We are interested in developing a small animal model to study pathogenesis of HAV. To do so, we produced transgenic mice carrying the hepatitis A virus cellular receptor-1 (havcr-1). Inoculation of HAV into the liver of havcr-1 transgenic and nontransgenic mice resulted in the production of anti-HAV antibodies. Since antibody production cleared the virus without apparent signs of disease, we decided to increase the virulence of HAV by adapting it to grow in a mouse liver cells. We hypothesized that a virus adapted to grow in mouse liver cells would replicate faster in the liver and have a better chance to cause disease. To test our hypothesis, we transfected mouse liver cells with HAV virion RNA and showed that the virus grew in these cells. Transient transfection of the cDNA coding for the HAV cellular receptor 1 (havcr-1) into mouse liver cells followed by virus infection showed that HAV grew in these cells. However, HAV replicated to low levels in mouse liver cells. Serial passages of HAV in the mouse liver cells are currently being done to facilitate the accumulation of mutations in the HAV genome that could result in the adaptation of HAV to grow more efficiently in the mouse liver cells. Changes that occurr in the HAV genome leading to adaptation to the mouse system will be characterized.
