PDF herunterladen
Z Gastroenterol 2011; 49(7): 836-844
DOI: 10.1055/s-0031-1273196
Übersicht

© Georg Thieme Verlag KG Stuttgart · New York

Die molekularen Mechanismen der Replikation des Hepatitis C Virus – Implikationen für die Entwicklung antiviraler Wirkstoffe

Molecular Mechanisms of Hepatitis C Virus (HCV) Replication – Implications for the Development of Antiviral DrugsS. Bühler1 , R. Bartenschlager1
  • 1Department für Infektiologie, Molekulare Virologie, Universitätsklinikum Heidelberg
Weitere Informationen

Publikationsverlauf

Manuskript eingetroffen: 18.10.2010

Manuskript akzeptiert: 13.2.2011

Publikationsdatum:
15. Juli 2011 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Zusammenfassung

Die chronische Infektion mit dem Hepatitis-C-Virus (HCV) ist auch mehr als 20 Jahre nach seiner Entdeckung ein wichtiges medizinisches Problem. 120 – 180 Millionen Menschen weltweit sind nach Schätzungen der Weltgesundheitsorganisation chronisch mit HCV infiziert, wovon etwa 5 Millionen Menschen in Westeuropa leben. Diese haben ein hohes Risiko für die Entwicklung einer Leberzirrhose oder eines hepatozellulären Karzinoms (HCC). Die aktuelle Therapie hat zahlreiche Limitationen und ein Vakzin ist nicht in Sicht. Intensive Forschungsaktivitäten, insbesondere die Entwicklung adäquater Zellkultursysteme, haben neue Einblicke in den viralen Vermehrungszyklus ergeben sowie grundlegende Strategien identifiziert, mit denen das Virus vermutlich der immunologischen Kontrolle entkommt. Adäquate Zellsysteme lieferten auch die Grundlage für die Entwicklung potenter und selektiver Wirkstoffe zur Behandlung der chronischen Hepatitis C und man rechnet 2011 / 2012 mit der Zulassung der NS 3 / 4A-Proteaseinhibitoren der ersten Generation. Dennoch gibt es eine Reihe wichtiger und bis heute ungeklärter Fragen, deren Beantwortung Forscher wie Kliniker die nächsten Jahre noch beschäftigen wird.

Abstract

More than 20 years after the discovery of the hepatitis C virus (HCV), chronic hepatitis C still is a major medical problem. According to the World Health Organisation 120 to 180 million people are chronically infected with HCV, with 5 million infected individuals living in Western Europe. These people have a high risk to develop serious liver disease such as liver cirrhosis and hepatocellular carcinoma (HCC). The standard-of-care therapy is not satisfying and there is no vaccine in sight. Owing to intense research activities, most notably the development of adequate cell culture systems, important insights into the viral replication cycle have been gained and several strategies used by HCV to overcome immune responses have been identified. Adequate cell culture systems also provided the basis for the development of potent and selective antivirals for treatment of chronic hepatitis C and it is expected that NS 3 / 4A protease inhibitors will be approved for clinical use in 2011 / 2012. Nevertheless, important questions are still unanswered and they will keep clinicians and basic researchers busy for the coming years.

Schlüsselwörter

Leber - Hepatitis C - antivirale Wirkstoffe - HCV-Replikation - HCV-Wirt-Interaktion

