Distinctive Roles for 2′,5′-Oligoadenylate Synthetases and Double-Stranded RNA-Dependent Protein Kinase R in the In Vivo Antiviral Effect of an Adenoviral Vector Expressing Murine IFN-β

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Abstract
To evaluate the anti-HSV-1 mechanisms of murine IFN-β in ocular infection, mice were transduced with an adenoviral vector expressing murine IFN-β (Ad:IFN-β). Ocular transduction with Ad:IFN-β resulted in enhanced survival following infection with HSV-1. The protective effect was associated with a reduction in 1) viral titer, 2) viral gene expression, 3) IFN-γ levels, and 4) the percentage of CD8+ T lymphocyte and NK cell infiltration in infected tissue. Expression of IFN-β resulted in an elevation of the IFN-induced antiviral gene 2′,5′-oligoadenylate synthetase (OAS1a) but not dsRNA-dependent protein kinase R (PKR) in the cornea and trigeminal ganglion (TG). Mice deficient in the downstream effector molecule of the OAS pathway, RNase L, were no more sensitive to ocular HSV-1 compared with wild-type controls in the TG based on measurements of viral titer. However, the efficacy of Ad:IFN-β was transiently lost in the eyes of RNase L mice. By comparison, PKR-deficient mice were more susceptible to ocular HSV-1 infection, and the antiviral efficacy following transduction with Ad:IFN-β was significantly diminished in the eye and TG. These results suggest that PKR is central in controlling ocular HSV-1 infection in the absence of exogenous IFN, whereas the OAS pathway appears to respond to exogenous IFN, contributing to the establishment of an antiviral environment in a tissue-restricted manner.

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