title: Penciclovir is a potent inhibitor of feline herpesvirus-1 with susceptibility determined at the level of virus-encoded thymidine kinase.
abstract: Feline herpesvirus-1 (FHV-1) is the causative agent of a severe ocular disease in cats for which a safe potent antiviral chemotherapeutic agent is highly demanded. The sensitivity of FHV-1 to inhibition by three anti-herpetic nucleoside analogues [acyclovir (ACV), penciclovir (PCV) and cidofovir (CDV)] was tested by means of yield reduction assay. ACV showed very poor ability to inhibit FHV-1 replication. At low multiplicity of infection (MOI), both PCV and CDV were nearly equally effective with IC50 values ranging between 6 and 8 microg/ml. However, when the MOI was raised to 3PFU/cell, the activity of CDV was markedly reduced (IC50 25 microg/ml), while that of PCV remained relatively low (IC50 10 microg/ml). Although FHV-1 is normally insensitive to ACV, it exhibited >1000-fold increase in sensitivity when the thymidine kinase (TK) encoded by herpes simplex virus-1 (HSV-1) was supplied in trans. Furthermore, three PCV-resistant FHV-1 variants selected in vitro were shown to carry mutations in the TK gene. Taken together, these data provided direct evidence that PCV is a potent selective inhibitor of FHV-1 and that the virus-encoded TK is an important determinant of the virus susceptibility to nucleoside analogues.
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors.forename: Islam T M
authors.initials: IT
authors.lastname: Hussein
authors.forename: Rebecca V
authors.initials: RV
authors.lastname: Menashy
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Field
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002415:Cats; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D006147:Guanine; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology / Q000821:virology; D008826:Microbial Sensitivity Tests / Q000379:methods; D009154:Mutation; D013937:Thymidine Kinase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C053539:penciclovir; D006147:Guanine; D013937:Thymidine Kinase; D000212:Acyclovir