Key words

liver - hepatitis C - antiviral drugs - HCV replication - HCV-host interaction

Literatur

  • 1 Marcellin P. Hepatitis B and hepatitis C in 2009.  Liver Int. 2009;  29 (Suppl 1) 1-8
    Suche in Google Scholar
  • 2 Ge D, Fellay J, Thompson A J et al. Genetic variation in IL 28B predicts hepatitis C treatment-induced viral clearance.  Nature. 2009;  461 399-401
    Suche in Google Scholar
  • 3 Tanaka Y, Nishida N, Sugiyama M et al. Genome-wide association of IL 28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.  Nat Genet. 2009;  41 1105-1109
    Suche in Google Scholar
  • 4 Suppiah V, Moldovan M, Ahlenstiel G et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.  Nat Genet. 2009;  41 1100-1104
    Suche in Google Scholar
  • 5 Thomas D L, Thio C L, Martin M P et al. Genetic variation in IL 28B and spontaneous clearance of hepatitis C virus.  Nature. 2009;  461 798-801
    Suche in Google Scholar
  • 6 Marcello T, Grakoui A, Barba-Spaeth G et al. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics.  Gastroenterology. 2006;  131 1887-1898
    Suche in Google Scholar
  • 7 Robek M D, Boyd B S, Chisari F V. Lambda interferon inhibits hepatitis B and C virus replication.  J Virol. 2005;  79 3851-3854
    Suche in Google Scholar
  • 8 Lohmann V, Körner F, Koch J O et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line.  Science. 1999;  285 110-113
    Suche in Google Scholar
  • 9 Kato T, Furusaka A, Miyamoto M et al. Sequence analysis of hepatitis C virus isolated from a fulminant hepatitis patient.  J Med Virol. 2001;  64 334-339
    Suche in Google Scholar
  • 10 Wakita T, Pietschmann T, Kato T et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome.  Nat Med. 2005;  11 791-796
    Suche in Google Scholar
  • 11 Bartenschlager R, Sparacio S. Hepatitis C virus molecular clones and their replication capacity in vivo and in cell culture.  Virus Res. 2007;  127 195-207
    Suche in Google Scholar
  • 12 Friebe P, Bartenschlager R. Genetic analysis of sequences in the 3’ nontranslated region of hepatitis C virus that are important for RNA replication.  J Virol. 2002;  76 5326-5338
    Suche in Google Scholar
  • 13 Jopling C L, Yi M, Lancaster A M et al. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA.  Science. 2005;  309 1577-1581
    Suche in Google Scholar
  • 14 Henke J I, Goergen D, Zheng J et al. microRNA-122 stimulates translation of hepatitis C virus RNA.  EMBO J. 2008;  27 3300-3310
    Suche in Google Scholar
  • 15 Jangra R K, Yi M Lemon SM. Regulation of Hepatitis C Virus Translation and Infectious Virus Production by the MicroRNA miR-122.  J Virol. 2010;  84 6615-6625
    Suche in Google Scholar
  • 16 Steinmann E, Penin F, Kallis S et al. Hepatitis C Virus p7 Protein Is Crucial for Assembly and Release of Infectious Virions.  PLoS Pathog. 2007;  3 e103
    Suche in Google Scholar
  • 17 Wozniak A L, Griffin S, Rowlands D et al. Intracellular proton conductance of the hepatitis C virus p7 protein and its contribution to infectious virus production.  PLoS Pathog. 2010;  6 e1001087
    Suche in Google Scholar
  • 18 Luik P, Chew C, Aittoniemi J et al. The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy.  Proc Natl Acad Sci U S A. 2009;  106 12 712-12 716
    Suche in Google Scholar
  • 19 Lorenz I C, Marcotrigiano J, Dentzer T G et al. Structure of the catalytic domain of the hepatitis C virus NS 2-3 protease.  Nature. 2006;  442 831-835
    Suche in Google Scholar
  • 20 Phan T, Beran R K, Peters C et al. Hepatitis C virus NS 2 protein contributes to virus particle assembly via opposing epistatic interactions with the E 1-E2 glycoprotein and NS 3-NS4A enzyme complexes.  J Virol. 2009;  83 8379-8395
