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

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.




This article has been cited by other articles:

  • Snyder, L. L., Ahmed, I., Steel, L. F. (2009). RNA polymerase III can drive polycistronic expression of functional interfering RNAs designed to resemble microRNAs. Nucleic Acids Res 37: e127-e127 [Abstract] [Full Text]  
  • Sugiyama, R., Habu, Y., Ohnari, A., Miyano-Kurosaki, N., Takaku, H. (2009). RNA Interference Targeted to the Conserved Dimerization Initiation Site (DIS) of HIV-1 Restricts Virus Escape Mutation. J Biochem 146: 481-489 [Abstract] [Full Text]  
  • Scheller, N., Mina, L. B., Galao, R. P., Chari, A., Gimenez-Barcons, M., Noueiry, A., Fischer, U., Meyerhans, A., Diez, J. (2009). Translation and replication of hepatitis C virus genomic RNA depends on ancient cellular proteins that control mRNA fates. Proc. Natl. Acad. Sci. USA 106: 13517-13522 [Abstract] [Full Text]  
  • Umbach, J. L., Cullen, B. R. (2009). The role of RNAi and microRNAs in animal virus replication and antiviral immunity. Genes Dev. 23: 1151-1164 [Abstract] [Full Text]  
  • Shin, D., Lee, H., Kim, S. I., Yoon, Y., Kim, M. (2009). Optimization of linear double-stranded RNA for the production of multiple siRNAs targeting hepatitis C virus. RNA 15: 898-910 [Abstract] [Full Text]  
  • 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]