The overall objective of this contract is to provide a resource for preclinical in vitro evaluation of new antiviral agents against members of the herpesvirus group. In the initial studies experimental compounds will be screened for antiviral activity against herpes simplex virus types 1 and 2, cytomegalovirus, varicella-zoster virus and Epstein-Barr virus using rapid screening assays in human cells. Toxicity of the compounds will also be assessed in each of the cell culture assay systems used for efficacy evaluation and by cell proliferation studies. Compounds that have a therapeutic or selectivity index of five or greater will be confirmed using additional assay systems, different cell lines and additional virus strains. Toxicity will be evaluated further in each of these systems and in a B lymphocyte proliferation assay. This battery of confirmatory tests is designed to select compounds that have potential for further evaluation in animal model and clinical trials. An arbitrary selectivity index of 50 or greater will be used to select those compounds that warrant follow-up evaluation. Any new antiviral agent that meets these criteria will be considered for additional studies including: 1) combination studies with antiviral agents that are currently being used for human herpesvirus infections 2) mechanism of action studies to understand better the selectivity of new agents and 3) further evaluation of toxicity using a bone marrow clonogenic assay.
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