Specific inhibition of hepatitis C virus replication by cyclosporin A.
The difficulty in eradicating hepatitis C virus (HCV) infection is attributable to the limited treatment options against the virus. Recently, cyclosporin A (CsA), a widely used immunosuppressive drug, has been reported to be effective against HCV infection [J. Gastroenterol. 38 (2003) 567], although little is understood about the mechanism of its action against HCV. In this study, we investigated the anti-viral effects of CsA using an HCV replicon system. Human hepatoma Huh7 cells were transfected with an HCV replicon expressing a chimeric gene encoding a luciferase reporter and neomycin phosphotransferase (Huh7/Rep-Feo). Treatment of the Huh7/Rep-Feo cells with CsA resulted in suppression of the replication of the HCV replicon in a dose-dependent manner, with an IC50 of approximately 0.5 microg/ml. There were no changes in the rate of cell growth or viability, suggesting that the effect of CsA against HCV is specific and not due to cytotoxicity. In contrast, FK506, another immunosuppressive drug, did not suppress HCV replication. CsA did not activate interferon-stimulated gene responses, suggesting that its action is independent of that of interferon. In conclusion, CsA inhibits HCV replication in vitro specifically at clinical concentrations. Further defining its mode of action against HCV replication potentially may be important for identifying novel molecular targets to treat HCV infection.
Nakagawa
Mina
M
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Sakamoto
Naoya
N
Enomoto
Nobuyuki
N
Tanabe
Yoko
Y
Kanazawa
Nobuhiko
N
Koyama
Tomoyuki
T
Kurosaki
Masayuki
M
Maekawa
Shinya
S
Yamashiro
Tsuyoshi
T
Chen
Cheng Hsin
CH
Itsui
Yasuhiro
Y
Kakinuma
Sei
S
Watanabe
Mamoru
M
D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology*; D016679:Genome, Viral; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D019868:Kanamycin Kinase / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D012313:RNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012093:Replicon / Q000187:drug effects / Q000235:genetics; D016559:Tacrolimus / Q000494:pharmacology; D014162:Transfection; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D016898:Interferon-alpha; D017361:Viral Nonstructural Proteins; D012313:RNA; D016572:Cyclosporine; D008156:Luciferases; D019868:Kanamycin Kinase; D016559:Tacrolimus