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...

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Published in:Biochemical and biophysical research communications 2004-01, Vol.313 (1), p.42-47
Main Authors: Nakagawa, Mina, Sakamoto, Naoya, Enomoto, Nobuyuki, Tanabe, Yoko, Kanazawa, Nobuhiko, Koyama, Tomoyuki, Kurosaki, Masayuki, Maekawa, Shinya, Yamashiro, Tsuyoshi, Chen, Cheng-Hsin, Itsui, Yasuhiro, Kakinuma, Sei, Watanabe, Mamoru
Format: Article
Language:English
Subjects:
Antiviral Agents - pharmacology
Cell Line, Tumor
Cyclophilins
Cyclosporin A
Cyclosporine - pharmacology
FK506
Genome, Viral
Hepacivirus - drug effects
Hepacivirus - physiology
Hepatitis C virus
Humans
Interferon-alpha - metabolism
ISRE
Kanamycin Kinase - genetics
Luciferases - genetics
Luciferases - metabolism
Plasmids - genetics
Replicon
Replicon - drug effects
Replicon - genetics
RNA - antagonists & inhibitors
RNA - biosynthesis
Tacrolimus - pharmacology
Transfection
Viral Nonstructural Proteins - antagonists & inhibitors
Viral Nonstructural Proteins - biosynthesis
Virus Replication - drug effects
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Summary: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 ∼0.5 μg/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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2003.11.080