title: Hepatitis C Virus Driven AXL Expression Suppresses the Hepatic Type I Interferon Response.
abstract: Treatment of chronic hepatitis C virus (HCV) infection is evolving rapidly with the development of novel direct acting antivirals (DAAs), however viral clearance remains intimately linked to the hepatic innate immune system. Patients demonstrating a high baseline activation of interferon stimulated genes (ISGs), termed interferon refractoriness, are less likely to mount a strong antiviral response and achieve viral clearance when placed on treatment. As a result, suppressor of cytokine signalling (SOCS) 3 and other regulators of the IFN response have been identified as key candidates for the IFN refractory phenotype due to their regulatory role on the IFN response. AXL is a receptor tyrosine kinase that has been identified as a key regulator of interferon (IFN) signalling in myeloid cells of the immune system, but has not been examined in the context of chronic HCV infection. Here, we show that AXL is up-regulated following HCV infection, both in vitro and in vivo and is likely induced by type I/III IFNs and inflammatory signalling pathways. AXL inhibited type IFNα mediated ISG expression resulting in a decrease in its antiviral efficacy against HCV in vitro. Furthermore, patients possessing the favourable IFNL3 rs12979860 genotype associated with treatment response, showed lower AXL expression in the liver and a stronger induction of AXL in the blood, following their first dose of IFN. Together, these data suggest that elevated AXL expression in the liver may mediate an IFN-refractory phenotype characteristic of patients possessing the unfavourable rs12979860 genotype, which is associated with lower rates of viral clearance.
authors: Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia.
authors: Scott A
authors: SA
authors: Read
authors: Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia.
authors: Enoch S
authors: ES
authors: Tay
authors: Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia.
authors: Mahsa
authors: M
authors: Shahidi
authors: Centre for Immunology and Allergy Research, University of Sydney at Westmead Hospital, Westmead, Australia.
authors: Kate S
authors: KS
authors: O'Connor
authors: Centre for Immunology and Allergy Research, University of Sydney at Westmead Hospital, Westmead, Australia.
authors: David R
authors: DR
authors: Booth
authors: Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia.
authors: Jacob
authors: J
authors: George
authors: Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia; Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, Australia.
authors: Mark W
authors: MW
authors: Douglas
mesh_terms: D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase; D000095022:Interferon Lambda
chemical_list: D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000094963:Axl Receptor Tyrosine Kinase; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C106644:SOCS3 protein, human