P53-DEPENDENT CELL-DEATH APOPTOSIS IS REQUIRED FOR A PRODUCTIVE ADENOVIRUS INFECTION

The p53 tumor suppressor protein binds to both cellular and viral prot eins, which influence its biological activity. One such protein is the large E1b tumor antigen(1) (E1b58kDa) from adenoviruses (Ads), which abrogates the ability of p53 to transactivate various promoters(2). Th is inactivation of p53 function is believed to be the mechanism by whi ch E1b58kDa contributes to the cell transformation process(2). Althoug h the p53-E1b58kDa complex occurs during infection(3) and is conserved among different serotypes(4), there are limited data demonstrating th at it has a role in virus replication. However, loss of p53 expression occurs after adenovirus infection of human cells(4,5) and an E1b58kDa deletion mutant (Onyx-015, also called dl 1520) selectively replicate s in p53-defective cells(6,7). These (and other) data indicate a plaus ible hypothesis is that loss of p53 function may be conducive to effic ient adenovirus replication. However, wild-type (wt) Ad5 grows more ef ficiently in cells expressing a wt p53 protein(5). These studies indic ate that the hypothesis may be an oversimplification. Here, we show th at cells expressing wt p53, as well as p53-defective cells, allow aden ovirus replication, but only cells expressing wt p53 show evidence of virus-induced cytopathic effect. This correlates with the ability of a denovirus to induce cell death. Our data indicate that p53 plays a nec essary part in mediating cellular destruction to allow a productive ad enovirus infection. In contrast, p53-deficient cells are less sensitiv e to the cytolytic effects of adenovirus and as such raise questions a bout the use of E1b58kDa-deficient adenoviruses in tumor therapy(6,7).