We estimate that herpes simplex virus (HSV) keratitis causes an economic loss of over $80 million annually in the USA. Herpetic ocular disease may range in severity from a relatively benign, self-limited dendrite that does not recur to a severe, blinding recurrent necrotizing keratouveitis, yet the question of why some victims of HSV ocular disease avoid significant visual loss while others are severely affected remains unanswered. Thus far, we have developed an inbred mouse model for HSV keratitis and have shown that, in this model, genetically-determined virus and host factors play a role in determining the severity of disease that results from primary corneal inoculation with HSV. We now wish to exploit the inbred mouse model to extend these investigations and to examine factors responsible for the establishment of latency and reactivation of latent infections, since the most severe damage from HSV keratitis in the human often is seen in individuals with multiple episodes of recrudescent disease. Using the inbred mouse model, we will study host mechanisms that control recrudescence of disease and correlate sites of establishment of latency, as determined by cultivation in vitro and in situ DNA hybridization, with propensity for recrudescence. Second, we wish to examine nonimmunogenic mechanisms by which HSV replication is restricted in structural cells from certain inbred strains of mice by measuring HSV protein, glycoprotein, and DNA synthesis in permissive and nonpermissive cell lines. Restriction of HSV replication in structural cells will be correlated with disease susceptibility in the inbred mouse model as well as the human to determine the significance of these nonimmunologic mechanisms in limiting progression of disease. Third, we wish to examine the immune response of inbred mice to HSV in vitro (using blastogenesis and cytotoxic T-lymphocyte generation assays) and in vivo (by immunization) in an effort to understand how various aspects of the immune response and previous infection with the virus influence the course of HSV keratitis in vivo.
