Pathogenesis and drug therapy of hepatitis C

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Λαδων Πυλαρινός
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1 196 Infect Dis Info, Vol. 23, No. 4, August 30, 2010 [ ] hepatitis C virus, 1 50% [ ] [ ] R [ ] A [ ] (2010) Pathogenesis and drug therapy of hepatitis C QI Zhong-tian Department of Microbiology, Second Military Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai , China [Abstract] Hepatitis C virus () can affect host immune responses in several ways so that it can replicate persistently in hosts and lead to chronic infection. Currently standard therapy of the patients with chronic hepatitis C is the combination of pegylated interferon and ribavirin, but about 50% of the patients with genotype 1 infection cannot achieve sustained virologic response with the combination therapy and adverse reactions are found. In recent years, with the further research on replication and the function of non-structural proteins, there have been great advances in the development of virus-specific agents that have demonstrated promising efficacy on reducing viral replication in -infected patients. This review focuses on the current progress of the studies on cell entry, replication, escape from host innate and adaptive immune responses and new anti- agents in clinical trials. [Key words] hepatitis C virus; immune escape; virus replication; cell entry; drug therapy HBV 50%~85% 10%~15% 1%~7% 1b pseudotype particles, pp [4] [1] RNA 9600 grown in cell culture, cc [5-6] PEG-IFN α RBV sustained virologic response, SVR 1 SVR CD81 [7] SR-B1 [8-9] Clau- 4 50% [2-3] din-1 CLDN1 [10] Occludin [11] CD81 SR-B1 E2-CD81 GTPase 1 E2-CD81 CLDN1 Occludin ph [12] CLDN1 Occludin

2 Infect Dis Info, Vol. 23, No. 4, August 30, 2010 [13] internal ribosome entry site, IRES 40S IFN T E2 3 7 NS3/4A NS5A NS5B E1 E2 p7 63 E2 RNA E2 [14] NS2-3 NS2 1/2 NS3 1/3 RNA double-stranded RNA-activated protein kinase, PKR E2 [15] NS2 PKR eukaryotic initiation factor, eif NS2 cc 2a E2 NS2 eif2a PKR eif2a [16] NS3-4A NS3 IFN N- 1/3 PKR NS3/4A C- 2/3 RNA NTP NS4A NS3 NS5A interferon regulatory factors, IRF -3 IFN IFN RNA NS5A IRF-3 NS5B RNA RNA RNA RNA RNA IRF-3 RNA IRF-3 Huh-7 CBP300 IFN [17] RNA NS3/4A 2 TRIF MAVS IRF- [19-20] 3 NF-κB RNA RNA B [18] B NS5B RNA E NS2 RNA T cytotoxic T lymphocyte, CTL 1.2 major histocompatibility complex, MHC T

3 198 Infect Dis Info, Vol. 23, No. 4, August 30, IFN RBV T IFN IFN α MHC T CTL IFN PEG-IFN α PEG-IFN α B T IFN PEG-IFN α IFN α B IFN α IFN α 1/3 Albumin-IFN α IFN α-2b 150 h RBV IFN RBV 48 SVR %~ 80% 1 40%~50% RBV RBV RBV Levovirin RBV RBV 2 Viramidine RBV RBV PEG-IFN α RBV RBV RBV 1 Figure 1 New anti- agents in clinical trials

