The Mechanism of Interferon Refractoriness During Hepatitis C Virus Infection and Its Reversal with a Peroxisome Proliferator-Activated Receptor α Agonist.
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.
1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia .
Scott A
SA
Read
1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia .
Enoch S
ES
Tay
1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia .
Mahsa
M
Shahidi
2 MRC-University of Glasgow Centre for Virus Research , Glasgow, United Kingdom .
John
J
McLauchlan
1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia .
Jacob
J
George
1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia .|2 MRC-University of Glasgow Centre for Virus Research , Glasgow, United Kingdom .|3 Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital , Westmead, Australia .
Mark W
MW
Douglas
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016174:Hepacivirus / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D000094963:Axl Receptor Tyrosine Kinase
D016898:Interferon-alpha; D047493:PPAR alpha; D047495:PPAR gamma; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D045162:Thiazolidinediones; C006253:pirinixic acid; D008687:Metformin; D008156:Luciferases; D020794:Receptor Protein-Tyrosine Kinases; D055372:AMP-Activated Protein Kinases; D000077205:Pioglitazone; D000094963:Axl Receptor Tyrosine Kinase