EFFECT OF HEPATOCYTE PROLIFERATION AND CELLULAR DNA-SYNTHESIS ON HEPATITIS-B VIRUS-REPLICATION

Background & Aims: Interrelationship between hepatitis B virus (HBV) r eplication and the stage of hepatocyte proliferation and differentiati on may play an important role in the pathogenesis of HBV infection. Th e aim of this study was to assess the effect of hepatocyte proliferati on and/or cell arrest on HBV replication. Methods: Hepatoblastoma cell s transfected with HBV were subjected to serum deprivation or treatmen t with aphidicolin or camptothecin. Cell cycle analysis was performed using flow cytometry, and cellular DNA synthesis was analyzed by asses sing 5-bromo-2'-deoxyuridine incorporation. Distribution of episomal H BV DNA and proliferating cell nuclear antigen in liver specimens was a ssessed by simultaneous in situ hybridization and immunohistochemistry . Results: Serum deprivation inhibited cellular DNA synthesis and incr eased levels of HBV messenger RNA (mRNA). Aphidicolin treatment result ed in cell arrest in G(1), with concomitant increases in levels of HBV mRNA and viral DNA. Cell entry into S phase inhibited expression of H BV mRNA. Camptothecin induced G(2) cell arrest and inhibited cellular DNA synthesis with increased amounts of viral replication and levels o f HBV mRNA. In vivo studies showed an inverse correlation between expr ession of proliferating cell nuclear antigen and presence of episomal HBV DNA in individual hepatocytes. Conclusions: HBV replication is cel l cycle dependent, supporting the concept of enhanced viral replicatio n in quiescent hepatocytes. The results may explain the mechanism of v iral elimination during cell regeneration.