    Suche in Google Scholar
  • 21 Egger D, Wolk B, Gosert R et al. Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex.  J Virol. 2002;  76 5974-5984
    Suche in Google Scholar
  • 22 Gosert R, Egger D, Lohmann V et al. Identification of the hepatitis C virus RNA replication complex in huh-7 cells harboring subgenomic replicons.  J Virol. 2003;  77 5487-5492
    Suche in Google Scholar
  • 23 Quintavalle M, Sambucini S, Summa V et al. Hepatitis C virus NS 5A is a direct substrate of casein kinase I-alpha, a cellular kinase identified by inhibitor affinity chromatography using specific NS 5A hyperphosphorylation inhibitors.  J Biol Chem. 2007;  282 5536-5544
    Suche in Google Scholar
  • 24 Quintavalle M, Sambucini S, Di Pietro C et al. The alpha isoform of protein kinase CKI is responsible for hepatitis C virus NS 5A hyperphosphorylation.  J Virol. 2006;  80 11 305-11 312
    Suche in Google Scholar
  • 25 Tellinghuisen T L, Foss K L, Treadaway J. Regulation of hepatitis C virion production via phosphorylation of the NS 5A protein.  PLoS Pathog. 2008;  4 e1000032
    Suche in Google Scholar
  • 26 Eng F J, Walewski J L, Klepper A L et al. 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
    Suche in Google Scholar
  • 27 Vassilaki N, Mavromara P. The HCV ARFP/F/core + 1 protein: production and functional analysis of an unconventional viral product.  IUBMB Life. 2009;  61 739-752
    Suche in Google Scholar
  • 28 Vassilaki N, Friebe P, Meuleman P et al. Role of the hepatitis C virus core + 1 open reading frame and core cis-acting RNA elements in viral RNA translation and replication.  J Virol. 2008;  82 11503-11515
    Suche in Google Scholar
  • 29 McMullan L K, Grakoui A, Evans M J et al. Evidence for a functional RNA element in the hepatitis C virus core gene.  Proc Natl Acad Sci U S A. 2007;  104 2879-2884
    Suche in Google Scholar
  • 30 Jiang J, Luo G. Apolipoprotein E but not B is required for the formation of infectious hepatitis C virus particles.  J Virol. 2009;  83 12680-12691
    Suche in Google Scholar
  • 31 Popescu C I, Dubuisson J. Role of lipid metabolism in hepatitis C virus assembly and entry.  Biol Cell. 2010;  102 63-74
    Suche in Google Scholar
  • 32 Coyne C B, Bergelson J M. Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions.  Cell. 2006;  124 119-131
    Suche in Google Scholar
  • 33 Welsch S, Miller S, Romero-Brey I et al. Composition and three-dimensional architecture of the dengue virus replication and assembly sites.  Cell Host Microbe. 2009;  5 365-375
    Suche in Google Scholar
  • 34 Moradpour D, Englert C, Wakita T et al. Characterization of cell lines allowing tightly regulated expression of hepatitis C virus core protein.  Virology. 1996;  222 51-63
    Suche in Google Scholar
  • 35 Barba G, Harper F, Harada T et al. Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets.  Proc Natl Acad Sci U S A. 1997;  94 1200-1205
    Suche in Google Scholar
  • 36 Miyanari Y, Atsuzawa K, Usuda N et al. The lipid droplet is an important organelle for hepatitis C virus production.  Nat Cell Biol. 2007;  9 1089-1097
    Suche in Google Scholar
  • 37 Shavinskaya A, Boulant S, Penin F et al. The lipid droplet binding domain of hepatitis C virus core protein is a major determinant for efficient virus assembly.  J Biol Chem. 2007;  282 37158-37169
    Suche in Google Scholar
  • 38 Boulant S, Targett-Adams P, McLauchlan J. Disrupting the association of hepatitis C virus core protein with lipid droplets correlates with a loss in production of infectious virus.  J Gen Virol. 2007;  88 2204-2213
