Identification of microRNA associated with the elimination of hepatitis C virus genotype 1b by direct-acting antiviral therapies.

Background And Aim: Direct-acting antiviral (DAA) therapies have been proven to be highly effective for the eradication of hepatitis C virus (HCV) without resistance-associated substitutions (RASs). However, even in cases with no detected RASs, treatment sometimes fails, suggestive of the existence of some host-related factors involved in HCV eradication by DAAs. To explore such factors, we analyzed the serum microRNAs (miRNAs) of patients who received DAA treatment.

Methods: The serum miRNA expression levels of 39 patients with chronic HCV infection without any detectable RASs, who achieved sustained virological response with asunaprevir/daclatasvir or grazoprevir/elbasvir therapy, were investigated cyclopedically, using oligonucleotide microarrays. The effects of specific miRNAs on the replication of HCV were measured in the HCV genomic replicon containing Huh-7 hepatoma cells.

Results: Along with the disappearance of HCV, the expression quantiles of 16 miRNAs in the asunaprevir/daclatasvir group and 18 miRNAs in the grazoprevir/elbasvir group showed a tendency to increase or decrease. Among these molecules, adjustments for multiple testing yielded a significant differential expression at a false discovery rate of less than 5% for only one molecule, hsa-miR-762. Its expression quantile increased after HCV exclusion in all patients who had achieved sustained virological response. Quantitative polymerase chain reaction analysis validated a significant increase in the serum hsa-miR-762 after disappearance of HCV. On the contrary, hsa-miR-762 was decreased in the relapse and breakthrough of HCV in DAA failures. Transfection of hsa-miR-762 into cultured HCV-infected hepatocytes significantly decreased HCV-RNA replication.

Conclusion: These data suggest that hsa-miR-762 is one of the host factors participating in HCV exclusion by DAA therapy.