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Nat Med. 2014 Aug;20(8):927-35. doi: 10.1038/nm.3610. Epub 2014 Jul 27.

Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation.

Author information

1
1] Department of Medicine, Division of Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
2
1] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
3
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
4
Department of Pathology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5
Department of Internal Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany.
6
Center for Integrated Protein Science Munich (CIPSM), Department of Life Sciences, Technical University Munich, Freising, Germany.
7
Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA.
8
1] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
9
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
10
Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
11
1] School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA. [2] Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA.
12
1] Department of Medicine, Division of Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [3] Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
13
1] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [3] Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
14
1] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
15
Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
16
1] Department of Medicine, Division of Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [3] Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Abstract

Oxidative tissue injury often accompanies viral infection, yet 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 in vitro, suggesting critical regulation of the conformation of the NS3-4A protease and the NS5B polymerase, membrane-bound HCV replicase components. Resistance to lipid peroxidation maps genetically to transmembrane and membrane-proximal residues within these proteins and is essential for robust replication in cell culture, as exemplified by the atypical JFH1 strain of HCV. Thus, the typical, wild-type HCV replicase is uniquely regulated by lipid peroxidation, providing a mechanism for attenuating replication in stressed tissue and possibly facilitating long-term viral persistence.

PMID:
25064127
PMCID:
PMC4126843
DOI:
10.1038/nm.3610
[Indexed for MEDLINE]
Free PMC Article

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