How a positive-strand RNA virus such as HCV can subvert autophagy?

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HCV infection causes a spectrum of diseases ranging from asymptomatic carrier to end-stage liver disease, which includes cirrhosis and hepatocellular carcinoma. With more than 2% of the worldwide population infected, the number of HCV- related death is estimated at 10 000 per year in the USA alone. Autophagy is a highly evolutionarily conserved process of all eukaryotic cells. It involves the sequestration of regions of cytosol within double-membrane vesicles and delivery of the contents to lysosome for degradation and the recycling of the material. Recent advance on autophagy has demonstrated that it also plays an important role in antiviral host defence. However, despite its antiviral properties, several positive-strand RNA viruses have evolved to utilize autophagy or autophagy-related proteins to promote their own replication. At the moment, the mechanisms underlying those processes are, for the most part, completely unknown. In this research proposal, we are interested in pursuing our ongoing research on the prerequisite of autophagy proteins in the replication cycle of HCV. We already demonstrated that proteins of the Autophagy-Elongation-Complex are localized at the HCV replication site and are required for viral replication. Therefore our goal is to determine how this complex plays a role in the formation of the membranous-web that is induced by the virus. The second objective is to understand how HCV can block the maturation of autophagosome to avoid its degradation. Although each virus possesses several unique features that set them apart from each other, we believe that resolution of the proposed goal should reveal general mechanisms used by several viruses that are known to need autophagy somehow for their replication. Even-though research on autophagy has expended tremendously in recent years, to my knowledge, my laboratory is still the only one working on this particular subject in Canada. Because this innovative research is at the frontier between what determine virus elimination or viral propagation, it is important that Canadian researchers remain in this emergent field.