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ISG15, a ubiquitin-like interferon stimulated gene, promotes Hepatitis C Virus production in vitro: Implications for chronic infection and response to treatment

University of Toronto

¹ E-mail: ian.mcgilvray{at}uhn.on.ca

Background & Aims: Up-regulation of interferon stimulated genes (ISGs), including interferon stimulated gene 15 (ISG15) and other members of the ISG15 pathway, in pre-treatment liver tissue of Hepatitis C virus (HCV) chronically-infected patients is associated with subsequent treatment failure (pegylated interferon-/ribavirin, pegIFN/rib). Here, we study the effect of ISG15 on HCV production in vitro. Methods: The levels of ISG15 and of its conjugation to target proteins (ISGylation) were increased by plasmid transfection, or ISGylation was inhibited by siRNA directed against the E1 activating enzyme Ube1L in Huh7.5 cells. Cells were infected with HCV J6/JFH1 virus, and HCV RNA and viral titers determined. Results: Levels of both HCV RNA and virus increased when levels of ISG15 and ISGylation were increased, and decreased when ISGylation was inhibited. The effects of ISGylation on HCV are independent of upstream IFN signaling: IFN-induced ISG expression is not altered by Ube1L knockdown. The effect is also not likely secondary to a cytokine effect: treatment of cells with purified ISG15 does not inhibit HCV production. Conclusions: Although ISG15 has antiviral activity against most viruses, ISG15 promotes HCV production. HCV might exploit ISG15 as a host immune evasion mechanism, and this may in part explain how increased expression of ISGs, especially ISG15, correlates with subsequent interferon-based treatment failure.

Received 17 August 2009; accepted 15 October 2009.