Efficient Suppression of Hepatitis C Virus Replication by Combination Treatment with MIR-122 Antagonism and Direct-acting Antivirals in Cell Culture Systems

Fanwei Liu, Tetsuro Shimakami, Kazuhisa Murai, Takayoshi Shirasaki, Masaya Funaki, Masao Honda, Seishi Murakami, Min Kyung Yi, Hong Tang, Shuichi Kaneko

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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 EC 50 values of simeprevir in simeprevir-resistant mutants were significantly decreased by combining simeprevir with anti-miR-122. A similar reduction in EC 50 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.

Original languageEnglish (US)
Article number30939
JournalScientific Reports
Volume6
DOIs
StatePublished - Aug 3 2016

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Virus Replication
Hepacivirus
Antiviral Agents
Cell Culture Techniques
Genotype
RNA
Drug Resistance
Simeprevir

ASJC Scopus subject areas

  • General

Cite this

Efficient Suppression of Hepatitis C Virus Replication by Combination Treatment with MIR-122 Antagonism and Direct-acting Antivirals in Cell Culture Systems. / Liu, Fanwei; Shimakami, Tetsuro; Murai, Kazuhisa; Shirasaki, Takayoshi; Funaki, Masaya; Honda, Masao; Murakami, Seishi; Yi, Min Kyung; Tang, Hong; Kaneko, Shuichi.

In: Scientific Reports, Vol. 6, 30939, 03.08.2016.

Research output: Contribution to journalArticle

Liu, Fanwei ; Shimakami, Tetsuro ; Murai, Kazuhisa ; Shirasaki, Takayoshi ; Funaki, Masaya ; Honda, Masao ; Murakami, Seishi ; Yi, Min Kyung ; Tang, Hong ; Kaneko, Shuichi. / Efficient Suppression of Hepatitis C Virus Replication by Combination Treatment with MIR-122 Antagonism and Direct-acting Antivirals in Cell Culture Systems. In: Scientific Reports. 2016 ; Vol. 6.
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