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Journal of Virology, December 1998, p. 9491-9502, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Recombinant, Replication-Defective Adenovirus Gene Transfer Vectors Induce Cell Cycle Dysregulation and Inappropriate Expression of Cyclin Proteins

Robert P. Wersto,1,* Eugene R. Rosenthal,2 Prem K. Seth,3 N. Tony Eissa,2 and Robert E. Donahue1

Hematology Branch1 and Pulmonary-Critical Care Medicine Branch,2 National Heart, Lung, and Blood Institute, and Medicine Branch, National Cancer Institute,3 National Institutes of Health, Bethesda, Maryland 20892

Received 5 May 1998/Accepted 20 August 1998

First-generation adenovirus (Ad) vectors that had been rendered replication defective by removal of the E1 region of the viral genome (Delta E1) or lacking the Ad E3 region in addition to E1 sequences (Delta E1Delta E3) induced G2 cell cycle arrest and inhibited traverse across G1/S in primary and immortalized human bronchial epithelial cells. Cell cycle arrest was independent of the cDNA contained in the expression cassette and was associated with the inappropriate expression and increase in cyclin A, cyclin B1, cyclin D, and cyclin-dependent kinase p34cdc2 protein levels. In some instances, infection with Delta E1 or Delta E1Delta E3 Ad vectors produced aneuploid DNA histogram patterns and induced polyploidization as a result of successive rounds of cell division without mitosis. Cell cycle arrest was absent in cells infected with a second-generation Delta E1Ad vector in which all of the early region E4 except the sixth open reading frame was also deleted. Consequently, E4 viral gene products present in Delta E1 or Delta E1Delta E3 Ad vectors induce G2 growth arrest, which may pose new and unintended consequences for human gene transfer and gene therapy.

* Corresponding author. Mailing address: Hematology Branch, NHLBI, Room 1B-05, 5 Research Court, Rockville, MD 20850. Phone: (301) 402-3929. Fax: (301) 402-8226. E-mail: werstor{at}gwgate.nhlbi.nih.gov.

Journal of Virology, December 1998, p. 9491-9502, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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