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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.

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


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.

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