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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-¹

Khaldun Al-khatib^*, Bryan R. G. Williams, Robert H. Silverman, William Halford and Daniel J. J. Carr^2,*

^* Departments of Ophthalmology, Microbiology, and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Department of Cancer Biology/NB40, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195; and Program in Molecular Pathogenesis and Immunity, Tulane University Medical Center, New Orleans, LA 70112

To evaluate the anti-HSV-1 mechanisms of murine IFN- in ocular infection, mice were transduced with an adenoviral vector expressing murine IFN- (Ad:IFN-). Ocular transduction with Ad:IFN- 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- levels, and 4) the percentage of CD8⁺ T lymphocyte and NK cell infiltration in infected tissue. Expression of IFN- 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- 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- 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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				B. A. Austin, W. P. Halford, B. R. G. Williams, and D. J. J. Carr Oligoadenylate Synthetase/Protein Kinase R Pathways and {alpha}beta TCR+ T Cells Are Required for Adenovirus Vector: IFN-{gamma} Inhibition of Herpes Simplex Virus-1 in Cornea J. Immunol., April 15, 2007; 178(8): 5166 - 5172. [Abstract] [Full Text] [PDF]

				B. A. Austin, C. James, R. H. Silverman, and D. J. J. Carr Critical Role for the Oligoadenylate Synthetase/RNase L Pathway in Response to IFN-{beta} during Acute Ocular Herpes Simplex Virus Type 1 Infection J. Immunol., July 15, 2005; 175(2): 1100 - 1106. [Abstract] [Full Text] [PDF]