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

Nature Medicine volume 22, pages 1475–1481 (2016)Cite this article

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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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References

  1. El-Serag, H.B. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142, 1264–1273.e1 (2012).

    PubMed  PubMed Central  Google Scholar 

  2. Lavanchy, D. Evolving epidemiology of hepatitis C virus. Clin. Microbiol. Infect. 17, 107–115 (2011).

    CAS  PubMed  Google Scholar 

  3. Shepard, C.W., Finelli, L. & Alter, M.J. Global epidemiology of hepatitis C virus infection. Lancet Infect. Dis. 5, 558–567 (2005).

    PubMed  Google Scholar 

  4. McFarland, A.P. et al. The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs. Nat. Immunol. 15, 72–79 (2014).

    CAS  PubMed  Google Scholar 

  5. Liang, T.J. & Ghany, M.G. Current and future therapies for hepatitis C virus infection. N. Engl. J. Med. 368, 1907–1917 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Manns, M.P. & von Hahn, T. Novel therapies for hepatitis C—one pill fits all? Nat. Rev. Drug Discov. 12, 595–610 (2013).

    CAS  PubMed  Google Scholar 

  7. Ghany, M.G., Nelson, D.R., Strader, D.B., Thomas, D.L. & Seeff, L.B. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 54, 1433–1444 (2011).

    PubMed  PubMed Central  Google Scholar 

  8. Lawitz, E. et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N. Engl. J. Med. 368, 1878–1887 (2013).

    CAS  PubMed  Google Scholar 

  9. Afdhal, N. et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N. Engl. J. Med. 370, 1889–1898 (2014).

    PubMed  Google Scholar 

  10. Pawlotsky, J.M. New hepatitis C therapies: the toolbox, strategies, and challenges. Gastroenterology 146, 1176–1192 (2014).

    CAS  PubMed  Google Scholar 

  11. Jayasekera, C.R., Barry, M., Roberts, L.R. & Nguyen, M.H. Treating hepatitis C in lower-income countries. N. Engl. J. Med. 370, 1869–1871 (2014).

    CAS  PubMed  Google Scholar 

  12. Pearlman, B.L. Protease inhibitors for the treatment of chronic hepatitis C genotype-1 infection: the new standard of care. Lancet Infect. Dis. 12, 717–728 (2012).

    CAS  PubMed  Google Scholar 

  13. Schinazi, R., Halfon, P., Marcellin, P. & Asselah, T. HCV direct-acting antiviral agents: the best interferon-free combinations. Liver Int. 34 (Suppl. 1), 69–78 (2014).

    CAS  PubMed  Google Scholar 

  14. Rauch, A. et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 138, 1338–1345, 1345.e1–1345.e7 (2010).

    CAS  PubMed  Google Scholar 

  15. Thomas, D.L. et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461, 798–801 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ge, D. et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399–401 (2009).

    CAS  PubMed  Google Scholar 

  17. Suppiah, V. et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat. Genet. 41, 1100–1104 (2009).

    CAS  PubMed  Google Scholar 

  18. Tanaka, Y. et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat. Genet. 41, 1105–1109 (2009).

    CAS  PubMed  Google Scholar 

  19. de Castellarnau, M. et al. Deciphering the interleukin 28B variants that better predict response to pegylated interferon-α and ribavirin therapy in HCV/HIV-1 coinfected patients. PLoS One 7, e31016 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. di Iulio, J. et al. Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance. Hepatology 53, 1446–1454 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Pedergnana, V. et al. Analysis of IL28B variants in an Egyptian population defines the 20 kilobases minimal region involved in spontaneous clearance of hepatitis C virus. PLoS One 7, e38578 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Prokunina-Olsson, L. et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat. Genet. 45, 164–171 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sheahan, T. et al. Interferon lambda alleles predict innate antiviral immune responses and hepatitis C virus permissiveness. Cell Host Microbe 15, 190–202 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Honda, M. et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology 139, 499–509 (2010).

    CAS  PubMed  Google Scholar 

  25. He, X.S. et al. Global transcriptional response to interferon is a determinant of HCV treatment outcome and is modified by race. Hepatology 44, 352–359 (2006).

    CAS  PubMed  Google Scholar 

  26. Welzel, T.M. et al. Variants in interferon-alpha pathway genes and response to pegylated interferon-Alpha2a plus ribavirin for treatment of chronic hepatitis C virus infection in the hepatitis C antiviral long-term treatment against cirrhosis trial. Hepatology 49, 1847–1858 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Fukuda, R. et al. Expression of interferon-alpha receptor mRNA in the liver in chronic liver diseases associated with hepatitis C virus: relation to effectiveness of interferon therapy. J. Gastroenterol. 31, 806–811 (1996).

