title: Efficient Suppression of Hepatitis C Virus Replication by Combination Treatment with miR-122 Antagonism and Direct-acting Antivirals in Cell Culture Systems.
abstract: Direct-acting antivirals (DAAs) against Hepatitis C virus (HCV) show effective antiviral activity with few side effects. However, the selection of DAA-resistance mutants is a growing problem that needs to be resolved. In contrast, miR-122 antagonism shows extensive antiviral effects among all HCV genotypes and a high barrier to drug resistance. In the present study, we evaluated three DAAs (simeprevir, daclatasvir, and sofosbuvir) in combination with anti-miR-122 treatment against HCV genotype 1a in cell cultures. We found that combination treatments with anti-miR-122 and a DAA had additive or synergistic antiviral effects. The EC50 values of simeprevir in simeprevir-resistant mutants were significantly decreased by combining simeprevir with anti-miR-122. A similar reduction in EC50 in daclatasvir-resistant mutants was achieved by combining daclatasvir with anti-miR-122. Combination treatment in HCV-replicating cells with DAA and anti-miR-122 sharply reduced HCV RNA amounts. Conversely, DAA single treatment with simeprevir or daclatasvir reduced HCV RNA levels initially, but the levels later rebounded. DAA-resistant mutants were less frequently observed in combination treatments than in DAA single treatments. In summary, the addition of miR-122 antagonism to DAA single treatments had additive or synergistic antiviral effects and helped to efficiently suppress HCV replication and the emergence of DAA-resistant mutants.
authors.affiliation: Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Fanwei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shimakami
authors.affiliation: Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Murai
authors.affiliation: Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Shirasaki
authors.affiliation: Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Funaki
authors.affiliation: Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.affiliation: Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Murakami
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555-0144, USA.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Yi
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C531907:MIRN122 microRNA, human; D035683:MicroRNAs