Analyzing the contribution of intracellular localization of hepatitis C virus replication complex for the drug resistance.

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This research is aimed to disclose the relationship between intracellular localization of hepatitis C virus (HCV) replication complex and the effect of anti-viral drugs such as interferon-alpha, and finally to develop new anti-HCV strategies through understanding of viral replication mechanism(s) in the replication complex.Recently, micro-domains of organelle membranes rich in sphingomyelin and cholesterol in the form of "lipid rafts" have been considered to act as a scaffold for HCV replication complex formation, indicating the possibility that the lipid raft could be a new therapeutic target. In the present study, we investigated the effect of myriocin, an inhibitor of sphingomyelin synthesis, on HCV replication using an HCV-subgenomic replicon system, as well as the infectious HCV culture system. We also investigated the combined effect of myriocin plus interferon-alpha, or myriocin plus simvastatin, on HCV replication. Myriocin suppressed intracellular RNA replication of both genotype lb subgenomic HCV replicon RNA and genotype 2a infectious HCV RNA in a time-and dose-dependent manner (subgenomic HCV-lb, max. 70% at 120 hours ; genomic HCV-2a, max. 60% at 96 hours). Combination treatment with myriocin plus IFN or simvastatin attenuated intracellular HCV-RNA replication synergistically.Our data demonstrate that both the sphingomyelin synthesis inhibitor and HMG-CoA inhibitor strongly suppress HCV replication, irrespective of genotype, indicating that the lipid metabolism of the host could be a novel target for HCV therapy.