VIDO research program area: Viral Pathogenesis & Vaccine Development Overview The hepatitis C virus (HCV) is an important human pathogen worldwide and is estimated to infect approximately 170 million people. Between 210,000 and 275,000 of these are Canadians. In addition, the infection rates in Canadian Aboriginal populations are a staggering eight times higher than in the general population (The Canadian Aboriginal AIDS Network), making HCV a particularly important pathogen in provinces with high aboriginal populations.
Approximately 70-90 per cent of HCV infections become chronic (Chisari, F. V. 2005) and can proceed to liver cirrhosis (30 per cent of these) or hepatocellular carcinoma (5 per cent of these)(Bowen, D. G., and C. M. Walker, 2005). Chronic HCV infection is currently the leading cause of liver transplants in Canada. HCV treatment is limited to combination therapy with interferon and ribavirin, but this therapy is only successful in approximately 50 per cent of all cases and no alternative therapies are available. There is no vaccine for HCV. Clearly, there is a need for the development of HCV therapies and vaccines.
Background:
We are interested in the basic biology of the hepatitis C virus, and in particular, interactions between the virus and the host cell required for virus replication. Viruses are intercellular parasites and must usurp host cellular machinery in order to reproduce themselves. It is through these interactions that viruses cause their characteristic pathologies.
We are focusing on how HCV interacts with microRNA pathways in the cell. Interestingly, HCV interacts with the host cellular miRNA pathway to promote its growth (Jopling, C. L., M. Yi et al, 2005). This is unusual since miRNA normally function to suppress translation and in some cases also suppress virus growth. The mechanisms by which HCV uses miRNA to promote growth are unknown.
Objectives:
1. We are interested in determining the molecular mechanism by which Argonaute promotes HCV translation and/or replication.
2. We are investigating the roles of proteins that are required for steps downstream of Argonaute in the miRNA pathway.
3. By characterizing essential virus/host interactions, we will devise novel methods to inhibit virus replication by stopping these interactions
Progress:
We have found that the hepatitis C virus interacts with another miRNA pathway protein called Argonaute 2. In addition, we have found that this interaction is required for optimal virus replication. Normally, Argonaute 2 binds to miRNAs and leads to messenger RNA translational suppression and transport to cellular structures called P-bodies. The mechanism of translational suppression is unresolved; however, Argonaute 2 is known to bind to miRNA and to mRNA cap structures, and also has RNA cleavage activity. We are currently analyzing Argonaute 2 to determine which of these Argonaute 2 functions are also required for HCV replication. In addition, we are assessing the possible role of P-bodies on HCV replication.
Publications: Joyce A. Wilson and Christopher D. Richardson. 2006. Future promise of siRNA and other nucleic acid based therapeutics for chronic hepatitis C. Infectious disorders drug targets. 6(1): 43-56. Review.
Joyce A. Wilson and Christopher D. Richardson 2005. Hepatitis C virus replicons escape RNA interference induced by a short interfering RNA directed against the NS5b coding region. Journal of Virology. 79(11):7050-8.
Joyce A. Wilson, Scott D. Forney, Alessondra M, Ricci, Emily M Graves, Kathy Hefferon and Lois K. Miller. 2005 Expression and mutational analysis of Autographa californica nucleopolyhedrovirus HCF-1: functional requirements for cysteine residues. Journal of Virology, Nov; 79 (22):13900-14.
Joyce A. Wilson and Christopher D. Richardson. 2003. Induction of RNA interference using short interfering RNA expression vectors in cell culture and animal systems. Current Opinion in Molecular Therapeutics. 5(4):389-96. Review.
Joyce A. Wilson, Sumedha Jayasena, Anastasia Khvorova, Sarah Sabatinos, Ian Gaël Rodrigue-Gervais, Sudha Arya, Farida Sarangi, Marees Harris-Brandts, Sylvie Beaulieu, and Christopher D. Richardson. RNA interference blocks gene expression and RNA synthesis from hepatitis C replicons propagated in human liver cells 2003. Proceedings of the National Academy of Science U S A. 2003 Mar 4;100(5):2783-8. Epub 2003 Feb 19.
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