Interaction of hepatitis C virus (HCV) with P53 family-induced apoptosis signaling pathways

Abstract

Introduction: Chronic hepatitis C virus (HCV) infection constitutes a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). Here we investigate the interaction of HCV with transcriptionally active (TA) and inactive (DeltaN) isoforms of the p53 family which play a central role in tumor development, treatment response and prognosis of HCC. Methods and results: Combined adenoviral transfer of wild-type p53 (wt p53) or TAp73 with HCV expression constructs led to a synergistic transactivation of the CD95 and the Bax gene (luciferase reporter assays) and to an increase in p53- and TAp73-mediated apoptosis in HepG2 cells (wt p53) and Hep3B cells (p53 -/-) (FACS analysis). For a biologically more relevant approach we used the HCV infectious tissue culture system replicating the Jc1 construct. HUH6 (wt p53) and HUH7-Lunet cells (mutant p53) were infected with the Jc1 construct following adenoviral transfer of wt p53, TAp73 or DeltaNp73. In addition, we performed silencing of the p53 family members by transfection of siRNA. HCV titers were measured using immunohistochemistry. Overexpression of TAp73 led to a decline in HCV infectivity whereas silencing of TAp73 enhanced HCV infectivity. Of note, upregulation of DeltaNp73 led to an increase of HCV titers. Conclusions: HCV, wt p53 and TAp73 cooperate in the activation of ‘classic’ p53-dependent apoptosis genes and p53 family-dependent apoptosis signaling pathways. Of clinical importance, TAp73 influences HCV infectivity. Thus, the interaction of HCV with anti-apoptotic (DeltaN) isoforms of the p53 family may be an underlying mechanism how the virus evades the cellular apoptotic defence and establishes a chronic infection. This may constitute a new mechanism by which HCV and oncogenic DeltaN isoforms of the p53 family could enhance the carcinogenic process in liver cells.