Disruption of Hepatitis C Virus RNA Replication through Inhibition of Host Protein Geranylgeranylation

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...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2003-12, Vol.100 (26), p.15865-15870
Main Authors: Ye, Jin, Wang, Chunfu, Sumpter, Rhea, Brown, Michael S., Goldstein, Joseph L., Gale, Michael
Format: Article
Language:English
Subjects:
Antibodies
Antiviral Agents - pharmacology
B lymphocytes
Base Sequence
Biological Sciences
Cell culture techniques
Cell Line
Cell lines
Cellular immunity
Cultured cells
DNA
DNA Primers
farnesol
Genome, Viral
geranylgeranylation
Hepacivirus - drug effects
Hepacivirus - genetics
Hepatitis C virus
Humans
Kinetics
lovastatin
Lovastatin - pharmacology
Open Reading Frames
protein geranylgeranyl transferase
Replicon
RNA
RNA, Viral - genetics
Viral Proteins - genetics
Viral RNA
Virus Replication - genetics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2237238100