    Suche in Google Scholar
  • 39 Chang K S, Jiang J, Cai Z et al. Human apolipoprotein e is required for infectivity and production of hepatitis C virus in cell culture.  J Virol. 2007;  81 13783-13793
    Suche in Google Scholar
  • 40 Huang H, Sun F, Owen D M et al. Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins.  Proc Natl Acad Sci U S A. 2007;  104 5848-5853
    Suche in Google Scholar
  • 41 Gastaminza P, Cheng G, Wieland S et al. Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion.  J Virol. 2008;  82 2120-2129
    Suche in Google Scholar
  • 42 Benga W J, Krieger S E, Dimitrova M et al. Apolipoprotein E interacts with hepatitis C virus nonstructural protein 5A and determines assembly of infectious particles.  Hepatology. 2010;  51 43-53
    Suche in Google Scholar
  • 43 Aizaki H, Morikawa K, Fukasawa M et al. Critical role of virion-associated cholesterol and sphingolipid in hepatitis C virus infection.  J Virol. 2008;  82 5715-5724
    Suche in Google Scholar
  • 44 Li K, Foy E, Ferreon J C et al. Immune evasion by hepatitis C virus NS 3 / 4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF.  Proc Natl Acad Sci USA. 2005;  102 2992-2997
    Suche in Google Scholar
  • 45 Meylan E, Curran J, Hofmann K et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus.  Nature. 2005;  437 1167-1172
    Suche in Google Scholar
  • 46 Bellecave P, Sarasin-Filipowicz M, Donze O et al. Cleavage of mitochondrial antiviral signaling protein in the liver of patients with chronic hepatitis C correlates with a reduced activation of the endogenous interferon system.  Hepatology. 2010;  51 1127-1136
    Suche in Google Scholar
  • 47 Garaigorta U, Chisari F V. Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation.  Cell Host Microbe. 2009;  6 513-522
    Suche in Google Scholar
  • 48 Arnaud N, Dabo S, Maillard P et al. Hepatitis C virus controls interferon production through PKR activation.  PLoS ONE. 2010;  5 e10575
    Suche in Google Scholar
  • 49 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
    Suche in Google Scholar
  • 50 Luquin E, Larrea E, Civeira M P et al. HCV structural proteins interfere with interferon-alpha Jak/STAT signalling pathway.  Antiviral Res. 2007;  76 194-197
    Suche in Google Scholar
  • 51 Frese M, Pietschmann T, Moradpour D et al. Interferon-alpha inhibits hepatitis C virus subgenomic RNA replication by an MxA-independent pathway.  J Gen Virol. 2001;  82 723-733
    Suche in Google Scholar
  • 52 Frese M, Schwarzle V, Barth K et al. Interferon-gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs.  Hepatology. 2002;  35 694-703
    Suche in Google Scholar
  • 53 Erickson A L, Kimura Y, Igarashi S et al. The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes.  Immunity. 2001;  15 883-895
    Suche in Google Scholar
  • 54 Dazert E, Neumann-Haefelin C, Bressanelli S et al. Loss of viral fitness and cross-recognition by CD 8 +  T cells limit HCV escape from a protective HLA-B27-restricted human immune response.  J Clin Invest. 2009;  119 376-386
    Suche in Google Scholar
  • 55 Dowd K A, Netski D M, Wang X H et al. Selection pressure from neutralizing antibodies drives sequence evolution during acute infection with hepatitis C virus.  Gastroenterology. 2009;  136 2377-2386
    Suche in Google Scholar
  • 56 Hahn von T, Yoon J C, Alter H et al. Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo.  Gastroenterology. 2007;  132 667-678
    Suche in Google Scholar
  • 57 Timpe J M, McKeating J A. Hepatitis C virus entry: possible targets for therapy.  Gut. 2008;  57 1728-1737
    Suche in Google Scholar
