**5. Contribution of HBx to pathogenesis of CLD by regulation of HBV replication**

HBx, the *trans*-activation protein of HBV, *trans*-activates virus gene expression and replication *in vitro* [54, 55]. The contribution of this regulatory protein to virus persistence in the carrier state was shown in woodchucks experimentally infected with the HBV-like virus, woodchuck hepatitis virus (WHV). Wild type WHV readily establishes a chronic infection, characterized by persistent virus replication and CLD that progresses to HCC [56]. However, experimental infection with a mutant of WHV that does not encode woodchuck hepatitis x (WHx) antigen yielded no carrier state and no CLD [57, 58], suggesting that *trans*-activation of virus gene expression and replication is central to the establishment of the carrier state. Among infected woodchucks, there was co-staining between WHV core antigen (where virus replication takes place) and WHx [59, 60], while in human infection, HBx often co-existed with HBe in serum [61] and replication complexes (i.e., with HBcAg) in the liver [62]. Thus, HBx expression is associated with virus replication.
