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Inhibition of Herpes Simplex Virus Replication by Purine Deoxyribonucleosides¹

Department of Biochemistry and Pharmacology, Tufts University, Schools of Medicine and Veterinary Medicine, Boston, Massachusetts 02111

The inhibition of herpes simplex virus (HSV) replication by 2'-deoxyadenosine (dAdo) is greatly potentiated by the presence of the inhibitor of adenosine deaminase, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). HSV replication is inhibited by dAdo [in the presence of EHNA] or by 2'-deoxyguanosine (dGuo) at concentrations slightly lower than are necessary to inhibit growth of uninfected HeLa cells. Under conditions where virus replication is inhibited by >99% with dAdo and EHNA, the level of dATP increases 50-fold or more, and synthesis of HSV DNA is inhibited. However, there is no depletion of any other DNA precursor, and HSV multiplication is not restored by simultaneous provision of dGuo, deoxythymidine, deoxycytidine, or a combination of all three of these nucleosides. Thus, the inhibition of HSV replication by dAdo cannot be explained as a block of precursor provision through inhibition of ribonucleotide reductase. In contrast, dGuo treatment of HSV-infected cells leads to depletion of dCTP, and virus multiplication is partially restored by provision of deoxycytidine.

HSV-infected cells may serve as a useful system for study of the toxic effects of dAdo that are unrelated to inhibition of ribonucleotide reductase by dATP.

¹ This work was supported by a grant from the Massachusetts Division of the American Cancer Society and a Biomedical Research Support Grant from the NIH.

² To whom requests for reprints should be addressed, at Department of Biochemistry and Pharmacology, Tufts University, Schools of Medicine and Veterinary Medicine, 136 Harrison Ave., Boston, MA 02111.

Received 9/29/83. Accepted 12/27/83.