Earlier studies have suggested that transient hepadnavirus
infections in mammals are associated with virus replication in a large fraction of hepatocytes. Although the
viremia that occurred during transient
infections in some individuals would presumably lead to virus replication in all hepatocytes, these studies did not reveal if this was the case. The question of the extent of hepatocyte
infection was therefore reinvestigated because of the implications of the results for the mechanisms of virus clearance. Woodchucks were inoculated with woodchuck hepatitis virus, and the course of hepatic
infection was determined. These studies indicated that essentially 100% of the hepatocytes became infected in the majority of woodchucks. In 7 of 10 woodchucks, the
viral infection was then rapidly cleared from the liver, generally in less than 4 weeks. In another three woodchucks, though productive
infection was just as rapidly cleared, viral covalently closed
circular DNA remained for weeks to months after other indicators of
virus infection had disappeared from the liver.
Bromodeoxyuridine labeling and anti-
proliferating cell nuclear antigen staining to detect hepatocytes passing through S phase indicated an increase in hepatocyte proliferation during the recovery phase of
infection. The rate of cell division appeared to be sufficient to replace no more than 2 to 3% of the hepatocytes per day, at the times at which the biopsies were performed. Histopathologic evaluation of the biopsy samples did not provide evidence for a massive amount of liver regeneration. Models to explain virus clearance, with or without massive immune system-mediated destruction of infected hepatocytes, are reviewed.