DEOXYURIDINE METABOLISM IN HERPES LABIALIS

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Herpes simplex virus (HSV) is the etiological agent of a number of diseases including herpes labialis and there is a correlation between HSV infections and the development of certain neoplastic diseases. HSV induces approximately 50 polypeptides in permissively infected cells and some of these possess enzymatic activity. However, except for the HSV induced DNA polymerase and thymidine kinase, little is known concerning the roles of other HSV-induced enzymes in replication or in antiviral chemotherapy. The goal of this research is to determine whether the HSV induced deoxyuridine triphosphate nucleotidohydrolase (dUTPase, EC 2.6.1.23) can be used as a target site for the development of specific antiviral compounds and to determine what role this enzyme may have in regulating the chemotherapeutic effectiveness of specific antiviral agents. To accomplish this, we plan to use purified HSV induced and cellular dUTPases to elucidate features concerning the active-site of the dUTPases, to determine differences in the steric-binding properties of these enzymes and to determine the mechanism(s) by which these dUTPases are inhibited by various mercury (II) compounds. We will construct, using insertional and site-directed mutagenesis HSV mutants that are defective in dUTPase activity and that have altered dUTPase activity. These mutants as well as wild-type virus will be used in in vivo studies to determine how changes in deoxyuridine (dUrd) pools will effect incorporation of dUTP into HSV DNA and to determine how incorporation of dUTP into the DNA effects HSV replication.