p53-dependent antiviral RNA-interference facilitates tumor-selective viral replication

Gürlevik, Engin
Woller, Norman
Schache, Peter
Malek, Nisar P.
Wirth, Thomas C.
Zender, Lars
Manns, Michael P.
Kubicka, Stefan
Kühnel, Florian

¹Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl Neuberg Str. 1, 30625 Hannover, Germany
²Department of Microbiology, University of Iowa, 51 Newton Road, Iowa City, IA 52242, USA

Received 13 November 2008; accepted 24 April 2009

^*To whom correspondence should be addressed. Tel: +49 511 532 9401; Fax: +49 511 532 2021; Email: [email protected]

Correspondence may also be addressed to Stefan Kubicka. Tel: +49 511 532 6766; Fax: +49 511 532 2021; Email: [email protected]

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acids Research 37(12):p e84, July 2009.

RNA-interference (RNAi) is a potent tool for specific gene silencing. In this study, we developed an adenovirus for conditional replication in p53-dysfunctional tumor cells that uses p53-selective expression of a microRNA-network directed against essential adenoviral genes. Compared to a control virus that expressed a scrambled microRNA-network, antiviral RNAi selectively attenuated viral replication in cells with transcriptionally active p53, but not in p53-dysfunctional tumor cells where both viruses replicated equivalently. Since these results were confirmed by an in vivo comparison of both viruses after infection of p53-knockout and normal mice, we could demonstrate that attenuated replication was indeed a result of p53-selective exhibition of antiviral RNAi. Addressing the therapeutic applicability, we could show that the application of RNAi-controlled virus efficiently lysed p53-dysfunctional tumors in vitro and in vivo but resulted in drastically reduced load of virus-DNA in the liver of treated mice. We have generated a broadly applicable adenovirus for selective destruction of p53-dysfunctional tumors and thereby demonstrate that virus-encoded RNAi-networks represent an efficient and versatile tool to modify viral functions. RNAi-networks can be applied to all transcriptionally regulated DNA-viruses to remodulate viral tropism and thus provide means to generate specifically replicating vectors for clinical applications.