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DOI: 10.1055/s-0031-1273196
© 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 DrugsPublikationsverlauf
Manuskript eingetroffen: 18.10.2010
Manuskript akzeptiert: 13.2.2011
Publikationsdatum:
15. Juli 2011 (online)

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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 31
Popescu C I, Dubuisson J.
Role of lipid metabolism in hepatitis C virus assembly and entry.
Biol Cell.
2010;
102
63-74
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 48
Arnaud N, Dabo S, Maillard P et al.
Hepatitis C virus controls interferon production through PKR activation.
PLoS ONE.
2010;
5
e10575
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 57
Timpe J M, McKeating J A.
Hepatitis C virus entry: possible targets for therapy.
Gut.
2008;
57
1728-1737
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 65
Lemon S M, McKeating J A, Pietschmann T et al.
Development of novel therapies for hepatitis C.
Antiviral Res.
2010;
86
79-92
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 67
Sarrazin C, Zeuzem S.
Resistance to direct antiviral agents in patients with hepatitis C virus infection.
Gastroenterology.
2010;
138
447-462
Reference Ris Wihthout Link
- 68
Bihl F, Negro F.
Treatment of chronic hepatitis C.
Minerva Med.
2009;
100
459-465
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 90
Wong-Staal F, Syder A J, McKelvy J F.
Targeting HCV Entry For Development of Therapeutics.
Viruses.
2010;
2
1718-1733
Reference Ris Wihthout Link
- 91
Griffin S.
Inhibition of HCV p7 as a therapeutic target.
Curr Opin Investig Drugs.
2010;
11
175-181
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 93
Legrand-Abravanel F, Nicot F, Izopet J.
New NS 5B polymerase inhibitors for hepatitis C.
Expert Opin Investig Drugs.
2010;
19
963-975
Reference Ris Wihthout Link
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