Type I IFNs (i.e., IFN-alpha and IFN-beta) play a key role in the host's innate defense against viral pathogens. To examine the biologic relevance of IFN-alpha to a viral pathogen within the confines of the nervous system, IFN-alpha1 transgenic mice whose transgene is under the control of the glial fibrillary acidic protein promoter (GFAP-IFN-alpha, astrocyte specific) were examined for resistance to an ocular herpes simplex virus type 1 (HSV-1) infection. GFAP-IFN-alpha mice expressed significantly higher levels of IFN-alphabeta (533 U) in the trigeminal ganglion compared with nontransgenic mice (70 U) 72 h postinfection that corresponded with a significant reduction in the mRNA expression of the HSV-1 immediate early gene infected cell polypeptide 27 and late gene VP16, as well as the chemokines monocyte-chemoattractant protein-1 and cytokine response gene-2 in the eye and trigeminal ganglion. Six days postinfection, the viral load and the expression of infected cell polypeptide 27, CD8, RANTES, IFN-gamma, and IFN-alpha mRNA levels were reduced in the trigeminal ganglion of GFAP-IFN-alpha mice compared with the wild-type mice. Following the establishment of HSV-1 latency (i.e., 30 days postinfection), only one of nine (11%) GFAP-IFN-alpha mice was found to be latent compared with seven of eight (88%) of the wild-type mice, as determined by the expression of the latency-associated transcript RNAs. Likewise, only three of nine GFAP-IFN-alpha mice screened showed seroconversion by day 30 postinfection compared with nine of ten wild-type mice screened. Collectively, the results show that the IFN-alpha1 transgenic mice are less susceptible to acute HSV-1 infection and the establishment of viral latency.