INHIBITION OF NF-KAPPA-B ACTIVATION IN COMBINATION WITH BCL-2 EXPRESSION ALLOWS FOR PERSISTENCE OF FIRST-GENERATION ADENOVIRUS VECTORS IN THE MOUSE-LIVER

NF-kappa B is a key regulator of the innate antiviral immune response, due in part to its transcriptional activation of cytokines and adhesi on 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) adenoviruse s induced NF-kappa B activation, elevation of serum cytokines, and hep atocellular apoptosis during the first days postinfusion, These events did not occur in mice infused with an adenovirus vector deleted for E 1, E2, E3, and late gene expression. In the present study, we used an adenovirus expressing an I kappa B alpha supersuppressor (Ad.I kappa B M) and bcl-2 transgenic mice to unravel the role of virus-induced NF-k appa B activation and apoptosis in the clearance of recombinant adenov irus vectors from the liver, The combined action of I kappa BM and Bcl -2 allowed for vector persistence in livers of C57BL/6 x C3H mice. In the absence of Bcl-2, I kappa BM expression in mouse livers significan tly reduced NF-kappa B activation, cytokine expression, leukocyte infi ltration, and the humoral immune response against the transgene produc t; however, this was not sufficient to prevent the decline of vector D NA in transduced cells. Infusion of Ad.I kappa BM caused extended apop tosis predominantly in periportal liver regions, indicating that NF-ka ppa B activation may protect transduced hepatocytes from apoptosis ind uced 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 I kappa BM, Expression of gen e products involved in early stages of apoptotic pathways was up-regul ated 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.