4 Infect Dis Info, Vol. 23, No. 4, August 30, 2010 [23-24] IRES RNA RNA NS NS3 IFN VX-950 SCH BMS ITMN IRES RNA p7 NS3 2.3 Thymosin 626. Nat Med, 2005, 11(7): [22] SVR IFN Debio-25 VX-950 VX- α- 950 NM283 NS3/4A HIV α 1 h α VX-950 Vertex MX α- SCH E1 E2 α- Scher- Whitby [25] ing-plough MX-3253 PEG-IFNα PEG-IFN α RBV MX-3253 PEG-IFN α RBV [21] NS5B RNA RNA RNA-dependence RNA polymerase, RDRP RDRP NS5B R1626 RNA RNA Roche RNA R1728 VCH- 759 BF ANA598 [1] Nakano T, Lu L, He Y, et al. Population genetic history of hepatitis C virus 1b infection in China[J]. J Gen Virol, 2006, 87(Pt 1): [2] Kemmer N, Neff GW. Managing chronic hepatitis C in the difficult-to-treat patient[j]. Liver Int, 2007, 27(10): [3] Hughes CA, Shafran SD. Chronic hepatitis C virus management: update[j]. Ann Pharmacother, 2006, 40(1): [4] Bartosch B, Dubuisson J, Cosset FL. Infectious hepatitis C virus pseudo -particles containing functional E1 -E2 envelope protein complexes[j]. J Exp Med, 2003, 197(5): [5] Lindenbach BD, Evans MJ, Syder AJ, et al. Complete replication of hepatitis C virus in cell culture[j]. Science, 2005, 309(5734):623- [6] Wakita T, Pietschmann T, Kato T, et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome[j]. [7] Pileri P, Uematsu Y, Campagnoli S, et al. Binding of hepatitis C virus to CD81[J]. Science, 1998, 282(5390): [8] Grove J, Huby T, Stamataki Z, et al. Scavenger receptor B and B expression levels modulate hepatitis C virus infectivity[j]. J Virol, 2.4 RNA 2007, 81(7): CD81 and scavenger receptor B type α NS5B [9] Kapadia SB, Barth H, Baumert T, et al. Initiation of hepatitis C virus infection is dependent on cholesterol and cooperativity between [J]. J Virol, 2007, 81(1):

5 Infect Dis Info, Vol. 23, No. 4, August 30, % 29% [1-2] ADV [3-4] ADV Marcellin [7] ADV 5 Zoulim [8] LAM ADV % HBV DNA Takamura [9] ADV et al et al et al et al et al et al et al et al LAM LAM 3 [10] ADV ADV 199 [10] Evans MJ, von Hahn T, Tscherne DM, et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry[j]. Nature, 2007, 446(7137): [11] Liu S, Yang W, Shen L, et al. Tight junction proteins claudin-1 and occludin control hepatitis C virus entry and are downregulated during infection to prevent superinfection[j]. J Virol, 2009, 83(4): [12] Timpe JM, Stamataki Z, Jennings A, et al. Hepatitis C virus cellcell transmission in hepatoma cells in the presence of neutralizing antibodies[j]. Hepatology, 2008, 47(1): [13] Pietschmann T. Virology: final entry key for hepatitis C[J]. Nature, 2009, 457(7231): [14] Griffin SD, Beales LP, Clarke DS, et al. The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine[J]. FEBS Lett, 2003, 535(1-3): [15] Pietschmann T, Kaul A, Koutsoudakis G, et al. Construction and characterization of infectious intragenotypic and intergenotypic hepatitis C virus chimeras[j]. Proc Natl Acad Sci U S A 2006, 103(19): [16] Noppornpanth S, Lien TX, Poovorawan Y, et al. Identification of a naturally occurring recombinant genotype 2/6 hepatitis C virus[j]. J Virol, 2006, 80(15): [17] 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]. J Virol, 2003, 77(9): [18] Watashi K, Ishii N, Hijikata M, et al. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase[j]. Mol Cell, 2005, 19(1): [19] Li K, Foy E, Ferreon JC, et al. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF[J]. Proc Natl Acad Sci U S A, 2005, 102 (8): [20] 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 [J]. Nature, 2005, 437(7062): [21] Sarrazin C, Rouzier R, Wagner F, et al. SCH , a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha- 2b for genotype 1 nonresponders [J]. Gastroenterology, 2007, 132 (4): [22] Inchauspe G, Feinstone S. Development of a hepatitis C virus vaccine[j]. Clin Liver Dis, 2003, 7(1):243-59, xi. [23] Chapel C, Garcia C, Roingeard P, et al. Antiviral effect of alphaglucosidase inhibitors on viral morphogenesis and binding properties of hepatitis C virus-like particles[j]. J Gen Virol, 2006, 87(Pt 4): [24] Inoue K, Umehara T, Ruegg UT, et al. Evaluation of a cyclophilin inhibitor in hepatitis C virus -infected chimeric mice in vivo [J]. Hepatology, 2007, 45(4): [25] Whitby K, Taylor D, Patel D, et al. Action of celgosivir (6 O-butanoyl castanospermine) against the pestivirus BVDV: implications for the treatment of hepatitis C[J]. Antivir Chem Chemother, 2004, 15(3):

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