title: Lipid metabolite profiling identifies desmosterol metabolism as a new antiviral target for hepatitis C virus.
abstract: Hepatitis C virus (HCV) infection has been clinically associated with serum lipid abnormalities, yet our understanding of the effects of HCV on host lipid metabolism and conversely the function of individual lipids in HCV replication remains incomplete. Using liquid chromatography-mass spectrometry metabolite profiling of the HCV JFH1 cell culture infection model, we identified a significant steady-state accumulation of desmosterol, an immediate precursor to cholesterol. Pharmacological inhibition or RNAi-mediated depletion of DHCR7 significantly reduced steady-state HCV protein expression and viral genomic RNA. Moreover, this effect was reversed when cultures were supplemented with exogenous desmosterol. Together, these observations suggest an intimate connection between HCV replication and desmosterol homeostasis and that the enzymes responsible for synthesis of desmosterol may be novel targets for antiviral design.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Rodgers
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Villareal
authors.forename: Esperance A
authors.initials: EA
authors.lastname: Schaefer
authors.forename: Lee F
authors.initials: LF
authors.lastname: Peng
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Corey
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.forename: Priscilla L
authors.initials: PL
authors.lastname: Yang
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D003897:Desmosterol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D003897:Desmosterol