4.8 Article

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

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NATURE MEDICINE
卷 20, 期 8, 页码 927-935

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NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3610

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资金

  1. US National Institutes of Health [RO1-AI095690, RO1-CA164029, U19-AI109965, R21-CA182322, R01-AI075090, RO1-AI073335, RO1-DE018304, F32-AI094941, U54-GM069338]
  2. National Cancer Institute [P30-CA016086]
  3. University of North Carolina Cancer Research Fund
  4. Deutsche Forschungsgemeinschaft [WE 4388/3-1, WE 4388/6-1]
  5. CIPSM Cluster of Excellence

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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.

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