Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism

Abstract Direct acting antivirals against hepatitis C virus (HCV) have markedly improved cure rates in the past few years. However, they are expensive, with only few targeting host cell factors, and affecting virus assembly and release. Huh7.5 cells infected with a JFH-1 clone of HCV were treated wi...

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Autores principales:	Mohammed A. Sarhan, Mohamed S. Abdel-Hakeem, Andrew L. Mason, D. Lorne Tyrrell, Michael Houghton
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f51753bd6d524097863f80264b9246e4
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spelling	oai:doaj.org-article:f51753bd6d524097863f80264b9246e42021-12-02T11:41:21ZGlycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism10.1038/s41598-017-02648-62045-2322https://doaj.org/article/f51753bd6d524097863f80264b9246e42017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02648-6https://doaj.org/toc/2045-2322Abstract Direct acting antivirals against hepatitis C virus (HCV) have markedly improved cure rates in the past few years. However, they are expensive, with only few targeting host cell factors, and affecting virus assembly and release. Huh7.5 cells infected with a JFH-1 clone of HCV were treated with two different glycogen synthase kinase (GSK3)-β inhibitors; AR-A014418 and lithium chloride. Intra- and extracellular HCV virions and specific infectivity was determined using real-time RT-PCR and TCID50, and changes in lipid production were identified by enzyme-linked immunoassay and mass spectrometry analyses. Similarly, effect on two HCV replicon cells were identified by the luciferase activity. Although there was limited effect on virus replication in Huh7.5 cells and replicons, Huh7.5 cells treated with GSK3β inhibitors produced significantly less viral particles in comparison to untreated cells. In addition, the treated cells synthesized significantly lower amounts of ApoB and trapped the ApoE lipoproteins in the cells. In conclusion, our study suggests that GSK3β plays a pivotal role in HCV virion assembly and release mediated in part through inhibition of apolipoprotein synthesis.Mohammed A. SarhanMohamed S. Abdel-HakeemAndrew L. MasonD. Lorne TyrrellMichael HoughtonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mohammed A. Sarhan Mohamed S. Abdel-Hakeem Andrew L. Mason D. Lorne Tyrrell Michael Houghton Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism
description	Abstract Direct acting antivirals against hepatitis C virus (HCV) have markedly improved cure rates in the past few years. However, they are expensive, with only few targeting host cell factors, and affecting virus assembly and release. Huh7.5 cells infected with a JFH-1 clone of HCV were treated with two different glycogen synthase kinase (GSK3)-β inhibitors; AR-A014418 and lithium chloride. Intra- and extracellular HCV virions and specific infectivity was determined using real-time RT-PCR and TCID50, and changes in lipid production were identified by enzyme-linked immunoassay and mass spectrometry analyses. Similarly, effect on two HCV replicon cells were identified by the luciferase activity. Although there was limited effect on virus replication in Huh7.5 cells and replicons, Huh7.5 cells treated with GSK3β inhibitors produced significantly less viral particles in comparison to untreated cells. In addition, the treated cells synthesized significantly lower amounts of ApoB and trapped the ApoE lipoproteins in the cells. In conclusion, our study suggests that GSK3β plays a pivotal role in HCV virion assembly and release mediated in part through inhibition of apolipoprotein synthesis.
format	article
author	Mohammed A. Sarhan Mohamed S. Abdel-Hakeem Andrew L. Mason D. Lorne Tyrrell Michael Houghton
author_facet	Mohammed A. Sarhan Mohamed S. Abdel-Hakeem Andrew L. Mason D. Lorne Tyrrell Michael Houghton
author_sort	Mohammed A. Sarhan
title	Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism
title_short	Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism
title_full	Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism
title_fullStr	Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism
title_full_unstemmed	Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism
title_sort	glycogen synthase kinase 3β inhibitors prevent hepatitis c virus release/assembly through perturbation of lipid metabolism
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f51753bd6d524097863f80264b9246e4
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Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism

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