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.
B Activation in Combination
with Bcl-2 Expression Allows for Persistence of First-Generation
Adenovirus Vectors in the Mouse Liver
Division of Medical Genetics,
Received 27 May 1998/Accepted 3 August 1998
NF-
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-
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 I
B
supersuppressor (Ad.I
BM) and
bcl-2 transgenic mice to unravel the role of virus-induced
NF-
B activation and apoptosis in the clearance of recombinant
adenovirus vectors from the liver. The combined action of I
BM and
Bcl-2 allowed for vector persistence in livers of C57BL/6 × C3H
mice. In the absence of Bcl-2, I
BM expression in mouse livers
significantly reduced NF-
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.I
BM caused
extended apoptosis predominantly in periportal liver regions,
indicating that NF-
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-
B protection was inactivated by
I
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.
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