title: Let-7b is a novel regulator of hepatitis C virus replication.
abstract: The non-coding microRNA (miRNA) is involved in the regulation of hepatitis C virus (HCV) infection and offers an alternative target for developing anti-HCV agent. In this study, we aim to identify novel cellular miRNAs that directly target the HCV genome with anti-HCV therapeutic potential. Bioinformatic analyses were performed to unveil liver-abundant miRNAs with predicted target sequences on HCV genome. Various cell-based systems confirmed that let-7b plays a negative role in HCV expression. In particular, let-7b suppressed HCV replicon activity and down-regulated HCV accumulation leading to reduced infectivity of HCVcc. Mutational analysis identified let-7b binding sites at the coding sequences of NS5B and 5'-UTR of HCV genome that were conserved among various HCV genotypes. We further demonstrated that the underlying mechanism for let-7b-mediated suppression of HCV RNA accumulation was not dependent on inhibition of HCV translation. Let-7b and IFNα-2a also elicited a synergistic inhibitory effect on HCV infection. Together, let-7b represents a novel cellular miRNA that targets the HCV genome and elicits anti-HCV activity. This study thereby sheds new insight into understanding the role of host miRNAs in HCV pathogenesis and to developing a potential anti-HCV therapeutic strategy.
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan, ROC. jccheng@mail.cmu.edu.tw
authors.forename: Ju-Chien
authors.initials: JC
authors.lastname: Cheng
authors.forename: Yung-Ju
authors.initials: YJ
authors.lastname: Yeh
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Tseng
authors.forename: Sheng-Da
authors.initials: SD
authors.lastname: Hsu
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Chang
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Hsien-Da
authors.initials: HD
authors.lastname: Huang
mesh_terms: D020121:5' Untranslated Regions; D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D016679:Genome, Viral; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000821:virology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016296:Mutagenesis; D011092:Polyethylene Glycols / Q000494:pharmacology; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012093:Replicon; D017361:Viral Nonstructural Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D020121:5' Untranslated Regions; D000998:Antiviral Agents; D017931:DNA Primers; D016898:Interferon-alpha; D035683:MicroRNAs; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; C487931:mirnlet7 microRNA, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C100416:peginterferon alfa-2a