Infectivity and expression of the early adenovirus proteins are important regulators of wild-type and Delta E1B adenovirus replication in human cells

An adenovirus mutant lacking the expression of the large E1B protein (Delta E1B) has been reported to replicate selectively in cells lacking the expre ssion of functionally wild-type (wt) p53. Based on these results the Delta E1B or ONYX-015 virus has been proposed to be an oncolytic virus which migh t be useful to treat p53-deficient tumors. Recently however, contradictory results have been published indicating that p53-dependent cell death is req uired for productive adenovirus infection. Since there is an urgent need fo r new methods to treat aggressive, mutant p53-expressing primary tumors and their metastases we carefully examined adenovirus replication in human cel ls to determine whether or not the Delta E1B virus can be used for tumor th erapy. The results we present here show that not all human tumor cell lines take up adenovirus efficiently. In addition, we observed inhibition of the expression of adenovirus early proteins in tumor cells. We present evidenc e that these two factors rather than the p53 status of the cell determine w hether adenovirus infection results in lytic cell death. Furthermore, the r esults we obtained by infecting a panel of different tumor cell lines show that viral spread of the Delta E1B is strongly inhibited in almost all p53- proficient and -deficient cell lines compared to the,vt virus. We conclude that the efficiency of the Delta E1B virus to replicate efficiently in tumo r cells is determined by the ability to infect cells and to express the ear ly adenovirus proteins rather than the status of p53.