    CAS  PubMed  Google Scholar 

  28. Fukuda, R. et al. Effectiveness of interferon-alpha therapy in chronic hepatitis C is associated with the amount of interferon-alpha receptor mRNA in the liver. J. Hepatol. 26, 455–461 (1997).

    CAS  PubMed  Google Scholar 

  29. Mathai, J. et al. IFN-alpha receptor mRNA expression in a United States sample with predominantly genotype 1a/I chronic hepatitis C liver biopsies correlates with response to IFN therapy. J. Interferon Cytokine Res. 19, 1011–1018 (1999).

    CAS  PubMed  Google Scholar 

  30. Morita, K. et al. Expression of interferon receptor genes in the liver as a predictor of interferon response in patients with chronic hepatitis C. J. Med. Virol. 58, 359–365 (1999).

    CAS  PubMed  Google Scholar 

  31. Morita, K. et al. Expression of interferon receptor genes (IFNAR1 and IFNAR2 mRNA) in the liver may predict outcome after interferon therapy in patients with chronic genotype 2a or 2b hepatitis C virus infection. J. Clin. Gastroenterol. 26, 135–140 (1998).

    CAS  PubMed  Google Scholar 

  32. Liu, J. et al. Virus-induced unfolded protein response attenuates antiviral defenses via phosphorylation-dependent degradation of the type I interferon receptor. Cell Host Microbe 5, 72–83 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Chandra, P.K. et al. HCV infection selectively impairs type I but not type III IFN signaling. Am. J. Pathos. 184, 214–229 (2014).

    CAS  Google Scholar 

  34. Schwerk, J., Jarret, A.P., Joslyn, R.C. & Savan, R. Landscape of post-transcriptional gene regulation during hepatitis C virus infection. Curr. Opin. Virol. 12, 75–84 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. van Rooij, E. et al. A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. Dev. Cell 17, 662–673 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu, S. et al. Measuring antiviral activity of benzimidazole molecules that alter IRES RNA structure with an infectious hepatitis C virus chimera expressing Renilla luciferase. Antiviral Res. 89, 54–63 (2011).

    CAS  PubMed  Google Scholar 

  37. Eldrup, A.B. et al. Structure-activity relationship of heterobase-modified 2′-C-methyl ribonucleosides as inhibitors of hepatitis C virus RNA replication. J. Med. Chem. 47, 5284–5297 (2004).

    CAS  PubMed  Google Scholar 

  38. Ank, N. et al. Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J. Virol. 80, 4501–4509 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zeuzem, S. et al. Pegylated Interferon-Lambda (PEGIFN-L) shows superior viral response with improved safety and toleraility versus PEGIFNa-2A in HCV patients (G1/2/3/4): Emerage phase IIB through week 12. J. Hepatol. 54, S538–S539 (2011).

    Google Scholar 

  40. Muir, A. J. et al. A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection. J. Hepatol. 61, 1238–1246 (2014).

    CAS  PubMed  Google Scholar 

  41. Gonzalez, G., Pfannes, L., Brazas, R. & Striker, R. Selection of an optimal RNA transfection reagent and comparison to electroporation for the delivery of viral RNA. J. Virol. Methods 145, 14–21 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

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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.

Author information

Author notes

  1. Adelle P McFarland, Stacy M Horner & Darren P Baker

    Present address: Present addresses: Molecular and Cellular Biology Program, Department of Microbiology, University of Washington, Seattle, Washington, USA (A.P.M.); Department of Molecular Genetics and Microbiology, Center for Virology, Duke University Medical Center, Durham, North Carolina, USA (S.M.H.); Sanofi-Genzyme, Cambridge, Massachusetts, USA (D.P.B.).,

  2. Adelle P McFarland and Stacy M Horner: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, University of Washington, Seattle, Washington, USA

    Abigail Jarret, Adelle P McFarland, Stacy M Horner, Alison Kell, Johannes Schwerk, MeeAe Hong, Samantha Badil, Rochelle C Joslyn, Michael Gale Jr & Ram Savan

  2. Biogen-Idec Inc., Cambridge, Massachusetts, USA

    Darren P Baker

  3. Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research–Frederick, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA

    Mary Carrington

  4. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA

    Mary Carrington

  5. Department of Medicine and Genetics Program, University of Arkansas for Medical Sciences, and The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA

    Curt H Hagedorn

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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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Competing interests

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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