Z Gastroenterol 2009; 47 - P4_36
DOI: 10.1055/s-0029-1191955

Interaction of Hepatitis B virus (HBV) with p53 family-induced apoptosis signaling pathways is involved in viral clearance

L Sun 1, A Langhein 1, AF Koch 1, K Lorenz 1, N Steinebrunner 1, W Stremmel 1, PH Krammer 2, U Protzer 3, M Müller 1
  • 1Innere Medizin IV, Universitätsklinikum Heidelberg
  • 2Abt. Immungenetik, Deutsches Krebsforschungszentrum
  • 3Institut für Virologie, Technische Universität München/Helmholtz Zentrum München

One major risk factor for development of hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV). We have previously shown in vivo that a functional p53 pathway and an intact CD95-apoptosis signaling pathway are essential for clearance of HBV infection. In addition, we have described a central role of the p53/p63/p73 network for tumor development, treatment response and prognosis of HCC. Upregulation of the antiapoptotic, dominant negative isoform of p73, ΔNp73, in patients with HCC correlated with reduced survival. Our data indicate that ΔNp73 is an important gene in hepatocarcinogenesis. Thus, we hypothesized if antiapoptotic, oncogenic ΔN isoforms of the p53 family would interfere with p53-, p63- and/or p73-induced apoptosis of HBV-infected liver cells.

HBV cooperated with wild-type p53, TAp63 and TAp73 in the induction of both, the extrinsic/death receptor-mediated apoptosis pathway as well as the intrinsic/mitochondria-mediated apoptosis pathway. Combined adenoviral transfer of wild-type p53 or TAp63 or TAp73 and HBV led to a synergistic transactivation of the CD95- and the Bax-genes. This resulted in a sensitization towards CD95-mediated apoptosis and an enhancement of mitochondrial membrane depolarization. A knock-out of the X protein significantly, but not completely reduced the transactivation, which was restored by trans-complementation of the X-protein. Of note, ΔN isoforms inhibited both, the synergistic induction of the extrinsic as well as the intrinsic apoptotic signaling pathway.

These data support the fact that the interaction of proapoptotic (TA) and antiapoptotic (ΔN) isoforms of the p53 family with HBV and the extrinsic and intrinsic apoptosis signaling pathways is an underlying mechanism of the diverse outcomes of an HBV infection (HBV clearance vs. chronicity). This suggests a new mechanism by which oncogenic ΔN isoforms could enhance the carcinogenic process in liver cells.