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Journal of Virology, November 2008, p. 11009-11015, Vol. 82, No. 22
0022-538X/08/$08.00+0     doi:10.1128/JVI.01608-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Generation of a Conditionally Replicating Adenovirus Based on Targeted Destruction of E1A mRNA by a Cell Type-Specific MicroRNA{triangledown}

Erkko Ylösmäki,1 Tanja Hakkarainen,2 Akseli Hemminki,2 Tapio Visakorpi,3 Raul Andino,4 and Kalle Saksela1*

Department of Virology, Haartman Institute, University of Helsinki, and HUSLAB, Helsinki University Central Hospital, Haartmaninkatu 3 (POB 21), FIN-00014 Helsinki, Finland,1 Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory, University of Helsinki, and HUSLAB, Helsinki University Central Hospital, FIN-00014 Helsinki, Finland,2 Institute of Medical Technology and Tampere University Hospital, University of Tampere, FIN-33014 Tampere, Finland,3 Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California 941434

Received 29 July 2008/ Accepted 8 September 2008

MicroRNAs have emerged as important players in tissue-specific mammalian gene regulation and have also been exploited in experimental targeting of gene expression. We have constructed a recombinant adenovirus that contains sequences complementary to the liver-specific microRNA 122 (miR122) in the 3' untranslated region of the E1A gene. In Huh7 cells, which resemble normal hepatocytes in expressing high levels of miR122, this feature resulted in strongly reduced levels of E1A mRNA and protein. This property allowed us to generate a novel recombinant adenovirus that was severely attenuated in cells of hepatic origin but replicated normally in other cells. This strategy may be useful in circumventing liver toxicity associated with the systemic delivery of oncolytic adenoviruses. These data provide the first example of exploiting differential microRNA expression patterns to alter the natural tropism of a DNA virus. In addition, these results suggest that other microRNAs expressed in a tissue- or transformation-specific manner may also be used for the targeting of adenoviral replication and that the same principle may be applied to other viruses that have shown promise as oncolytic or gene delivery platforms.

* Corresponding author. Mailing address: Department of Virology, Haartman Institute, University of Helsinki, Haartmaninkatu 3 (POB 21), FIN-00014 Helsinki, Finland. Phone: 358-9-191 26770. Fax: 358-9-191 26491. E-mail: kalle.saksela{at}helsinki.fi

{triangledown} Published ahead of print on 17 September 2008.

Journal of Virology, November 2008, p. 11009-11015, Vol. 82, No. 22
0022-538X/08/$08.00+0     doi:10.1128/JVI.01608-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Umbach, J. L., Cullen, B. R. (2009). The role of RNAi and microRNAs in animal virus replication and antiviral immunity. Genes Dev. 23: 1151-1164 [Abstract] [Full Text]  


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