Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling.

Published

Journal Article

Hepatitis C virus (HCV) infects 200 million people globally, and 60-80% of cases persist as a chronic infection that will progress to cirrhosis and liver cancer in 2-10% of patients. We recently demonstrated that HCV induces aberrant expression of two host microRNAs (miRNAs), miR-208b and miR-499a-5p, encoded by myosin genes in infected hepatocytes. These miRNAs, along with AU-rich-element-mediated decay, suppress IFNL2 and IFNL3, members of the type III interferon (IFN) gene family, to support viral persistence. In this study, we show that miR-208b and miR-499a-5p also dampen type I IFN signaling in HCV-infected hepatocytes by directly down-regulating expression of the type I IFN receptor chain, IFNAR1. Inhibition of these miRNAs by using miRNA inhibitors during HCV infection increased expression of IFNAR1. Additionally, inhibition rescued the antiviral response to exogenous type I IFN, as measured by a marked increase in IFN-stimulated genes and a decrease in HCV load. Treatment of HCV-infected hepatocytes with type I IFN increased expression of myosins over HCV infection alone. Since these miRNAs can suppress type III IFN family members, these data collectively define a novel cross-regulation between type I and III IFNs during HCV infection.

Full Text

Duke Authors

Cited Authors

  • Jarret, A; McFarland, AP; Horner, SM; Kell, A; Schwerk, J; Hong, M; Badil, S; Joslyn, RC; Baker, DP; Carrington, M; Hagedorn, CH; Gale, M; Savan, R

Published Date

  • December 2016

Published In

Volume / Issue

  • 22 / 12

Start / End Page

  • 1475 - 1481

PubMed ID

  • 27841874

Pubmed Central ID

  • 27841874

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

Digital Object Identifier (DOI)

  • 10.1038/nm.4211

Language

  • eng

Conference Location

  • United States