis C virus 1 b isolates and relation to interferon sensitivity.  J Gen Virol. 1998;  79 1373-1381
• 67 Nousbaum J, Polyak S J, Ray S C. et al . Prospective characterization of full-length hepatitis C virus NS5A quasispecies during induction and combination antiviral therapy.  J Virol. 2000;  74 9028-9038
• 68 Sarrazin C, Herrmann E, Bruch K. et al . Hepatitis C virus nonstructural 5A protein and interferon resistance: a new model for testing the reliability of mutational analyses.  J Virol. 2002;  76 11 079-11 090
• 69 Murakami T, Enomoto N, Kurosaki M. et al . Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection.  Hepatology. 1999;  30 1045-1053
• 70 Kobayashi M, Watanabe K, Ishigami M. et al . Amino acid substitutions in the nonstructural region 5A of hepatitis C virus genotypes 2 a and 2 b and its relation to viral load and response to interferon.  Am J Gastroenterol. 2002;  97 988-998
• 71 Sarrazin C, Kornetzky I, Rüster B. et al . Mutations within the E2 and NS5A protein in patients infected with hepatitis C virus type 3 a and correlation with treatment response.  Hepatology. 2000;  31 1360-1370
• 72 Saiz J C, Lopez-Labrador F X, Ampurdanes S. et al . The prognostic relevance of the nonstructural 5A gene interferon sensitivity determining region is different in infections with genotype 1 b and 3 a isolates of hepatitis C virus.  J Infect Dis. 1998;  177 839-847
• 73 Abid K, Quadri R, Negro F. Hepatitis C virus, the E2 envelope protein, and alpha-interferon resistance.  Science. 2000;  287 1555
• 74 Polyak S J, Nousbaum J B, Larson A M. et al . The protein kinase-interacting domain in the hepatitis C virus envelope glycoprotein-2 gene is highly conserved in genotype 1-infected patients treated with interferon.  J Infect Dis. 2000;  182 397-404
• 75 Sarrazin C, Bruckner M, Herrmann E. et al . Quasispecies heterogeneity of the carboxy-terminal part of the E2 gene including the PePHD and sensitivity of hepatitis C virus 1 b isolates to antiviral therapy.  Virology. 2001;  289 150-163
• 76 Berg T, Mas M A, Hohne M. et al . Mutations in the E2-PePHD and NS5A region of hepatitis C virus type 1 and the dynamics of hepatitis C viremia decline during interferon alfa treatment.  Hepatology. 2000;  32 1386-1395
• 77 Saito T, Ito T, Ishiko H. et al . Sequence analysis of PePHD within HCV E2 region and correlation with resistance of interferon therapy in Japanese patients infected with HCV genotypes 2 a and 2 b.  Am J Gastroenterol. 2003;  98 1377-1383
• 78 Watanabe H, Nagayama K, Enomoto N. et al . Amino acid substitutions in PKR-eIF2 phosphorylation homology domain (PePHD) of hepatitis C virus E2 protein in genotype 2a/2 b and 1 b in Japan and interferon efficacy.  Hepatol Res. 2003;  26 268-274
• 79 Hofmann W P, Sarrazin C, Kronenberger B. et al . Mutations within the CD81-binding sites and hypervariable region 2 of the envelope 2 protein: correlation with treatment response in hepatitis C virus-infected patients.  J Infect Dis. 2003;  187 982-987
• 80 Gerotto M, Dal P ero F, Pontisso P. et al . Two PKR inhibitor HCV proteins correlate with early but not sustained response to interferon.  Gastroenterology. 2000;  119 1649-1655
• 81 Murphy M D, Rosen H R, Marousek G I. et al . Analysis of sequence configurations of the ISDR, PKR-binding domain, and V3 region as predictors of response to induction interferon-alpha and ribavirin therapy in chronic hepatitis C infection.  Dig Dis Sci. 2002;  47 1195-1205
• 82 Yamamoto C, Enomoto N, Kurosaki M. et al . Nucleotide sequence variations in the internal ribosome entry site of hepatitis C virus-1 b: no association with efficacy of interferon therapy or serum HCV-RNA levels.  Hepatology. 1997;  26 1616-1620
• 83 Horiike N, Michitaka K, Masumoto T. et al . Relationship between the effect of interferon therapy and the change of hepatitis C virus non-structural 5B gene.  J Gastroenterol Hepatol. 1999;  14 345-351
• 84 Tao Q, Wei L, Chang J. et al . Relationship between interferon therapy and variability in nonstructural gene 5 b of hepatitis C virus.  J Gastroenterol. 1998;  33 684-693
• 85 Sarrazin C, Mihm U, Schönberger B. et al . Detection of mutations necessary for HCV replication in the in vitro replicon system in patients with chronic hepatitis C.  Journal of Hepatology. 2003;  38 (Suppl 2) 169A
• 86 Paterson M, Laxton C D, Thomas H C. et al . Hepatitis C virus NS5A protein inhibits interferon antiviral activity, but the effects do not correlate with clinical response.  Gastroenterology. 1999;  117 1187-1197
• 87 Polyak S J, Paschal D M, McArdle S. et al . Characterization of the effects of hepatitis C virus nonstructural 5A protein expression in human cell lines and on interferon-sensitive virus replication.  Hepatology. 1999;  29 1262-1271
• 88 Song J, Fujii M, Wang F. et al . The NS5A protein of hepatitis C virus partially inhibits the antiviral activity of interferon.  J Gen Virol. 1999;  80 (Pt 4) 879-886
• 89 Francois C, Duverlie G, Rebouillat D. et al . Expression of hepatitis C virus proteins interferes with the antiviral action of interferon independently of PKR-mediated control of protein synthesis.  J Virol. 2000;  74 5587-5596
• 90 Polyak S J, Khabar K S, Paschal D M. et al . 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
• 91 Mihm U, Hermann E, Sarrazin U. et al . Correlation of serum IL8 levels with virologic response to antiviral therapy in patients with chronic hepatitis C.  J Hepatol. 2004;  40 845-852
• 92 Moradpour D, Kary P, Rice C M. et al . Continuous human cell lines inducibly expressing hepatitis C virus structural and nonstructural proteins.  Hepatology. 1998;  28 192-201
• 93 Heim M H, Moradpour D, Blum H E. Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway.  J Virol. 1999;  73 8469-8475
• 94 Blindenbacher A, Duong F H, Hunziker L. et al . Expression of hepatitis c virus proteins inhibits interferon alpha signaling in the liver of transgenic mice.  Gastroenterology. 2003;  124 1465-1475
• 95 Duong F H, Filipowicz M, Tripodi M. et al . Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A.  Gastroenterology. 2004;  126 263-277