  • 58 Diepolder H M, Zachoval R, Hoffmann R M et al. Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection.  Lancet. 1995;  346 1006-1007
    Suche in Google Scholar
  • 59 Gerlach J T, Diepolder H M, Jung M C et al. Recurrence of hepatitis C virus after loss of virus-specific CD 4(+ ) T-cell response in acute hepatitis C.  Gastroenterology. 1999;  117 933-941
    Suche in Google Scholar
  • 60 Lechner F, Gruener N H, Urbani S et al. CD8 +  T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained.  Eur J Immunol. 2000;  30 2479-2487
    Suche in Google Scholar
  • 61 Thimme R, Oldach D, Chang K M et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection.  J Exp Med. 2001;  194 1395-1406
    Suche in Google Scholar
  • 62 Crawford A, Wherry E J. The diversity of costimulatory and inhibitory receptor pathways and the regulation of antiviral T cell responses.  Curr Opin Immunol. 2009;  21 179-186
    Suche in Google Scholar
  • 63 Neumann-Haefelin C, Blum H E, Chisari F V et al. T cell response in hepatitis C virus infection.  J Clin Virol. 2005;  32 75-85
    Suche in Google Scholar
  • 64 Tester I, Smyk-Pearson S, Wang P et al. Immune evasion versus recovery after acute hepatitis C virus infection from a shared source.  J Exp Med. 2005;  201 1725-1731
    Suche in Google Scholar
  • 65 Lemon S M, McKeating J A, Pietschmann T et al. Development of novel therapies for hepatitis C.  Antiviral Res. 2010;  86 79-92
    Suche in Google Scholar
  • 66 Shimakami T, Lanford R E, Lemon S M. Hepatitis C: recent successes and continuing challenges in the development of improved treatment modalities.  Curr Opin Pharmacol. 2009;  9 537-544
    Suche in Google Scholar
  • 67 Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection.  Gastroenterology. 2010;  138 447-462
    Suche in Google Scholar
  • 68 Bihl F, Negro F. Treatment of chronic hepatitis C.  Minerva Med. 2009;  100 459-465
    Suche in Google Scholar
  • 69 Gao M, Nettles R E, Belema M et al. Chemical genetics strategy identifies an HCV NS 5A inhibitor with a potent clinical effect.  Nature. 2010;  465 96-100
    Suche in Google Scholar
  • 70 Lemm J A, O’Boyle D, Liu M et al. Identification of hepatitis C virus NS 5A inhibitors.  J Virol. 2010;  84 482-491
    Suche in Google Scholar
  • 71 Fridell R A, Qiu D, Wang C et al. Resistance analysis of the hepatitis C virus NS 5A inhibitor BMS-790052 in an in vitro replicon system.  Antimicrob Agents Chemother. 2010;  54 3641-3650
    Suche in Google Scholar
  • 72 Gao M, Wang C, Sun J et al. Genotypic and phenotypic analysis of HCV NS 5A inhibitor resitance variants: Correlation between in vitro and in vivo (2010), Abstracts 1880-2047.  Hepatology. 2010;  52 1214A-1291A DOI: 10.1002 /hep.23997
    Suche in Google Scholar
  • 73 Kaul A, Stauffer S, Berger C et al. Essential role of cyclophilin A for hepatitis C virus replication and virus production and possible link to polyprotein cleavage kinetics.  PLoS Pathog. 2009;  5 e1000546
    Suche in Google Scholar
  • 74 Yang F, Robotham J M, Nelson H B et al. Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro.  J Virol. 2008;  82 5269-5278
    Suche in Google Scholar
  • 75 Chatterji U, Bobardt M, Selvarajah S et al. The isomerase active site of cyclophilin A is critical for hepatitis C virus replication.  J Biol Chem. 2009;  284 16998-17005
    Suche in Google Scholar
  • 76 Hanoulle X, Badillo A, Wieruszeski J M et al. Hepatitis C virus NS 5A protein is a substrate for the peptidyl-prolyl cis/trans isomerase activity of cyclophilins A and B.  J Biol Chem. 2009;  284 13589-13601
    Suche in Google Scholar
