Acyclovir is phosphorylated by the human cytomegalovirus UL97 protein

Acyclovir (ACV) has shown efficacy in the prophylactic suppression of human cytomegalovirus (HCMV) reactivation in immunocompromised renal transplant patients without the toxicity associated with ganciclovir (GCV). The HCMV U L97 gene product, a protein kinase, is responsible for the phosphorylation of GCV in HCMV-infected cells. This report provides evidence for the phosph orylation of ACV by UL97. Anabolism studies with the HCMV wild-type strain AD169 and with recombinant mutants derived from marker transfer experiments performed by using mutant UL97 DNA from both clinical isolates and a labor atory-derived strain resistant to GCV showed that mutations in the UL97 gen e cripple the ability of recombinant virus-infected cells to anabolize both GCV and ACV. These mutant UL97 recombinant viruses were less susceptible t o both GCV and ACV than was the wild-type strain. A recombinant herpes simp lex virus type 1 strain, in which the thymidine kinase gene is deleted and the UL13 gene is replaced with the HCMV UL97 gene, was able to induce the p hosphorylation of ACV in infected cells. Finally, purified UL97 phosphoryla ted both GCV and ACV to their monophosphates. Our results indicate that UL9 7 promotes the selective activity of ACV against HCMV.