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Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation
Although oxidative tissue injury often accompanies viral infection, there is little understanding of how it influences virus replication. We show that multiple hepatitis C virus (HCV) genotypes are exquisitely sensitive to oxidative membrane damage, a property distinguishing them from other pathogen...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126843/ https://www.ncbi.nlm.nih.gov/pubmed/25064127 http://dx.doi.org/10.1038/nm.3610 |
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author | Yamane, Daisuke McGivern, David R. Wauthier, Eliane Yi, MinKyung Madden, Victoria J. Welsch, Christoph Antes, Iris Wen, Yahong Chugh, Pauline E. McGee, Charles E. Widman, Douglas G. Misumi, Ichiro Bandyopadhyay, Sibali Kim, Seungtaek Shimakami, Tetsuro Oikawa, Tsunekazu Whitmire, Jason K. Heise, Mark T. Dittmer, Dirk P. Kao, C. Cheng Pitson, Stuart M Merrill, Alfred H. Reid, Lola M. Lemon, Stanley M. |
author_facet | Yamane, Daisuke McGivern, David R. Wauthier, Eliane Yi, MinKyung Madden, Victoria J. Welsch, Christoph Antes, Iris Wen, Yahong Chugh, Pauline E. McGee, Charles E. Widman, Douglas G. Misumi, Ichiro Bandyopadhyay, Sibali Kim, Seungtaek Shimakami, Tetsuro Oikawa, Tsunekazu Whitmire, Jason K. Heise, Mark T. Dittmer, Dirk P. Kao, C. Cheng Pitson, Stuart M Merrill, Alfred H. Reid, Lola M. Lemon, Stanley M. |
author_sort | Yamane, Daisuke |
collection | PubMed |
description | Although oxidative tissue injury often accompanies viral infection, there is little understanding of how it influences virus replication. We show that multiple hepatitis C virus (HCV) genotypes are exquisitely sensitive to oxidative membrane damage, a property distinguishing them from other pathogenic RNA viruses. Lipid peroxidation, regulated in part through sphingosine kinase 2, severely restricts HCV replication in Huh-7 cells and primary human hepatoblasts. Endogenous oxidative membrane damage lowers the 50% effective concentration of direct-acting antivirals, suggesting critical regulation of the conformation of the NS3/4A protease and NS5B polymerase, membrane-bound HCV replicase components. Resistance to lipid peroxidation maps genetically to trans-membrane and membrane-proximal residues within these proteins, and is essential for robust replication in cell culture, as exemplified by the atypical JFH1 strain. Thus, the typical, wild-type HCV replicase is uniquely regulated by lipid peroxidation, providing a novel mechanism for attenuating replication in stressed tissue and possibly facilitating long-term viral persistence. |
format | Online Article Text |
id | pubmed-4126843 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-41268432015-02-01 Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation Yamane, Daisuke McGivern, David R. Wauthier, Eliane Yi, MinKyung Madden, Victoria J. Welsch, Christoph Antes, Iris Wen, Yahong Chugh, Pauline E. McGee, Charles E. Widman, Douglas G. Misumi, Ichiro Bandyopadhyay, Sibali Kim, Seungtaek Shimakami, Tetsuro Oikawa, Tsunekazu Whitmire, Jason K. Heise, Mark T. Dittmer, Dirk P. Kao, C. Cheng Pitson, Stuart M Merrill, Alfred H. Reid, Lola M. Lemon, Stanley M. Nat Med Article Although oxidative tissue injury often accompanies viral infection, there is little understanding of how it influences virus replication. We show that multiple hepatitis C virus (HCV) genotypes are exquisitely sensitive to oxidative membrane damage, a property distinguishing them from other pathogenic RNA viruses. Lipid peroxidation, regulated in part through sphingosine kinase 2, severely restricts HCV replication in Huh-7 cells and primary human hepatoblasts. Endogenous oxidative membrane damage lowers the 50% effective concentration of direct-acting antivirals, suggesting critical regulation of the conformation of the NS3/4A protease and NS5B polymerase, membrane-bound HCV replicase components. Resistance to lipid peroxidation maps genetically to trans-membrane and membrane-proximal residues within these proteins, and is essential for robust replication in cell culture, as exemplified by the atypical JFH1 strain. Thus, the typical, wild-type HCV replicase is uniquely regulated by lipid peroxidation, providing a novel mechanism for attenuating replication in stressed tissue and possibly facilitating long-term viral persistence. 2014-07-27 2014-08 /pmc/articles/PMC4126843/ /pubmed/25064127 http://dx.doi.org/10.1038/nm.3610 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Yamane, Daisuke McGivern, David R. Wauthier, Eliane Yi, MinKyung Madden, Victoria J. Welsch, Christoph Antes, Iris Wen, Yahong Chugh, Pauline E. McGee, Charles E. Widman, Douglas G. Misumi, Ichiro Bandyopadhyay, Sibali Kim, Seungtaek Shimakami, Tetsuro Oikawa, Tsunekazu Whitmire, Jason K. Heise, Mark T. Dittmer, Dirk P. Kao, C. Cheng Pitson, Stuart M Merrill, Alfred H. Reid, Lola M. Lemon, Stanley M. Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation |
title | Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation |
title_full | Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation |
title_fullStr | Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation |
title_full_unstemmed | Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation |
title_short | Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation |
title_sort | regulation of the hepatitis c virus rna replicase by endogenous lipid peroxidation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126843/ https://www.ncbi.nlm.nih.gov/pubmed/25064127 http://dx.doi.org/10.1038/nm.3610 |
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