Site‐specific mutation of the interferon sensitivity‐determining region (ISDR) modulates hepatitis C virus replication
- 26 June 2006
- journal article
- Published by Wiley in Journal of Viral Hepatitis
- Vol. 13 (9), 582-590
- https://doi.org/10.1111/j.1365-2893.2006.00739.x
Abstract
Summary. The number of amino acid substitutions in the interferon sensitivity‐determining region (ISDR) in the nonstructural 5A (NS5A) gene of hepatitis C virus (HCV) is closely associated with the interferon (IFN) response and viral load. Several HCV replicon‐based studies have reported that ISDR sequences had an influence on viral replication in vitro. However, it is unclear as to how different ISDR sequences affect HCV replication. Various clinically observed ISDR sequences were introduced into HCV replicons and their contribution to viral replication was investigated using a colony formation assay and/or a transient replication assay. A mapping study of the ISDR was performed to identify the amino acid positions that critically affect replication. While no colonies were formed in the colony formation assay using HCV replicons with few mutations (0, 1 and 3) in the ISDR, numerous colonies (>200) appeared when using constructs with six mutations. Introduction of various distinct ISDR sequences with multiple mutations resulted in replication enhancement in transient assays. A mapping study identified several specific sites in the ISDR that critically affected replication, including codon 2209 which, in patients, was closely associated with a strong response to IFN. ISDR sequences associated with a clinical IFN response and viral load modulated the replication of HCV replicons, suggesting the importance of the ISDR sequence in HCV infection.Keywords
This publication has 41 references indexed in Scilit:
- Regulation of Hepatitis C Virus Replication by Interferon Regulatory Factor 1Journal of Virology, 2004
- Introduction of NS5A mutations enables subgenomic HCV replicon derived from chimpanzee-infectious HC-J4 isolate to replicate efficiently in Huh-7 cellsJournal of Viral Hepatitis, 2004
- Hepatitis C pathogenesis: Mechanisms of viral clearance and liver injuryLiver Transplantation, 2003
- HCV NS5A interacts with p53 and inhibits p53-mediated apoptosisOncogene, 2002
- Number and Position of Mutations in the Interferon (IFN) Sensitivity–Determining Region of the Gene for Nonstructural Protein 5A Correlate with IFN Efficacy in Hepatitis C Virus Genotype 1b InfectionThe Journal of Infectious Diseases, 2001
- Efficient Initiation of HCV RNA Replication in Cell CultureScience, 2000
- Nonstructural Protein 5A of Hepatitis C Virus Inhibits the Function of Karyopherin β3Journal of Virology, 2000
- Hepatitis C virus NS5A protein protects against TNF-α mediated apoptotic cell deathVirus Research, 2000
- Hepatitis C Virus NS5A Protein Modulates Transcription through a Novel Cellular Transcription Factor SRCAPPublished by Elsevier BV ,2000
- Repression of the PKR protein kinase by the hepatitis C virus NS5A protein: a potential mechanism of interferon resistanceClinical and Diagnostic Virology, 1998