2. Academic Validation
  3. Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation

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

  • Nat Med. 2014 Aug;20(8):927-35. doi: 10.1038/nm.3610.
Daisuke Yamane 1,  David R McGivern 1,  Eliane Wauthier 2,  MinKyung Yi 3,  Victoria J Madden 4,  Christoph Welsch 5,  Iris Antes 6,  Yahong Wen 7,  Pauline E Chugh 8,  Charles E McGee 9,  Douglas G Widman 10,  Ichiro Misumi 9,  Sibali Bandyopadhyay 11,  Seungtaek Kim 12,  Tetsuro Shimakami 1,  Tsunekazu Oikawa 2,  Jason K Whitmire 13,  Mark T Heise 14,  Dirk P Dittmer 8,  C Cheng Kao 7,  Stuart M Pitson 15,  Alfred H Merrill Jr 11,  Lola M Reid 2,  Stanley M Lemon 16
Affiliations

Affiliations

  • 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.
PMID: 25064127 DOI: 10.1038/nm.3610
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15005
    99.97%, HCV Inhibitor
    HCV