Regulation of the hepatitis C virus genome replication by miR-199a

Background/Aims: Hepatitis C virus (HCV) infection causes chronic hepatitis and hepatocellular carcinoma. Current anti-HCV therapies are based on interferon therapy, which is insufficiently effective. microRNAs (miRNAs) are non-coding RNAs that regulate gene expression, and they have recently been shown to play an important role in viral replication. Methods:An algorithm-based search for miRNAs that target the HCV genome yielded one miRNA, miR-199a*, with a sequence similar to the HCV genome that is conserved among HCV genotypes. Results: Overexpression of miR-199a* inhibited HCV genome replication in two cells bearing replicons (replicon cell) HCV-1b or -2a, however, miRNA inhibition by specific antisense oligonucleotide (ASO) accelerated viral replication. Prior transfection of immortalized hepatocytes which were infected with serum of HCV genotype 1b and 2a-infected patients, with miR-199a* reduced HCV RNA replication activity. Mutation in the miR-199a* target site in the replicon reduced the effect of the miR-199a*. HCV replicon RNA is accumulated to the RNA-induced silencing complex (RISC) when miR-199a* was overexpressed to the replicon cell. This antiviral effect by miR-199a* was independent of the interferon pathway. Conclusions:The results of this study suggest that miR-199a* directly regulates HCV replication and may serve as a novel antiviral therapy. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.