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Journal of Virology, November 1998, p. 9267-9277, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Inhibition of NF-kappa B Activation in Combination with Bcl-2 Expression Allows for Persistence of First-Generation Adenovirus Vectors in the Mouse Liver

André Lieber,1,* Chen-Yi He,1,2 Leonard Meuse,1,2 Charis Himeda,1 Christopher Wilson,3 and Mark A. Kay1,2,*

Division of Medical Genetics, Department of Medicine,1 and Departments of Pediatrics and Immunology,3 University of Washington, Seattle, Washington 98115, and Departments of Pediatrics and Genetics, Stanford University, Stanford, California 943052

Received 27 May 1998/Accepted 3 August 1998

NF-kappa B is a key regulator of the innate antiviral immune response, due in part to its transcriptional activation of cytokines and adhesion molecules, which, in turn, function in chemotaxis and activation of inflammatory cells. We reported earlier that viral gene expression in hepatocytes transduced with first-generation (E1-deleted) adenoviruses induced NF-kappa B activation, elevation of serum cytokines, and hepatocellular apoptosis during the first days postinfusion. These events did not occur in mice infused with an adenovirus vector deleted for E1, E2, E3, and late gene expression. In the present study, we used an adenovirus expressing an Ikappa Balpha supersuppressor (Ad.Ikappa BM) and bcl-2 transgenic mice to unravel the role of virus-induced NF-kappa B activation and apoptosis in the clearance of recombinant adenovirus vectors from the liver. The combined action of Ikappa BM and Bcl-2 allowed for vector persistence in livers of C57BL/6 × C3H mice. In the absence of Bcl-2, Ikappa BM expression in mouse livers significantly reduced NF-kappa B activation, cytokine expression, leukocyte infiltration, and the humoral immune response against the transgene product; however, this was not sufficient to prevent the decline of vector DNA in transduced cells. Infusion of Ad.Ikappa BM caused extended apoptosis predominantly in periportal liver regions, indicating that NF-kappa B activation may protect transduced hepatocytes from apoptosis induced by adenovirus gene products. To confer vector persistence, bcl-2 transgene expression was required to block virus-induced apoptosis if NF-kappa B protection was inactivated by Ikappa BM. Expression of gene products involved in early stages of apoptotic pathways was up-regulated in response to virus infusion in bcl-2 transgenic mice, which may represent a compensatory effect. Our study supports the idea that the suppression of innate defense mechanisms improves vector persistence.

* Corresponding author. Mailing address for André Lieber: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98115. Phone: (206) 543-0109. Fax: (206) 685-8675. E-mail: lieber00{at}u.washington.edu. Mailing address for Mark A. Kay: Departments of Pediatrics and Genetics, Stanford University, 300 Pasteur Dr., Rm. G-305A, Stanford, CA 94305. Phone: (650) 498-6531. Fax: (650) 498-6540. E-mail: markay{at}stanford.edu.

Journal of Virology, November 1998, p. 9267-9277, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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