HBX PROTEIN AND HEPATITIS B VIRUS INFECTION

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The objective of this fellowship is to understand the role of the woodchuck hepatitis B virus (WHV) HBx gene in viral infection. The association of HCC and chronic HBV infection is not well understood, but the viral HBx protein is thought to be an important factor. HBx is both a cytoplasmic activator of Ras and c-Src, and a nuclear activator of certain transcription elements such as the WHV enhancers. Several HBx mutants have been described previously from the Schneider lab that will be invaluable for this study, because they separate cytoplasmic activities of HBx from the nuclear activities. The fellowship proposes to understand the essential role of HBx in WHV infection and its involvement in viral persistence. These studies will not investigate HBx protein in isolation in transformed tissue culture cells, but instead during HBV infection of rodent liver explants. Only by investigating the role of HBx in WHV infection in this system can the real function of HBx in infection be studied, since WHV and HBV ordinarily only infect primary liver cells that contain liver specific factors which may play specialized roles in infection. Studies performed in continuous hepatocyte tissue culture cells, while useful,, have been criticised for possibly lacking biological relevance. Consequently, wildtype WHV or mutant WHV genomes which lack the HBx gene will be transduced into explanted primary hepatocytes by piggybacking on replication-defective adenovirus vectors, and complemented for the loss of HBx in trans with wildtype or mutant HBx genes (carried on Ad vectors).