The Role of the Tumour Suppressor p53 in the Elimination of Hepatitis B Virus-infected Hepatocytes - Implications for Viral Clearance

Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC) and more than 350 million people are chronically infected with HBV worldwide. The non-cytopathic hepatitis B virus is acting as a “stealth” virus and is, therefore, hardly detected by the innate immune system, thus, contributing to chronicity. So far, it is known that infiltrating cytotoxic T cells are the main effector cells involved in the elimination of HBV-infected hepatocytes. However, the direct molecular mechanisms through which HBV-infected cells are eliminated by the immune system, as well as the signalling pathways up-regulated in infected host cells to combat the virus remain unclear. The present study was designed to investigate both the influence of the hepatocytes’ p53 status on the outcome of HBV infection and vice versa the influence of HBV infection on p53 and p53 target gene activation in hepatocytes. In summary, hepatitis B virus infection triggers the activation of the DNA damage response leading to the stabilization and activation of the tumour suppressor p53 in an ATM/ATR-dependent manner. Activation of p53 upon HBV infection induces the up-regulation of different p53 target genes playing important roles in the extrinsic and the intrinsic apoptosis signalling pathway. In the present study the functionality of the CD95 pathway has been identified to be an essential factor for the elimination of HBV-infected hepatocytes. The expression of proteins involved in apoptosis signalling leads to the alteration of the mitochondrial membrane potential, the subsequent release of cytochrome c and finally to apoptosis induction of HBV-infected hepatocytes. Furthermore, HBV infection triggers the induction of CD95L gene transactivation in an AP-1-dependent manner which leads to the, so far, unrecognized capability of virus-infected hepatocytes to secret CD95L by themselves. Our results propose a new p53-dependent model for virus elimination in HBV-infected hepatocytes and show that p53 beyond its role as a tumour suppressor also plays an important role in viral clearance. The identification of prominent members of the apoptosis signalling pathways as crucial proteins activated upon HBV-infection demonstrate an underlying mechanism for the diverse outcomes (clearance vs. chronicity) of a HBV infection. The significant contribution of p53 in cellular antiviral defence suggests a potential implication in the pathogenesis of HBV infection and opens new therapeutic options via stabilization of p53