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Nat Med. 2016 Dec;22(12):1475-1481. doi: 10.1038/nm.4211. Epub 2016 Nov 14.

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

Author information

1
Department of Immunology, University of Washington, Seattle, Washington, USA.
2
Biogen-Idec Inc., Cambridge, Massachusetts, USA.
3
Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research-Frederick, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
4
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.
5
Department of Medicine and Genetics Program, University of Arkansas for Medical Sciences, and The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA.

Abstract

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.

PMID:
27841874
PMCID:
PMC5551900
DOI:
10.1038/nm.4211
[Indexed for MEDLINE]
Free PMC Article

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