The original and all subsequent potent antivirals for treating herpes simplex virus (HSV) have been nucleosides. In addition to limited activity, they all share cross resistance. BAY 57-1293 is a helicase primase inhibitor that is more potent and may be safer than acyclovir, but it is almost untested in the eye. Acyclovir prevents only 40 - 50% of recurrences of HSV, and no topical agent prevents recurrences.
In Specific Aim 1, topical and systemic BAY 57-1293 will be compared with acyclovir and trifluridine to determine its efficacy in models of epithelial keratitis, stromal keratitis, and iritis and to determine if BAY 57-1293 can prevent recurrences of herpes when administered both topically and systemically. A recombinant strain of McKrae HSV (McKrae-EGFP) that expresses a fluorescent green protein will be used. The sensitivity of using the green fluorescence to identify experimental lesions will be evaluated, especially in recurrent keratitis which may lack typical dendritic lesions. PCR makes it possible, for the first time, to correlate not only demographics, but also seropositivity and titers of antibody and the results of cell-mediated immunity testing, with HSV-1 DMA shedding. In our recent study of HSV DNA in tears and saliva, viral DNA was recovered from antibody-negative and antibody-positive persons. One question is: How valuable and reliable are the antibody tests? In Specific Aim 2, IgG and IgM antibodies, as well as cell-mediated immunity, will be correlated with the presence and frequency of shedding in human subjects; viral production in tears and saliva will also be correlated with age and ethnicity. This may permit the defining of risk factors for recurrence for people with previous disease and perhaps for people who need to be immunosuppressed or treated with corticosteroids.
In Specific Aim 3, the production of viral DNA in tears and saliva will be used as a surrogate to test drug efficacy in human subjects. Aspirin and COX-2 inhibitors suppress virus production and infection in rabbits and mice, but the cyclooxygenase system works somewhat differently in man. Acyclovir provides only incomplete protection against reinfection in man. If we find that aspirin and COX-2 inhibitors suppress virus production, this would provide a rationale for the expensive and extensive testing of these drugs against infection in man. If they are additive to or synergistic with acyclovir in suppressing viral DNA production, tests on human infection could almost certainly follow. ? ? ?
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