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Journal of Virology, February 1999, p. 1046-1053, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Replication-Incompetent Adenovirus Vector with the Preterminal Protein Gene Deleted Efficiently Transduces Mouse Ears

John W. Moorhead,1 Gerald H. Clayton,2 Roderic L. Smith,2 and Jerome Schaack3,*

Department of Clinical Immunology,1 Department of Neurology,2 and Department of Microbiology, Program in Molecular Biology, Biomedical Sciences Program, University of Colorado Cancer Center,3 University of Colorado Health Sciences Center, Denver, Colorado

Received 3 August 1998/Accepted 20 October 1998

Adenoviruses offer great potential as gene therapy agents but are limited by the strong inflammatory response that occurs in response to the recombinant virus. Since the degree of inflammation correlates in part with the potential of the viral vector for replication, we constructed a preterminal protein (pTP) deletion mutant adenovirus type 5 vector, Ad5dl308Delta pTPbeta -gal, that is replication incompetent due to deletion of the pTP gene and that has the E1 genes replaced by the Escherichia coli lacZ reporter gene under the control of the cytomegalovirus major immediate-early promoter. This virus was compared with a first-generation, replication-defective adenovirus vector, Ad5dl308beta -gal, that is isogenic except that it contains a wild-type pTP gene. To examine transduction efficiency and induction of inflammation, we developed a novel system involving intradermal injection of BALB/c mouse ears. Mouse ears can be accurately measured to determine the degree of edema as an indirect measurement of inflammation. Edema and inflammation were induced in a dose- and time-dependent manner by both viruses and correlated well. LacZ activity correlated inversely with edema and inflammation. The pTP-defective vector Ad5dl308Delta pTPbeta -gal transduced mouse ears much more efficiently and induced edema and inflammatory cell infiltration approximately 10-fold less efficiently than the first-generation vector Ad5dl308beta -gal. The diminished inflammatory response and increased efficiency of transduction observed with Ad5dl308Delta pTPbeta -gal indicate its promise as a gene therapy agent for other tissues. The results also demonstrate that the mouse ear model offers potential for the study of adenovirus-induced inflammation because of the ready access of the ears, the relative ease of continuous measurement, and the sensitivity to adenovirus transducing vectors.

* Corresponding author. Mailing address: University of Colorado Health Sciences Center, Department of Microbiology, Box B175, 4200 East 9th Ave., Denver, CO 80262. Phone: (303) 315-6883. Fax: (303) 315-6785. E-mail: jerry.schaack{at}uchsc.edu.

Journal of Virology, February 1999, p. 1046-1053, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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