The p53 family is involved in the elimination of Hepatitis B virus (HBV)-infected hepatocytes

The p53 family members each use multiple promoters and alternative splicing to generate an array of isoforms. Full length isoforms with a transactivation (TA-) domain activate target genes exerting roles in the apoptosis signaling. Dominant-negative (ΔN-) isoforms can oppose the transactivation capabilities of the TA-isoforms. We have previously shown that the CD95 gene is a target gene of the p53 family and that an intact CD95-mediated apoptosis signaling pathway is essential for the elimination of an HBV-infection in vivo.This study was designed to analyze the influence of the p53 family status on the outcome of an HBV-infection based on the hypothesis that the interaction of the p53 family network of TA- and ΔN-isoforms with HBV and apoptosis signaling pathways may be an underlying mechanism of the diverse outcomes of an HBV infection (HBV clearance vs. chronicity). Adenoviral transfer of HBV into Hep3B cells or primary human hepatocytes led to an accumulation of p53 and p73. Combined adenoviral transfer of wt p53, TAp63 or TAp73 and HBV led to a synergistic transactivation of the CD95 gene, consecutive upregulation of the CD95 receptor and a sensitization of HBV-infected hepatocytes towards CD95-mediated apoptosis. Furthermore, HBV-infection resulted in an accumulation of the mitochondrial proteins Bax, Puma and Noxa, depolarization of the mitochondrial membrane and release of cytochrome c. On the contrary, transduction of ΔN-isoforms of the p53 family led to an inhibition of both, the activation of the extrinsic as well as the intrinsic apoptotic signaling pathway. Our data show that p53 family regulated apoptosis signaling pathways play a significant role in the elimination of HBV-infected hepatocytes. Thus, the specific interaction of proapoptotic TA- and antiapoptotic ΔN-isoforms of the p53 family with HBV might be an essential mechanism of the diverse outcome of an HBV-infection.