2 Houghton 1989 A B RNA Science 2 λgt11 A B 2 NS3 A B C Hepatitis C virus HCV 1992 HCV A B C HCV A B 1999 HCV HCV HCV 3 HCV a JFH1 4 HCV

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1 C C HCV HCV HCV HCV HCV C I A E 5 RNA DNA RNA A E B C A B D B B C B C HCV RNA RNA 20 A B A B A B 80 nm RNA RNA A B

2 2 Houghton 1989 A B RNA Science 2 λgt11 A B 2 NS3 A B C Hepatitis C virus HCV 1992 HCV A B C HCV A B 1999 HCV HCV HCV 3 HCV a JFH1 4 HCV 5 HCV HCV HCV HCV HCV II DNA RNA HCV

3 C 3 1. HCV RNA RNA RNA E1 E2 2 RNA 5 3 HCV mrna CAP A RNA 5 IRES Internal ribosome entry site E1 E2 Nonstructural protein, NS 6 E1 E2 NS2 C NS3 NS3 NS3 NS4A NS3 NS4B NS5A NS5B RNA RNA

4 4 2. HCV HCV GAG CD81 SRBI CLDN1 Occludin ph III HCV HCV HCV HCV 2 HCV HCV

5 C 5 GAG CD81 7 SR-BI 8 CD81 SR-BI Claudin- Occludin 7 9 Niemann-Pick C1-like 1 cholesterol absorption receptor 10 IRES NS2/3 E1 C SPP 177 DRM SPP SPP DRM RNA RNA RNA NS5A 14 DRM E1 E1 15 E1 E2 E1 HCV VAP-A 16 VAP-B 17 mir Cyclophilin Cyp FKBP8 21 Hsp90 21 Hsp90 ATP NS5A FK506- FK506-binding protein, FKBP FKBP8 21 FKBP8 FKBP FK506 FK506 FKBP8 FKBP8 NS5A HCV FKBP8 NS5A 22 butyrate-induced transcript 1 B-ind1 NS5A FKBP8 Hsp90 A 23 5 B-ind1 Hsp90 p23 Hsp90 F-X-X-W X

6 6 3. HCV HCV LXRα/RXRα SREBP-1c TNFα Hsp90-FKBP8- hb-ind1 HCV 23 IV HCV C HCV HCV 24 HCV Tg HCV Tg LXRα RXRα 27 MAPK MAPK AP-1

7 C 7 30 C 2 Tg 31 TNFα 31 PA28γ PA28γ PA28γ 34 PA28γ Tg PA28γ VT1A 35 PA28γ PA28γ HCV 3 HCV V HCV RNA C18:1 stearoyl-coa desaturase HCV HCV HCV 37 PA28γ 38 PA28γ HCV PA28γ HCV 1 Krugman S, Ward R, Giles JP.: The natural history of infectious hepatitis. Am. J. Med., 32: , Choo QL, Kuo G, Weiner AJ, et al.: Isolation of a cdna clone derived from a blood-borne non-a, non-b viral hepatitis genome. Science, 244: , Lohmann V, Korner F, Koch J, et al.: Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science, 285: , Wakita T, Pietschmann T, Kato T, et al.: Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat. Med., 11: , Mercer DF, Schiller DE, Elliott JF, et al.: Hepatitis C virus replication in mice with chimeric human livers. Nat. Med., 7: , Moriishi K, Matsuura Y.: Host factors involved in the replication of hepatitis C virus. Rev. Med. Virol., 17: , Pileri P, Uematsu Y, Campagnoli S, et al.: Binding of hepatitis C virus to CD81. Science, 282: , Scarselli E, Ansuini H, Cerino R, et al.: The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J., 21: , Mee CJ, Grove J, Harris HJ, et al.: Effect of cell polarization on hepatitis C virus entry. J. Virol., 82: , Sainz B, Jr., Barretto N, Martin DN, et al.: Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor. Nat Med, 18: , Okamoto K, Mori Y, Komoda Y, et al.: Intram-

