title: Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation.
abstract: Hepatitis C virus (HCV) RNA replication depends on viral protein association with intracellular membranes, but the influence of membrane composition on viral replication is unclear. We report that HCV RNA replication and assembly of the viral replication complex require geranylgeranylation of one or more host proteins. In cultured hepatoma cells, HCV RNA replication was disrupted by treatment with lovastatin, an inhibitor of 3-hydroxy-3-methyglutaryl CoA reductase, or with an inhibitor of protein geranylgeranyl transferase I, each of which induced the dissolution of the HCV replication complex. Viral replication was not affected by treatment of cells with an inhibitor of farnesyl transferase. When added to lovastatin-treated cells, geranylgeraniol, but not farnesol, restored replication complex assembly and viral replication. Inasmuch as the HCV genome does not encode a canonical geranylgeranylated protein, the data suggest the involvement of a geranylgeranylated host protein in HCV replication. Inhibition of its geranylgeranylation affords a therapeutic strategy for treatment of HCV infection.
authors.affiliation: Departments of Molecular Genetics and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Ye
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wang
authors.forename: Rhea
authors.initials: R
authors.lastname: Sumpter
authors.forename: Michael S
authors.initials: MS
authors.lastname: Brown
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Goldstein
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D016679:Genome, Viral; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D008148:Lovastatin / Q000494:pharmacology; D016366:Open Reading Frames; D012367:RNA, Viral / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D017931:DNA Primers; D012367:RNA, Viral; D014764:Viral Proteins; D008148:Lovastatin