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Journal of Virology, March 2004, p. 2863-2874, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2863-2874.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Distinct Classes of Proteasome-Modulating Agents Cooperatively Augment Recombinant Adeno-Associated Virus Type 2 and Type 5-Mediated Transduction from the Apical Surfaces of Human Airway Epithelia

Ziying Yan,1,2 Roman Zak,1,2 Yulong Zhang,1,2 Wei Ding,1,2 Simon Godwin,3 Keith Munson,3 Richard Peluso,3 and John F. Engelhardt1,2*

Department of Anatomy and Cell Biology,1 Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases, University of Iowa College of Medicine, Iowa City, Iowa 52242,2 Targeted Genetics Corporation, Seattle, Washington 981013

Received 12 August 2003/ Accepted 21 November 2003

Tripeptidyl aldehyde proteasome inhibitors have been shown to effectively increase viral capsid ubiquitination and transduction of recombinant adeno-associated virus type 2 (rAAV-2) and rAAV-5 serotypes. In the present study we have characterized a second class of proteasome-modulating agents (anthracycline derivatives) for their ability to induce rAAV transduction. The anthracycline derivatives doxorubicin and aclarubicin were chosen for analysis because they have been shown to interact with the proteasome through a mechanism distinct from that of tripeptidyl aldehydes. Our studies demonstrated that doxorubicin and aclarubicin also significantly augmented rAAV transduction in airway cell lines, polarized human airway epithelia, and mouse lungs. Both tripeptidyl aldehyde and anthracycline proteasome-modulating agents similarly augmented nuclear accumulation of rAAV in A549 and IB3 airway cell lines. However, these two cell types demonstrated cell specificity in the ability of N-acetyl-L-leucyl-L-leucyl-L-norleucine (LLnL) or doxorubicin to augment rAAV transduction. Interestingly, the combined administration of LLnL and doxorubicin resulted in substantially increased transduction (>2,000-fold) following apical infection of human polarized epithelia with either rAAV-2 or rAAV-5. In summary, the cell type specificity of LLnL and doxorubicin to induce rAAV transduction, together with the ability of these compounds to synergistically enhance rAAV transduction in polarized airway epithelial induction, suggests that these two classes of compounds likely modulate different proteasome functions that affect rAAV transduction. Findings from this study provide new insights into how modulation of proteasome function can be effectively used to augment rAAV transduction in airway epithelia for gene therapy of cystic fibrosis.

* Corresponding author. Mailing address: Department of Anatomy and Cell Biology, University of Iowa, College of Medicine, Room 1-111, Bowen Science Building, 51 Newton Rd., Iowa City, IA 52242-1109. Phone: (319) 335-7753. Fax: (319) 335-6581. E-mail: john-engelhardt{at}uiowa.edu.

Journal of Virology, March 2004, p. 2863-2874, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2863-2874.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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