Herpesviruses cause latent infections that persist for the lifetime of the host and these viruses have developed mechanisms to counteract host defenses so as to allow the virus to persist. Using sophisticated computer programs we are identifying herpesvirus genes that have cellular homologs. These genes are being expressed in various systems to determine how the genes may interact with host cell proteins, including those of the immune system, to influence the course of infection. Identification of these genes may help define new targets for antiviral therapy or new insights into modulating the immune system. Varicella-zoster virus (VZV) ORF13 encodes a viral thymidylate synthetase. This enzyme catalyzes the methylation of deoxyuridylate to thymidylate. We have constructed a VZV mutant that cannot express the viral thymidylate synthetase by inserting stop codons into the gene. We plan to inoculate guinea pigs with the VZV mutant to determine whether the viral thymidylate synthetase is important for infection with the virus or for its ability to spread to the central nervous system and maintain latent infection. Epstein-Barr virus (EBV) encodes a protein that contains seven putative transmembrane domains and shares homology to the G protein-coupled receptor superfamily. We have cloned this EBV gene, expressed a protein, and are currently assaying the protein for biological activity. Additional herpesvirus homologs of known mammalian proteins have been identified. Promising candidates will be studied in appropriate systems in collaboration with M. Spriggs at Immunex.