Acyclovir Treatment Stimulates dCMP Deaminase Activity in HSV-1-Infected Cells

Abstract

Herpes simplex virus (HSV) infection induces enzymes involved in DNA precursor metabolism and DNA synthesis. The level of the DNA precursors dCTP, dTTP and dGTP increases after HSV infection, while the dATP level decreases. Inhibition of viral DNA synthesis by acyclovir (ACV) increases all four deoxyribonucleoside triphosphate levels, in particular that of dTTP. In the present work the dynamics of metabolism of pyrimidine deoxyribonucleotides and changes in the dTTP and dCTP pools in HSV-1-infected HL cells and in infected cells where viral DNA synthesis was inhibited by ACV were studied. In the absence of the drug the major part of the dCDP synthesized was incorporated into DNA. ACV treatment inhibited DNA synthesis completely but increased de novo dTMP synthesis. A continued ribonucleotide reductase activity in ACV-treated HSV-1-infected cells contributes to the increasing dTTP pool. The allosteric regulation of dCMP deaminase activity in HSV-1-infected cells was investigated. The great increase of de novo dTMP synthesis was shown to be due to stimulation of dCMP deaminase activity by an increasing dCTP pool. The high dTTP pool is suggested to be of secondary importance to the dCTP pool in the regulation of dCMP deaminase activity in HSV-1-infected cells.