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

Read SA, Tay ES, Shahidi M, O'Connor KS, Booth DR, George J, Douglas MW - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

AXL knockdown reduces SOCS3 expression but does not affect HCV replication.AXL specific siRNA knockdown reduced AXL expression by approximately 75%, also resulting in a significant reduction of SOCS3 by approximately 40% (A). AXL knockdown was maintained for 24 h after 50 U/ml IFNα stimulation, with a non-significant trend towards reduced SOCS3 expression (B). AXL knockdown did not reduce HCV viral replication following IFNα treatment (red triangles) (* p<0.05, ** p<0.01). Data represents the mean and standard error of two biological replicates performed in duplicate.
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pone.0136227.g003: AXL knockdown reduces SOCS3 expression but does not affect HCV replication.AXL specific siRNA knockdown reduced AXL expression by approximately 75%, also resulting in a significant reduction of SOCS3 by approximately 40% (A). AXL knockdown was maintained for 24 h after 50 U/ml IFNα stimulation, with a non-significant trend towards reduced SOCS3 expression (B). AXL knockdown did not reduce HCV viral replication following IFNα treatment (red triangles) (* p<0.05, ** p<0.01). Data represents the mean and standard error of two biological replicates performed in duplicate.

Mentions: To determine the role of AXL in SOCS3 induction, as well as in the interferon response to HCV infection, AXL was knocked down in JFH1 infected Huh-7 cells using 10nM AXL siRNA. SiRNA mediated knock down of AXL by approximately 75% significantly reduced SOCS3 expression, by approximately 40% (Fig 3A). AXL knockdown was maintained for 24 h after 50 U/ml IFNα treatment, while SOCS3 expression remained down-regulated, albeit modestly (Fig 3B). AXL knockdown had no effect on HCV replication, either at baseline or following IFNα treatment (red triangles), nor did it have any effect on ISG expression (data not shown).


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

Read SA, Tay ES, Shahidi M, O'Connor KS, Booth DR, George J, Douglas MW - PLoS ONE (2015)

AXL knockdown reduces SOCS3 expression but does not affect HCV replication.AXL specific siRNA knockdown reduced AXL expression by approximately 75%, also resulting in a significant reduction of SOCS3 by approximately 40% (A). AXL knockdown was maintained for 24 h after 50 U/ml IFNα stimulation, with a non-significant trend towards reduced SOCS3 expression (B). AXL knockdown did not reduce HCV viral replication following IFNα treatment (red triangles) (* p<0.05, ** p<0.01). Data represents the mean and standard error of two biological replicates performed in duplicate.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4551482&req=5

pone.0136227.g003: AXL knockdown reduces SOCS3 expression but does not affect HCV replication.AXL specific siRNA knockdown reduced AXL expression by approximately 75%, also resulting in a significant reduction of SOCS3 by approximately 40% (A). AXL knockdown was maintained for 24 h after 50 U/ml IFNα stimulation, with a non-significant trend towards reduced SOCS3 expression (B). AXL knockdown did not reduce HCV viral replication following IFNα treatment (red triangles) (* p<0.05, ** p<0.01). Data represents the mean and standard error of two biological replicates performed in duplicate.
Mentions: To determine the role of AXL in SOCS3 induction, as well as in the interferon response to HCV infection, AXL was knocked down in JFH1 infected Huh-7 cells using 10nM AXL siRNA. SiRNA mediated knock down of AXL by approximately 75% significantly reduced SOCS3 expression, by approximately 40% (Fig 3A). AXL knockdown was maintained for 24 h after 50 U/ml IFNα treatment, while SOCS3 expression remained down-regulated, albeit modestly (Fig 3B). AXL knockdown had no effect on HCV replication, either at baseline or following IFNα treatment (red triangles), nor did it have any effect on ISG expression (data not shown).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia.

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.

No MeSH data available.


Related in: MedlinePlus