Ocular HSV-1, Stromal Keratitis, & T Cell Costimulation

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DESCRIPTION (provided by applicant): Herpes simplex virus type 1 (HSV-1) corneal infection leads to establishment of a latent infection in the sensory and autonomic ganglia. HSV-1 reactivates at intervals and causes recurrent corneal infection. Repeated inflammation in the corneal stroma can lead to herpetic stromal keratitis (HSK), an immune inflammatory process that results in blindness. For optimal activation, T cells require costimulation in addition to antigen receptor signals. Constitutive receptors such as CD28 are known to provide costimulation to naive T cells. We have also shown that 4-1BB, an inducible receptor, provides costimulation to activated and memory T cells. However, whether costimulatory receptors play a role in acute, latent, and recurrent HSV-1 infection, and in HSK, is not known. It is also not known whether induction of T-cell energy by blocking costimulation can prevent HSK. Our goals are to determine the role of T-cell costimulatory molecules in herpes infection, to identify factors involved in the pathogenesis of HSK, and to investigate the therapeutic potential of blocking costimulation in HSK. Three specific aims are proposed: 1] Test the hypothesis that the costimulatory receptors, 4-1BB and CD28, are involved in modulating acute HSV-1 infection, latency, and recurrence using 4-1BB- and/or CD28-deficient mice. 2] Determine the roles of the costimulatory receptors 4-1BB and CD28 in the pathogenesis of HSK. 3] Test the hypothesis that blocking costimulation is effective in preventing HSK. This approach (inhibition of costimulation) should be both specific and nontoxic, compared to the use of immunosuppressive drugs. These studies will aid in understanding the immunological mechanisms involved in the blinding eye condition, HSK, and allow development of strategies for the treatment of this and other ocular inflammatory diseases.