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Effect of hypoxia on Ad5 infection, transgene expression and replication

Gene Therapy volume 12, pages 902–910 (2005)Cite this article

Abstract

Oxygen deprivation (hypoxia) is a common feature of various human maladies, including cardiovascular diseases and cancer; however, the effect of hypoxia on Ad-based gene therapies has not been described. In this study, we evaluated how hypoxia (1% pO2) affects different aspects of Ad-based therapies, including attachment and uptake, transgene expression, and replication, in a series of cancer cell lines and primary normal cells. We found that hypoxia had no significant effect on the expression or function of the Ad5 attachment (Coxsackievirus and Adenovirus Receptor) and internalization (αv integrins) proteins, nor on the human cytomegalovirus-driven expression of an exogenous gene carried by a replication-incompetent Ad. Viral replication, however, was compromised by hypoxic conditions. Our studies revealed hypoxia-induced reductions in E1A levels that were mediated at the post-transcriptional level. E1A drives cells into the viral replication optimal S phase of the cell cycle; consequently, the combination of reduced E1A protein and hypoxia-induced G1 arrest of cells may be responsible for the lack of efficient viral replication under hypoxic conditions. Consequently, while traditional replication-incompetent Ad-based vectors appear to be viable delivery systems for hypoxia-associated disease indications, our studies suggest that Oncolytic Ads may need additional factors to efficiently treat hypoxic regions of human tumors.

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Acknowledgements

We thank Cecile Chartier and Fang Jin for providing us Ad5 and Ad5-Luc; Juan Irwin for anti-CAR monoclonal antibody; Alan Brooks, Peiyin Wang, Chris Haskell, Maxine Bauzon, Paul Harden and Irene Kuhn for excellent technical support and helpful discussions; Rhonda Humm, Jean MacRobbie and Eileen Paulo-Chrisco for providing cell lines; Richard N Harkins and Gabor Rubanyi for critical reading of the manuscript. This work is supported by a PFO fellowship from Schering AG.

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  1. Department of Gene Therapy, Berlex Biosciences, Richmond, California, USA

    B H Shen & T W Hermiston

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Shen, B., Hermiston, T. Effect of hypoxia on Ad5 infection, transgene expression and replication. Gene Ther 12, 902–910 (2005). https://doi.org/10.1038/sj.gt.3302448

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