Grant: CIHR Fellowship

Current estimates indicate that 130-170 million people worldwide are infected with hepatitis C virus (HCV), a pathogen that targets hepatocytes within the liver of those it infects. Many individuals are unable to clear the virus post-infection, often leading to the development of liver cirrhosis and/or liver cancer within these patients. Accordingly, hepatitis C virus in now the main cause for liver transplantation in the USA and Europe. Unfortunately, no HCV vaccine exists and current treatments are poorly tolerated and frequently ineffective. The production of infectious hepatitis C virus in cell culture has only recently become possible, permitting investigation into how the virus is assembled and released from infected hepatocytes. Studies utilizing this novel system highlight the importance of several virus-encoded proteins to this process. One virus protein, core, is thought to self-interact to form the virus capsid - the protein shell into which the viral genetic code is packaged. Evidence suggests that core may also interact with other viral proteins in order to facilitate the capsid assembly process. However, the core-core interaction regions and the role of other viral proteins in capsid assembly are poorly characterized. In this project, we have identified a small region of core that is essential for the production of infectious virus. We possess the necessary systems to determine whether this region is (i) important for assembly of the viral capsid, or (ii) required for a step that is subsequently important for virus infectivity. We can also detect any other mutations within the viral genetic code that may arise and restore virus production from this deleterious core mutant. Such studies could identify novel protein-protein interactions that are essential for the generation of infectious HCV and ultimately, identify targets for improved HCV therapy.