Although very different at a molecular level, hepatitis viruses B and C (HBV and HCV) both infect only humans and chimpanzees which means that there is a lack of suitable small animal models for studying viral lifecycles and for testing new drugs. One alternative would be to study the viruses and test new compounds in liver cells grown in vitro, but human hepatocytes are very difficult to grow and maintain in culture.
A team of researchers led by scientists at the Salk Institute has now provided a solution to the problem by generating a mouse with a liver that is almost completely ‘humanised’. The team had previously generated a mouse with a partially humanised liver but wanted to achieve more complete transformation. Around 95% of the liver cells of the new mice are human in origin and the animals are susceptible to infection by both HBV and HCV. Mice infected with HCV were shown to respond to drugs such as pegylated interferon α2a and ribavirin that are used to treat human patients. Adefovir dipivoxil, used to treat HBV patients, was found to lower viral titres in mice infected with HBV.
The mice were generated by using genetic and pharmacological pressures to lead to a growth disadvantage for mouse hepatocytes and positive selection for transplanted human hepatocytes. The mice provide a new way to study pathogens that target the human liver and to test drugs to treat human hepatitis. In the future, the mice could also be used to study other hepatotrophic pathogens such as malaria, as well as cirrhosis and liver cancer.
The study is published in the Journal of Clinical Investigation.