8 8 embrane processing by signal peptide peptidase regulates the membrane localization of hepatitis C virus core protein and viral propagation. J. Virol., 82: , Miyanari Y, Atsuzawa K, Usuda N, et al.: The lipid droplet is an important organelle for hepatitis C virus production. Nat. Cell Biol., 9: , 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., 76: , Masaki T, Suzuki R, Murakami K, et al.: Interaction of hepatitis C virus nonstructural protein 5A with core protein is critical for the production of infectious virus particles. J. Virol., 82: , Nakai K, Okamoto T, Kimura-Someya T, et al.: Oligomerization of hepatitis C virus core protein is crucial for interaction with the cytoplasmic domain of E1 envelope protein. J. Virol., 80: , Tu H, Gao L, Shi ST, et al.: Hepatitis C virus RNA polymerase and NS5A complex with a SNARElike protein. Virology, 263: 30 41, Hamamoto I, Nishimura Y, Okamoto T, et al.: Human VAP-B is involved in hepatitis C virus replication through interaction with NS5A and NS5B. J. Virol., 79: , Jopling CL, Yi M, Lancaster AM, et al.: Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science, 309: , Watashi K, Ishii N, Hijikata M, et al.: Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol. Cell, 19: , Yang F, Robotham JM, Nelson HB, et al.: Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro. J. Virol., 82: , Okamoto T, Nishimura Y, Ichimura T, et al.: Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90. EMBO J., 25: , Okamoto T, Omori H, Kaname Y, et al.: A singleamino-acid mutation in hepatitis C virus NS5A disrupting FKBP8 interaction impairs viral replication. J. Virol., 82: , Taguwa S, Okamoto T, Abe T, et al.: Human butyrate-induced transcript 1 interacts with hepatitis C virus NS5A and regulates viral replication. J. Virol., 82: , Koike K, Tsutsumi T, Miyoshi H, et al.: Molecular basis for the synergy between alcohol and hepatitis C virus in hepatocarcinogenesis. J. Gastroenterol. Hepatol., 23 Suppl 1: S87 91, Moriya K, Fujie H, Shintani Y, et al.: The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat. Med., 4: , Moriya K, Yotsuyanagi H, Shintani Y, et al.: Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J. Gen. Virol., 78: , Moriishi K, Okabayashi T, Nakai K, et al.: Proteasome activator PA28gamma-dependent nuclear retention and degradation of hepatitis C virus core protein. J. Virol., 77: , Tsutsumi T, Suzuki T, Moriya K, et al.: Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice. Hepatology, 38: , Moriya K, Nakagawa K, Santa T, et al.: Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res., 61: , Koike K.: Hepatocarcinogenesis in hepatitis viral infection: lessons from transgenic mouse studies. J. Gastroenterol., 37 Suppl 13: 55 64, Shintani Y, Fujie H, Miyoshi H, et al.: Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology, 126: , Miyamoto H, Moriishi K, Moriya K, et al.: Involvement of PA28gamma-Dependent Pathway in Insulin Resistance Induced by Hepatitis C Virus Core Protein. J. Virol., 81: , Moriishi K, Mochizuki R, Moriya K, et al.: Critical role of PA28gamma in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. Proc. Natl. Acad. Sci. USA, 104: , Moriishi K, Shoji I, Mori Y, et al.: Involvement of PA28gamma in the propagation of hepatitis C virus. Hepatology, 52: , Tripathi LP, Kambara H, Moriishi K, et al.: Proteomic Analysis of Hepatitis C Virus (HCV) Core Protein Transfection and Host Regulator PA28gamma Knockout in HCV Pathogenesis: A Network-Based Study. J. Proteome Res., 11: , Moriya K, Shintani Y, Fujie H, et al.: Serum lipid profile of patients with genotype 1b hepatitis C viral infection in Japan. Hepatol. Res., 25: , Sakamoto H, Okamoto K, Aoki M, et al.: Host sphingolipid biosynthesis as a target for hepatitis C virus therapy. Nat. Chem. Biol., 1: , Murata S, Kawahara H, Tohma S, et al.: Growth retardation in mice lacking the proteasome activator PA28gamma. J Biol Chem, 274: , 1999.

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表1.eps Vol.1 C ontents 1 2 cell-free EMBO J Proc. Natl. Acad. Sci. USA NatureEMBO J 3 RNA NatureEMBO J Nature EMBO J 4 5 HCV HCV HCV HCV RNA HCV in situ 6 7 8 Nat Struct Mol Biol J Biol Chem Nat Commun J Virol