WOODCHUCK HEPATITIS-VIRUS INFECTIONS - VERY RAPID RECOVERY AFTER A PROLONGED VIREMIA AND INFECTION OF VIRTUALLY EVERY HEPATOCYTE

Earlier studies have suggested that transient hepadnavirus infections in mammals are associated with virus replication in a large fraction o f hepatocytes. Although the viremia that occurred during transient inf ections 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 rei nvestigated because of the implications of the results for the mechani sms of virus clearance. Woodchucks were inoculated with woodchuck hepa titis virus, and the course of hepatic infection was determined. These studies indicated that essentially 100% of the hepatocytes became inf ected in the majority of woodchucks. in 7 of 10 woodchucks, the viral infection was then rapidly cleared from the liver, generally in less t han 4 weeks. In another three woodchucks, though productive infection was just as rapidly cleared, viral covalently closed circular DNA rema ined for weeks to months after other indicators of virus infection had disappeared from the liver, Bromodeoxyuridine labeling and anti-proli ferating cell nuclear antigen staining to detect hepatocytes passing t hrough S phase indicated an increase in hepatocyte proliferation durin g 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 pe r day, at the times at which the biopsies were performed. Histopatholo gic evaluation of the biopsy samples did not provide evidence for a ma ssive amount of liver regeneration. Models to explain virus clearance, with or without massive immune system-mediated destruction of infecte d hepatocytes, are reviewed.