Hepatitis C virus hijacks host microRNAs to dampen antiviral interferon signaling

Abstract

Abstract Hepatitis C virus (HCV) is a hepatotrophic ssRNA virus that infects over 160 million people worldwide and 60–80% of HCV cases will persist to a chronic infection, a serious risk factor for liver diseases. We recently discovered that HCV infection of hepatocytes induces expression of two microRNAs (miRNAs), miR-208b and miR-499a-5p. We found that these miRNA are capable of decreasing IFNL2 and IFNL3 expression to aid viral replication. Here we show that miR-208b and miR-499a-5p block type I IFN signaling in HCV-infected hepatocytes by directly targeting and down regulating the interferon (alpha, beta and omega) receptor 1 (IFNAR1) mRNA. Inhibition of these miRNAs during HCV infection of hepatoma cells rescued expression of IFNAR1 and improved the antiviral response to exogenous type I IFN. Interestingly, prolonged treatment of HCV-infected hepatocytes with type I IFNs led to a synergistic induction of miR-208b and miR-499a-5p, suggesting a critical role for type I IFN in the regulation of these miRNAs. As miR-208b and miR-499a-5p can target and suppress the IFNL3 risk allele, it is possible that increased miRNA expression following IFN treatment may partly explain why this genotype associates with poor response to IFN based therapies. Collectively these data define a new role for miR-208b and miR-499a-5p as HCV-induced suppressors of type I IFN signaling and add to our understanding of HCV immune evading strategies.