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Journal of Virology, August 2001, p. 7602-7611, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7602-7611.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Human Papillomavirus E6E7-Mediated Adenovirus Cell Killing: Selectivity of Mutant Adenovirus Replication in Organotypic Cultures of Human Keratinocytes

Cristina Balagué,1,2,* Francisco Noya,3 Ramon Alemany,1 Louise T. Chow,3 and David T. Curiel1

Division of Human Gene Therapy, Departments of Medicine, Pathology, and Surgery, Gene Therapy Center,1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology,2 and Department of Biochemistry and Molecular Genetics,3 University of Alabama at Birmingham, Birmingham, Alabama 35294

Received 5 March 2001/Accepted 4 May 2001

Replication-competent adenoviruses are being investigated as potential anticancer agents. Exclusive virus replication in cancer cells has been proposed as a safety trait to be considered in the design of oncolytic adenoviruses. From this perspective, we have investigated several adenovirus mutants for their potential to conditionally replicate and promote the killing of cells expressing human papillomavirus (HPV) E6 and E7 oncoproteins, which are present in a high percentage of anogenital cancers. For this purpose, we have employed an organotypic model of human stratified squamous epithelium derived from primary keratinocytes that have been engineered to express HPV-18 oncoproteins stably. We show that, whereas wild-type adenovirus promotes a widespread cytopathic effect in all infected cells, E1A- and E1A/E1B-deleted adenoviruses cause no deleterious effect regardless of the coexpression of HPV18 E6E7. An adenovirus deleted in the CR2 domain of E1A, necessary for binding to the pRB family of pocket proteins, shows no selectivity of replication as it efficiently kills all normal and E6E7-expressing keratinocytes. Finally, an adenovirus mutant deleted in the CR1 and CR2 domains of E1A exhibits preferential replication and cell killing in HPV E6E7-expressing cultures. We conclude that the organotypic keratinocyte culture represents a distinct model to evaluate adenovirus selectivity and that, based on this model, further modifications of the adenovirus genome are required to restrict adenovirus replication to tumor cells.

* Corresponding author. Mailing address: Gene Therapy Center, 1824 6th Ave. South, WTI 620, Birmingham, AL 35294-3300. Phone: (205) 975-0171. Fax: (205) 975-7949. E-mail: cristina.balague{at}ccc.uab.edu.

Journal of Virology, August 2001, p. 7602-7611, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7602-7611.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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