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Infectivity and expression of the early adenovirus proteins are important regulators of wild-type and ΔE1B adenovirus replication in human cells

Oncogene volume 18, pages 5032–5043 (1999)Cite this article

Abstract

An adenovirus mutant lacking the expression of the large E1B protein (ΔE1B) has been reported to replicate selectively in cells lacking the expression of functionally wild-type (wt) p53. Based on these results the ΔE1B or ONYX-015 virus has been proposed to be an oncolytic virus which might be useful to treat p53-deficient tumors. Recently however, contradictory results have been published indicating that p53-dependent cell death is required for productive adenovirus infection. Since there is an urgent need for new methods to treat aggressive, mutant p53-expressing primary tumors and their metastases we carefully examined adenovirus replication in human cells to determine whether or not the ΔE1B virus can be used for tumor therapy. 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 evidence that these two factors rather than the p53 status of the cell determine whether adenovirus infection results in lytic cell death. Furthermore, the results we obtained by infecting a panel of different tumor cell lines show that viral spread of the ΔE1B is strongly inhibited in almost all p53-proficient and -deficient cell lines compared to the wt virus. We conclude that the efficiency of the ΔE1B virus to replicate efficiently in tumor cells is determined by the ability to infect cells and to express the early adenovirus proteins rather than the status of p53.

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Acknowledgements

We thank Mrs E van der Raaij-Helmer and Professor Dr R Willemse for the generous gift of the primary keratinocytes and Dr R Steenbergen and Professor Dr J Walbomers for the FK18B HPV-transformed keratinocytes. We are grateful to Mrs A-M Van den Hoeven-Kaiser and Dr Ph. de Groot for the primary endothelial cells. Dr AG Jochemsen was thanked for the G401-mt stable transfectant and for carefully reading the manuscript. We would like to thank Dr Kolls for the CMVLacZ virus. Furthermore, we are grateful to Drs I Ganly, A Balmain and F McCormick for helpful discussion throughout the project and to Dr F Fallaux for helpful discussion and technical assistance. This project was supported by a grant from the Dutch Cancer Society.

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  1. Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, Utrecht University, PO Box 80042, Utrecht, 3508 TA, The Netherlands

    Wilma T Steegenga, Nicole Riteco & Johannes L Bos

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Steegenga, W., Riteco, N. & Bos, J. Infectivity and expression of the early adenovirus proteins are important regulators of wild-type and ΔE1B adenovirus replication in human cells. Oncogene 18, 5032–5043 (1999). https://doi.org/10.1038/sj.onc.1202886

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