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. 1999 Aug;43(8):1941-6.
doi: 10.1128/AAC.43.8.1941.

Acyclovir is phosphorylated by the human cytomegalovirus UL97 protein

C L Talarico  1 , T C Burnette, W H Miller, S L Smith, M G Davis, S C Stanat, T I Ng, Z He, D M Coen, B Roizman, K K Biron
Affiliations

Acyclovir is phosphorylated by the human cytomegalovirus UL97 protein

C L Talarico et al. Antimicrob Agents Chemother. 1999 Aug.

Abstract

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 UL97 gene product, a protein kinase, is responsible for the phosphorylation of GCV in HCMV-infected cells. This report provides evidence for the phosphorylation 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 laboratory-derived strain resistant to GCV showed that mutations in the UL97 gene cripple the ability of recombinant virus-infected cells to anabolize both GCV and ACV. These mutant UL97 recombinant viruses were less susceptible to both GCV and ACV than was the wild-type strain. A recombinant herpes simplex 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 phosphorylation of ACV in infected cells. Finally, purified UL97 phosphorylated both GCV and ACV to their monophosphates. Our results indicate that UL97 promotes the selective activity of ACV against HCMV.

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Figures

FIG. 1
FIG. 1
Anion-exchange HPLC profiles of wild-type GST-UL97 enzyme reactions at 8 h with 3H-labeled GCV (A) or 3H-labeled ACV (B), as described in the Materials and Methods section. Retention times of authentic carriers which appear in the UV profile are as follows: ACV, 1.8 min; GCV, 1.8 min; AMP, 12.2 min; GCV-MP, 14.3 min; ACV-MP, 15.9 min; GMP, 17.1 min; ADP, 20.4 min; ATP, 25.0 min; and GTP, 27.2 min. The UV peak at 19.5 min is an unknown peak generated from the UL97 preparation. Radioactive peaks were collected as 1-ml fractions. The scale for the counts per minute (cpm) was expanded to more clearly show the MP cpm; the cpm in fraction 2 were approximately 600,000, and those in fraction 3 were approximately 80,000.
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