Read, S. A., Tay, E. S., Shahidi, M., McLauchlan, J. , George, J. and Douglas, M. (2015) The mechanism of interferon refractoriness during hepatitis C virus Infection and Its reversal with a peroxisome proliferator-activated receptor α agonist. Journal of Interferon and Cytokine Research, 35(6), pp. 488-497. (doi: 10.1089/jir.2014.0209) (PMID:25734487)
Full text not currently available from Enlighten.
Abstract
Patients who respond poorly to therapies for hepatitis C virus (HCV) infection display a characteristic phenotype with high basal hepatic interferon-stimulated gene (ISG) expression, but limited induction following interferon (IFN) treatment. The molecular pathways that mediate this refractory state are not known. We examined whether the AMPK activator metformin, the PPARγ agonist pioglitazone, or the PPARα agonist WY-14643 could potentiate IFN responses, reverse IFN refractoriness, and enhance viral eradication in hepatocytes. WY-14643 demonstrated the strongest antiviral synergy with IFN-α and so was tested in the context of chronic IFN activation. Cells rendered refractory to IFN by IFN-α pretreatment were resensitized by WY-14643, as demonstrated by improved STAT1 phosphorylation, promoter activation, and ISG expression. WY-14643 treatment reduced the expression of key negative regulators of IFN signaling: the AXL receptor tyrosine kinase, suppressor of cytokine signaling (SOCS) 1 and 3, which are upregulated in the IFN-refractory state. AXL is a novel regulator of IFN-α signaling that is induced by HCV infection in vitro and which may drive SOCS3 expression. Our data suggests that PPARα agonists could be a useful adjunct treatment for chronic HCV infection by reducing the expression of AXL/SOCS and increasing the sensitivity to IFN.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | McLauchlan, Professor John |
| Authors: | Read, S. A., Tay, E. S., Shahidi, M., McLauchlan, J., George, J., and Douglas, M. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
| Journal Name: | Journal of Interferon and Cytokine Research |
| Publisher: | Mary Ann Liebert, Inc. |
| ISSN: | 1079-9907 |
| ISSN (Online): | 1557-7465 |
University Staff: Request a correction | Enlighten Editors: Update this record
Deposit and Record Details
Deposit and Record Details