  • 77 Ciesek S, Steinmann E, Wedemeyer H et al. Cyclosporine A inhibits hepatitis C virus nonstructural protein 2 through cyclophilin A.  Hepatology. 2009;  50 1638-1645
    Suche in Google Scholar
  • 78 Watashi K, Hijikata M, Hosaka M et al. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes.  Hepatology. 2003;  38 1282-1288
    Suche in Google Scholar
  • 79 Ma S, Boerner J E, TiongYip C et al. NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon.  Antimicrob Agents Chemother. 2006;  50 2976-2982
    Suche in Google Scholar
  • 80 Paeshuyse J, Kaul A, De Clercq E et al. The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro.  Hepatology. 2006;  43 761-770
    Suche in Google Scholar
  • 81 Flisiak R, Horban A, Gallay P et al. The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus.  Hepatology. 2008;  47 817-826
    Suche in Google Scholar
  • 82 Crabbe R, Vuagniaux G, Dumont J M et al. An evaluation of the cyclophilin inhibitor Debio 025 and its potential as a treatment for chronic hepatitis C.  Expert Opin Investig Drugs. 2009;  18 211-220
    Suche in Google Scholar
  • 83 Puyang X, Poulin D L, Mathy J E et al. Mechanism of resistance of hepatitis C virus replicons to structurally distinct cyclophilin inhibitors.  Antimicrob Agents Chemother. 2010;  54 1981-1987
    Suche in Google Scholar
  • 84 Chatterji U, Lim P, Bobardt M D et al. HCV resistance to cyclosporin A does not correlate with a resistance of the NS 5A-cyclophilin A interaction to cyclophilin inhibitors.  J Hepatol. 2010;  53 50-56
    Suche in Google Scholar
  • 85 Liu Z, Robida J M, Chinnaswamy S et al. Mutations in the hepatitis C virus polymerase that increase RNA binding can confer resistance to cyclosporine A.  Hepatology. 2009;  50 25-33
    Suche in Google Scholar
  • 86 Lanford R E, Hildebrandt-Eriksen E S, Petri A et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection.  Science. 2010;  327 198-201
    Suche in Google Scholar
  • 87 Ploss A, Evans M J, Gaysinskaya V A et al. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells.  Nature. 2009;  457 882-886
    Suche in Google Scholar
  • 88 Zeuzem S, Buggisch P, Agarwal K et al. Dual, Triple, and quadruble combination treatmnet with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with Ribavirin (RBV) or PEGIFN/RBV for up to 28 days in treatment naïve, genotype 1 HCV subjects (2010), Oral presentations.  Hepatology. 2010;  52 51A-120A. DOI: 10.1002/hep.23971
    Suche in Google Scholar
  • 89 Pietschmann T, Kaul A, Koutsoudakis G et al. Construction and characterization of infectious intragenotypic and intergenotypic hepatitis C virus chimeras.  Proc Natl Acad Sci U S A. 2006;  103 7408-7413
    Suche in Google Scholar
  • 90 Wong-Staal F, Syder A J, McKelvy J F. Targeting HCV Entry For Development of Therapeutics.  Viruses. 2010;  2 1718-1733
    Suche in Google Scholar
  • 91 Griffin S. Inhibition of HCV p7 as a therapeutic target.  Curr Opin Investig Drugs. 2010;  11 175-181
    Suche in Google Scholar
  • 92 Raney K D, Sharma S D, Moustafa I M et al. Hepatitis C virus non-structural protein 3 (HCV NS 3): a multifunctional antiviral target.  J Biol Chem. 2010;  285 22725-22731
    Suche in Google Scholar
  • 93 Legrand-Abravanel F, Nicot F, Izopet J. New NS 5B polymerase inhibitors for hepatitis C.  Expert Opin Investig Drugs. 2010;  19 963-975
    Suche in Google Scholar

Prof. Dr. Ralf Bartenschlager

Department für Infektiologie, Molekulare Virologie, Universitätsklinikum Heidelberg

Im Neuenheimer Feld 345

69120 Heidelberg

Telefon: ++ 49/62 21/56 42 25

Fax: ++ 49/62 21/56 45 70

eMail: ralf_bartenschlager@med.uni-heidelberg.de