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Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection
- Source :
- Gastroenterology. 131(5)
- Publication Year :
- 2006
-
Abstract
- Background & Aims: Modulation of the host innate immune response is an attractive means of inhibiting hepatitis C virus (HCV) replication. Having previously determined that expression of the interferon-sensitive gene (ISG)15 protease USP18 is increased in the liver biopsy specimens of patients who do not respond to interferon (IFN)-alfa therapy, we hypothesized that USP18 might hinder the ability of IFN to inhibit HCV replication. Methods: The role of USP18 in IFN antiviral activity was examined using an in vitro model of HCV replication that reproduces the full viral life cycle. USP18 was silenced specifically using small inhibitory RNAs (siRNAs), and the dose response of HCV replication and infectious virus production to IFN-alfa was measured. Results: The siRNA knockdown of USP18 in human cells consistently potentiated the ability of IFN to inhibit HCV-RNA replication and infectious virus particle production by a factor of 1–2 log 10 . USP18 knockdown also resulted in a number of cellular changes consistent with increased sensitivity to IFN. Decreasing USP18 expression led to increased cellular protein ISGylation in response to exogenous IFN-alfa, prolonged tyrosine phosphorylation of signal transducer and activation of transcription (STAT1), and a general enhancement of IFN-stimulated gene expression. Conclusions: These data suggest that USP18 modulates the anti-HCV type I IFN response, and is a possible therapeutic target for the treatment of HCV infection.
- Subjects :
- Small interfering RNA
Hepatitis C virus
medicine.disease_cause
Antiviral Agents
Cell Line
Viral life cycle
Interferon
Endopeptidases
medicine
Gene silencing
Humans
STAT1
Gene Silencing
Ubiquitins
Gene knockdown
Hepatology
biology
Gastroenterology
virus diseases
Interferon-alpha
Janus Kinase 1
Virology
Hepatitis C
digestive system diseases
STAT1 Transcription Factor
biology.protein
Cytokines
Signal transduction
Ubiquitin Thiolesterase
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 00165085
- Volume :
- 131
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Gastroenterology
- Accession number :
- edsair.doi.dedup.....2ac7f6bb7943cd0eea7c1906f0cfe57e