This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wilson, J. A. Articles by Richardson, C. D. Search for Related Content PubMed PubMed Citation Articles by Wilson, J. A. Articles by Richardson, C. D.

 Previous Article  |  Next Article 

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

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.

This article has been cited by other articles:

• von Eije, K. J., Brake, O. t., Berkhout, B. (2008). Human Immunodeficiency Virus Type 1 Escape Is Restricted When Conserved Genome Sequences Are Targeted by RNA Interference. J. Virol. 82: 2895-2903 [Abstract] [Full Text]  
• Aalto, A. P., Sarin, L. P., van Dijk, A. A., Saarma, M., Poranen, M. M., Arumae, U., Bamford, D. H. (2007). Large-scale production of dsRNA and siRNA pools for RNA interference utilizing bacteriophage {phi}6 RNA-dependent RNA polymerase. RNA 13: 422-429 [Abstract] [Full Text]  
• Kanda, T., Steele, R., Ray, R., Ray, R. B. (2007). Small Interfering RNA Targeted to Hepatitis C Virus 5' Nontranslated Region Exerts Potent Antiviral Effect. J. Virol. 81: 669-676 [Abstract] [Full Text]  
• Nishitsuji, H., Kohara, M., Kannagi, M., Masuda, T. (2006). Effective Suppression of Human Immunodeficiency Virus Type 1 through a Combination of Short- or Long-Hairpin RNAs Targeting Essential Sequences for Retroviral Integration.. J. Virol. 80: 7658-7666 [Abstract] [Full Text]  
• Kusov, Y., Kanda, T., Palmenberg, A., Sgro, J.-Y., Gauss-Muller, V. (2006). Silencing of Hepatitis A Virus Infection by Small Interfering RNAs.. J. Virol. 80: 5599-5610 [Abstract] [Full Text]  
• Simon-Mateo, C., Garcia, J. A. (2006). MicroRNA-Guided Processing Impairs Plum Pox Virus Replication, but the Virus Readily Evolves To Escape This Silencing Mechanism. J. Virol. 80: 2429-2436 [Abstract] [Full Text]  
• Sabariegos, R., Gimenez-Barcons, M., Tapia, N., Clotet, B., Martinez, M. A. (2006). Sequence Homology Required by Human Immunodeficiency Virus Type 1 To Escape from Short Interfering RNAs. J. Virol. 80: 571-577 [Abstract] [Full Text]