Enzymology and pathogenicity in mice of a herpes simplex virus type 1 mutant resistant to 2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodocytosine.
The deoxypyrimidine nucleoside analog 2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodocytosine (FIAC) is a potent and selective inhibitor of herpes simplex virus type 1 in vitro (C. Lopez, K. A. Watanabe, and J. J. Fox, Antimicrob. Agents Chemother. 17:803-806, 1980). Isopycnographic analysis demonstrated that 1 microM FIAC inhibited herpes simplex virus DNA replication by more than 95% but inhibited cellular DNA replication by only 32%. Mutant herpes simplex virus type 1 selected resistant to FIAC displayed linked resistance to other nucleoside analogs, including arabinosylthymine and acyclovir. Lysates derived from Vero cells infected with FIAC-resistant virus showed markedly lower levels of thymidine kinase activity and were unable to phosphorylate selectively arabinosylthymine or FIAC, in contrast to lysates from cells infected with wild-type herpes simplex virus type 1. Finally, drug-resistant virus displayed a 6,000-fold decrease in pathogenicity when inoculated intraperitoneally into genetically susceptible A/J mice. These results indicate that resistance to deoxypyrimidine nucleoside analogs is due, at least in part, to alterations in viral thymidine kinase and is accompanied by decreased pathogenicity in vivo.
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002499:Centrifugation, Density Gradient; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004279:DNA, Viral / Q000032:analysis; D004352:Drug Resistance, Microbial; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D013937:Thymidine Kinase / Q000378:metabolism; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D004279:DNA, Viral; D003561:Cytarabine; C026023:fiacitabine; D013937:Thymidine Kinase