Ocular adenoviral infections occur in epidemics worldwide, and are associated with significant patient morbidity. Currently, there is no effective antiviral therapy, nor has there been an animal model in which to study the pathogenesis of ocular disease or to test new antivirals.
The specific aims of the current proposal are: 1) to begin the study of the pathogenesis of adenoviral ocular infection in our NZ rabbit ocular model. Specifically, to determine the molecular basis for differences in serotype virulence, and the mechanism of host range extension of Ad 5 in our successful model; and 2) to evaluate new antivirals as potential therapeutic agents in vitro and in the NZ rabbit ocular model. Preliminary ocular studies in 44 NZ rabbits suggested differences in adenovirus pathogenicity based on viral serotype: Ad 5 (productive infection), Ad 8 (abortive infection), and Ad 19 (no infection). A successful ocular model of adenovirus infection was developed in 32 NZ rabbits infected with Ad 5 McEwen, a clinical isolate, using a paired-eye design. Reproducible acute ocular infection was demonstrated with viral replication for 8 consecutive days. Peak ocular viral titers (103 pfu/ml) were achieved on day 3 p.i. and represented a two log increase (x100) over tivitis (24/32 eyes, 75 percent), and delayed onset of presumed immune-mediated clinical disease: blepharoconjunctivitis (21/32 eyes, 66 percent), iritis (29/32 eyes, 91 percent), corneal edema (32/32 eyes, 100 percent), and subepithelial corneal infiltrates (30/32 eyes, 94 percent). Preliminary in vitro antiviral studies with S-HMPHA and 2'-nor-cGMP demonstrated potent inhibitory activity against several human ocular serotypes: Ad 5, Ad 8, and Ad 19. The current proposal seeks to test these promising agents in our new in vivo rabbit ocular model. The applicant's long term goals are to achieve a better understanding of the molecular basis of the pathogenesis of adenoviral ocular infections, and to develop effective treatment to reduce patient suffering.
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