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

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 patients1,2,3. 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 hepatocytes4. 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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Figure 1: Inhibition of miR-208b and miR-499a-5p during HCV infection improves hepatocyte response to IFN-β by increasing IFNAR1.
Figure 2: myomiR overexpression reduces IFNAR1 expression, dampening downstream Jak-STAT signaling and induction of ISGs.
Figure 3: Myosin induction is dependent on viral replication.
Figure 4: Type I but not type III IFNs amplify myosin expression.

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Acknowledgements

This project was funded partly by the Department of Immunology, Royalty Research Fund, University of Washington (R.S.) and by National Institutes of Health grants AI108765 (R.S.), AI060389, AI40035 (M.G.), and CA148068 (C.H.H.). This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E (M.C.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, and Center for Cancer Research. We thank S. Lemon and C. Rice for generously providing the H77D and JC1 viral strains, respectively; Y. Loo, S. Ozarkar and L. Kropp for experimental support; and C. Lim, A. Stone and the Gale and Savan labs for the discussions and feedback on the manuscript.

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Contributions

A.J., A.P.M., and R.S. designed the study. A.J. analyzed the data and wrote the manuscript. R.S. directed the study. A.J., A.P.M., J.S., R.C.J. and M.H. performed experiments. A.J., S.M.H., A.K. and S.B. performed infections and flow cytometry preparations. D.P.B. provided reagents and reviewed the manuscript. D.P.B. was an employee of Biogen Idec and owns company stock. C.H.H., M.C. and M.G. provided intellectual input.

Corresponding author

Correspondence to Ram Savan.

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Darren P Baker is an employee of Biogen Idec and an owner of Biogen Idec stock.

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Jarret, A., McFarland, A., Horner, S. et al. Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling. Nat Med 22, 1475–1481 (2016). https://doi.org/10.1038/nm.4211

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