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002 MODULATING INTERFERON SENSITIVITY IN HEPATITIS C VIRUS INFECTION: THE ROLE OF THE ISG15/USP18 PATHWAY L Chen1,2, G Randall3,6, J Sun1, J Heathcote4, C Rice3, A Edwards1,2, I McGilvray5 BACKGROUND AND AIMS: Chronic Hepatitis C virus (HCV) infection is one of the most common causes of liver disease worldwide. The current standard of care, combination therapy with pegylated interferon-alfa/ribavarin (PegIFN/Rib), eliminates the infection in only 50% of patients: there is an urgent need for a more effective treatments. Having previously determined, by cDNA microarray, that expression of the ISG15 protease USP18 is increased in the pre-treatment liver biopsies of patients who do not respond to PegIFN/Rib therapy (Chen et al, Gastroenterology 2005), we hypothesized that USP18 might hinder the ability of IFN to inhibit HCV replication and the newly defined ISG15/USP18 pathway may be involved in virus resistance to IFN.
1Banting and Best Department of Medical Research, 2Departments of Molecular and Medical Genetics, 4Medicine, 5Surgery, University of Toronto, Toronto, Ontario; 3Center for the Study of Hepatitis C, Rockefeller University; 6Department of Microbiology, University of Chicago, Chicago, Illinois, USA
METHODS: The role of USP18 in interferon antiviral activity was examined using an in vitro model of HCV replication that reproduces the full viral life cycle. USP18 expression was inhibited with small interfering RNAs (siRNAs), and the dose response of HCV replication and infectious virus production to interferon-alpha was measured.
RESULTS: The siRNA knockdown of USP18 in human cells consistently potentiated the ability of interferon to inhibit HCV RNA replication and infectious virus particle production by a factor of 1-2 log10. USP18 knockdown also resulted in a number of cellular changes consistent with increased sensitivity to interferon. Decreasing USP18 expression led to increased cellular protein ISGylation in response to exogenous IFNalpha, prolonged STAT1 activation and a general enhancement of interferon-stimulated gene expression. Other molecular mechanisms involved in this potentiating effect of IFN against HCV infection is under further investigation.
CONCLUSIONS: These data suggest that USP18 modulates the anti-HCV type I IFN response, and is a potential therapeutic target for the treatment of HCV infection.