Molecular Basis of Cytokine-induced Clearance of HBV RNA

Uprichard, Susan

Abstract

Induction of cytokines in the mouse liver can cause the disappearance of HBV RNA by a post-transcriptional mechanism. This suggest that cytokines produced in the liver of infected patients can suppress viral gene expression. Most likely this involves inducing the hepatocytes to become participants in the antiviral process through activation of genes and/or gene products that consequently """"""""cure"""""""" the cell. Identification of the intracellular mechanisms responsible for this antiviral effect is the long term goal of which the proposed work is a part. The following studies focus on defining viral RNA target elements and intracellular proteins that mediate this cytokine regulation. Previously the ceJiular La protein was observed to be cleaved coincident with the inhibition of HBV RNA. We propose to do a more functional-based analysis to test the hypothesis that HBV gene expression is in fact regulated by La. In addition, by using a general mutagenesis approach we will test the hypothesis that a cytokine-responsive target element(s) may exist within the HBV transcripts which renders these RNAs susceptible to down-regulation. Importantly, we are proposing to do these molecular analyses in vivo using the HBV transgenic mouse model as the in vivo nature of this system suggests that the results might closely reflect what occurs during a natural infection. If we can learn how the immune system is able in some cases to successfully combat the virus, we may be able to mimic that strategy or trigger that antiviral pathway in all infected patients. Ultimately, such knowledge could also prove to be relevant to the treatment of other persistent hepatic viral infections, particularly HCV.