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Journal of Virology, June 2005, p. 7050-7058, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.7050-7058.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Replicons Escape RNA Interference Induced by a Short Interfering RNA Directed against the NS5b Coding Region

Joyce A. Wilson1 and Christopher D. Richardson1,2*

Ontario Cancer Institute/University Health Network, 620 University Ave. Suite 706, Toronto, Canada M5G 2C1,1 Department of Medical Biophysics, University of Toronto, 610 University Ave., Toronto, Canada M5G 2M92

Received 27 July 2004/ Accepted 28 January 2005

RNA interference represents an exciting new technology that could have therapeutic applications for the treatment of viral infections. Hepatitis C virus (HCV) is a major cause of chronic liver disease and affects over 270 million individuals worldwide. The HCV genome is a single-stranded RNA that functions as both an mRNA and a replication template, making it an attractive target for therapeutic approaches using short interfering RNA (siRNA). We have shown previously that double-stranded siRNA molecules designed to target the HCV genome block gene expression and RNA synthesis from hepatitis C replicons propagated in human liver cells. However, we now show that this block is not complete. After several treatments with a highly effective siRNA, we have shown growth of replicon RNAs that are resistant to subsequent treatment with the same siRNA. However, these replicon RNAs were not resistant to siRNA targeting another part of the genome. Sequence analysis of the siRNA-resistant replicons showed the generation of point mutations within the siRNA target sequence. In addition, the use of a combination of two siRNAs together severely limited escape mutant evolution. This suggests that RNA interference activity could be used as a treatment to reduce the devastating effects of HCV replication on the liver and the use of multiple siRNAs could prevent the emergence of resistant viruses.

* Corresponding author. Mailing address: 620 University Ave., Suite 706, Toronto, Ontario, Canada M5G 2C1. Phone: (416) 946-2849. Fax: (416) 204-2278. E-mail: chrisr{at}uhnres.utoronto.ca.

Journal of Virology, June 2005, p. 7050-7058, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.7050-7058.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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