ROLE OF TUMOR SUPPRESSORS P53 AND P73 IN THE CELLULAR DEFENCE AGAINST HEPATITIS C VIRUS

Introduction: Wild-type p53 (wtp53) and transcriptional active (TA-) p73 execute their tumor-suppressor function mainly by induction of apoptosis which can be counteracted by overexpression of the dominant-negative isoform of p73 (DNp73). The interaction of proapoptotic and antiapoptotic isoforms of the p53 family with Hepatitis C Virus (HCV) and p53-family dependent apoptosis may be an underlying mechanism of the diverse outcomes of HCV infection (clearance vs. chronicity). In this study we therefore aimed to clarify the impact of HCV infection on the activation of the p53-family as well as the influence of the p53-status of the cell and p53-family dependent apoptosis signalling on HCV replication and propagation.

Results: HCV infection of Lunet-HUH7 cells led to a classic DNA-Damage response followed by the accumulation of p53 and TAp73 and transcriptional activation of p53/TAp73 target genes of both the extrinsic and intrinsic apoptosis signalling pathway. This lead to a sensitization towards p53- and p73-mediated apoptosis, which was counteracted by DNp73. Of note, stabilization of p53 and TAp73 by either treatment with the small molecules Nutlin and RETRA or adenoviral transfer of wtp53 or TAp73 lead to a dramatic inhibition of HCV replication and propagation, whereas overexpression of DNp73 enhanced HCV infectivity.

Conclusion: With the present study, we describe a new function of the p53-tumor suppressor family in HCV infection. Wtp53 and TAp73 act as a host innate defence mechanism upon HCV-infection by transactivation of p53-target genes and sensitization of HCV-infected cells towards apoptosis. Accordingly, targeting the p53 family by either small molecules or adenoviral transfer to specifically induce apoptosis of HCV-infected cells lead to a decline of HCV replication and propagation and therefore constitutes a new approach in anti-HCV-therapy.

HCV - apoptosis - p53 - p73