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Hepatitis C Virus Driven AXL Expression Suppresses the Hepatic Type I Interferon Response

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...

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Autores principales: Read, Scott A., Tay, Enoch S., Shahidi, Mahsa, O’Connor, Kate S., Booth, David R., George, Jacob, Douglas, Mark W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551482/
https://www.ncbi.nlm.nih.gov/pubmed/26313459
http://dx.doi.org/10.1371/journal.pone.0136227
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author Read, Scott A.
Tay, Enoch S.
Shahidi, Mahsa
O’Connor, Kate S.
Booth, David R.
George, Jacob
Douglas, Mark W.
author_facet Read, Scott A.
Tay, Enoch S.
Shahidi, Mahsa
O’Connor, Kate S.
Booth, David R.
George, Jacob
Douglas, Mark W.
author_sort Read, Scott A.
collection PubMed
description 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.
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spelling pubmed-45514822015-09-01 Hepatitis C Virus Driven AXL Expression Suppresses the Hepatic Type I Interferon Response Read, Scott A. Tay, Enoch S. Shahidi, Mahsa O’Connor, Kate S. Booth, David R. George, Jacob Douglas, Mark W. PLoS One Research Article 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. Public Library of Science 2015-08-27 /pmc/articles/PMC4551482/ /pubmed/26313459 http://dx.doi.org/10.1371/journal.pone.0136227 Text en © 2015 Read et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Read, Scott A.
Tay, Enoch S.
Shahidi, Mahsa
O’Connor, Kate S.
Booth, David R.
George, Jacob
Douglas, Mark W.
Hepatitis C Virus Driven AXL Expression Suppresses the Hepatic Type I Interferon Response
title Hepatitis C Virus Driven AXL Expression Suppresses the Hepatic Type I Interferon Response
title_full Hepatitis C Virus Driven AXL Expression Suppresses the Hepatic Type I Interferon Response
title_fullStr Hepatitis C Virus Driven AXL Expression Suppresses the Hepatic Type I Interferon Response
title_full_unstemmed Hepatitis C Virus Driven AXL Expression Suppresses the Hepatic Type I Interferon Response
title_short Hepatitis C Virus Driven AXL Expression Suppresses the Hepatic Type I Interferon Response
title_sort hepatitis c virus driven axl expression suppresses the hepatic type i interferon response
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551482/
https://www.ncbi.nlm.nih.gov/pubmed/26313459
http://dx.doi.org/10.1371/journal.pone.0136227
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