The woodchuck model of hepadnavirus infection.

Since discovery of the hepatitis B virus (HBV),closely related viruses have been described in several animal species. The first of these was the woodchuck hepatitis virus (WHV),identified in woodchucks (Marmota monax)that were maintained at the Philadelphia Zoological Garden and which had experienced a high prevalence of chronic hepatitis and hepatocellular carcinoma (HCC). On the basis of morphological and molecular analyses,it was concluded that WHV was closely related to HBV. Since description of WHV,infection with viruses that belong to the family Hepadnaviridae have been described in the California ground squirrel (Spermophilus beecheyi)and the Arctic ground squirrel (Spermophilus parryi), two species closely related phylogenetical- ly to woodchucks,and in six avian species. A total of four well characterized,mammalian hepadnaviruses now have been associated with development of HCC. These observations on naturally acquired hepadnavirus infections combined with the development of HCC in woodchucks following experimental infection with WHV or with the California ground squirrel virus (GSHV)provides,by analogy,convincing comparative medical evidence for the hepatocarcinogenicity of HBV. The woodchuck has become useful as an experimental animal model for research on the pathogenesis of HBV infection and for investigation of the molecular mechanisms of hepatocarcinogenesis. The woodchuck also has been useful in the discovery and preclinical development of antiviral drugs for treatment of HBV infection and for testing new forms of immunotherapy using cytokines and therapeutic vaccination. In particular, the woodchuck has been valuable for determining the impact of long-term antiviral treatment on the outcome of chronic hepadnavirus infection in placebo controlled,lifetime survival studies which have been predictive of the results of subsequent clinical trials.