We have explored a role for the adenovirus (Ad5) E1b58kDa/p53 protein complex in adenovirus replication. This was done by using virus mutants containing different defects in the E1b58kDa gene and cell lines that express either a wild-type p53 protein or a mutant p53 protein. We find that infection of wild-type p53-containing cells with wild-type Ad5 causes a shutoff of p53 and alpha-actin protein synthesis by distinct mechanisms, but neither occurs in mutant p53 cells. Our data also indicate that the shutoff is dependent on formation of the p53/E1b complex and may also involve another virus protein, E4ORF6. Following from these observations we asked whether failure to form the complex resulted in impaired adenovirus replication. Our experiments showed that neither wild-type Ad5 nor the E1b mutant dl338 could replicate in cells expressing a mutant p53 protein, but that wild-type adenovirus replicated well in wild-type p53-expressing cells. Collectively, our data suggest that the interaction between p53 and the E1b58kDa protein is necessary for efficient adenovirus replication. This is the first time such a direct link between the complex and virus replication has been demonstrated. These data raise serious questions about the usefulness of E1b-defective viruses in tumor therapy.

The adenovirus mutant ONYX-015 is in phase III clinical trials as a novel antitumor therapy. Its apparent efficacy is thought to be due to its ability to replicate selectively in tumor cells defective in the signaling pathway for p53. Recent data have shown that p14 ARF , a positive regulator of p53, inhibits ONYX-015 replication in cells with a wild-type p53, a phenotype that characterizes normal cells. We, however, found that ONYX-015 activates p53 in tumor cells and in normal cells and that this can occur without p14 ARF induction. We also show that ONYX-015 is not attenuated in cells with functional p53, whether or not p14 ARF is expressed, and that where attenuation does occur, it is cell type specific.

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Trisomy 7, in mosaic state, was identified at chorionic villus sampling. The pregnancy was closely followed, and proceeded uneventfully. Mosaic trisomy 7 was confirmed in the term placenta, the organ having no structural abnormalities; the karyotype of the phenotypically normal baby was 46,XY. Trisomy 7, mosaic or nonmosaic, detected at chorionic villus sampling in an ultrasonographically normal pregnancy, appears typically to be associated with a normal fetal karyotype, and placental growth, structure, and function are not discernibly compromised.