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Efficient Induction of Cell Death by Adenoviruses Requires Binding of E1B55k and p53¹

Cell Transformation Group, Department of Pathology, Dunedin School of Medicine, Dunedin, New Zealand 9001

The use of an E1b55k-deficient adenovirus, ONYX-015, to selectively target tumor cells containing a mutated p53 gene has produced promising results. However, recent reports have questioned the selectivity of this virus, showing that ONYX-015 can replicate in cells containing a wild-type p53 and that p53 may actually be required for cell death. To address these apparent contradictions in the literature, we infected a number of mutant and wild-type p53-containing cell lines with ONYX-015 and wild-type adenovirus and observed their death profiles up to 10 days postinfection. We demonstrate that two distinct cell death phenotypes exist, one of which is rapid and dependent on the presence of p53 and one of which is p53 independent. Using adenoviruses expressing E1b55k proteins deficient in their ability to bind p53, we show that formation of a complex between p53 and the adenoviral E1b55k protein is necessary for the activation of the rapid cell death pathway. In the absence of p53 or the absence of complex formation between p53 and E1b55k, cell death is delayed considerably. These data suggest three things: that the selectivity of killing appears to be dependent on the presence of the E1b55k/p53 complex; that viruses lacking E1b55k (such as ONYX-015) kill cells in a delayed manner independent of p53; and that binding of E1b55k to p53 does not merely serve to inactivate p53, but rather is required for the induction of rapid cell death. The components of this complex that lead to rapid cell death remain to be determined.

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