Over the years, various animal models, including chimpanzees, woodchucks, ducks, and HBV transgenic mice, were established for development and evaluation of novel therapeutic strategies. Considering the cost, ethical reasons, and available amount, HBV transgenic mice are the most widely used models. Studies using HBV transgenic mouse models demonstrated that DNA immunization with the expression plasmids encoding different HBV proteins could induce HBV-specific antibodies and stimulate CTL responses. However, the functionality of HBV-specific CTLs induced in transgenic mice may be not fully developed [80] [81] [82] . Improvement of DNA vaccination regimen [83] and blockade of PD-1/PD-L1 interaction [34, 84] could enhance functional T cell responses and lead to inhibition of viral replication in vivo without causing hepatitis. Apart from the DNA immunizations, the other therapeutic approaches including administration of Toll-like receptor (TLR) ligands, HBV-specific siRNA, and direct activation of APCs were evaluated in HBV transgenic mice [85] [86] [87] . Those strategies were able to effectively reduce the HBV replication, and are currently under investigation as combined therapies. Nevertheless, this model has a significant limitation. As the HBV genome is inserted into the mouse chromosome, full HBV life cycle does not take place in the transgenic mice and no liver inflammation can be observed [88] . Thus, the animal models with naturally occurring hepadnaviral infection are required for the longterm evaluation of the therapeutic effect. In comparison to chimpanzees, woodchucks are easily available and affordable.