Acyclovir in mouse cytomegalovirus infections.
A virus-specified thymidine kinase appears to be a general requirement for herpes virus susceptibility to the antiviral effect of acyclovir. Surprisingly, mouse cytomegalovirus (MCMV), which does not encode for a thymidine kinase, is exquisitely sensitive to the drug both in vitro and in vivo. The drug is active against the virus in the absence of a cellular thymidine kinase and the antiviral activity is not diminished in the presence of excess thymidine or a variety of nucleosides and deoxynucleosides. Thus, a thymidine phosphorylation pathway is not required for the drug's activation of this infection. The enzyme system responsible for phosphorylation of the drug has not been identified. Mouse cytomegalovirus mutants resistant to the drug have been isolated, indicating that the antiMCMV effect results from selective inhibition of viral replication rather than indirectly through toxicity to the host cell. Eight resistant mutants appear to be in the same complementation group and seven of the mutants demonstrate coresistance to phosphonoacetic acid, a marker for the DNA polymerase locus of herpes viruses. The evidence to date indicates that the MCMV DNA polymerases is the final site of action of the drug. Investigations of the antiMCMV activity of acyclovir should provide insights into the antiviral effects of this drug and other nucleoside analogs in other herpes virus infections in which the virus does not code for a thymidine kinase (for example, human cytomegalovirus and Epstein-Barr virus).
D000212:Acyclovir; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003587:Cytomegalovirus / Q000187:drug effects / Q000201:enzymology; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D004351:Drug Resistance; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008805:Mice, Inbred A; D009154:Mutation; D010746:Phosphonoacetic Acid / Q000494:pharmacology; D013937:Thymidine Kinase / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D006147:Guanine; D013937:Thymidine Kinase; D010746:Phosphonoacetic Acid; D000212:Acyclovir