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Journal of Virology, July 2003, p. 7689-7695, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7689-7695.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Episomal Persistence of Recombinant Adenoviral Vector Genomes during the Cell Cycle In Vivo

Anja Ehrhardt, Hui Xu, and Mark A. Kay*

Departments of Pediatrics and Genetics, School of Medicine, Stanford University, Stanford, California 94305

Received 15 November 2002/ Accepted 14 April 2003

Previously we showed that recombinant adenoviral helper-dependent (HD) vectors result in long-term transgene expression levels in vivo which slowly declined by 95% over a period of 1 year. In this study, we further establish that this was not predominantly immune mediated. To determine if cell turnover was responsible for the loss of transgene expression, we induced rapid hepatocyte cell cycling in mouse liver, by performing a surgical two-thirds partial hepatectomy. We observed a 55 and 65% reduction in transgene expression levels and a 50 and 71% loss of vector genomes for the HD vector and the first-generation adenoviral vector. In sharp contrast, in nonviral, episomal plasmid DNA-injected mice, transgene expression levels and DNA copy numbers decreased by 95 and 99%, respectively. These findings suggest that cell division alone was not the primary reason for the slow decrease in transgene expression levels and that recombinant adenoviral vectors have a more robust mechanism for maintaining persistence during cell cycling. Several potential mechanisms are proposed.

* Corresponding author. Mailing address: Departments of Pediatrics and Genetics, Room G305, School of Medicine, Stanford University, 300 Pasteur Dr., Stanford, CA 94305. Phone: (650) 498-6531. Fax: (650) 498-6540. E-mail: markay{at}stanford.edu.

Journal of Virology, July 2003, p. 7689-7695, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7689-7695.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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