PENCICLOVIR AND PATHOGENESIS PHENOTYPES OF DRUG-RESISTANT HERPES-SIMPLEX VIRUS MUTANTS

We compared the penciclovir susceptibilities and pathogenesis phenotyp es of mutants of Herpes simplex virus type 1 that are resistant to acy clovir and/or foscarnet. The mutants, which were derived from laborato ry strain KOS, included six DNA polymerase mutants, a thymidine kinase negative mutant, a thymidine kinase partial mutant, and a double muta nt. Two of four polymerase mutants not previously examined for pencicl ovir susceptibility exhibited modest resistance to this drug. A thymid ine kinase negative mutant exhibited similar to 20-fold resistance whi le a thymidine kinase partial mutant was penciclovir-sensitive. Follow ing intracerebral inoculation of 7-week old CD1 mice, the mutants rang ed from exhibiting near wild-type neurovirulence (thymidine kinase par tial) to modest attenuation (e.g. thymidine kinase negative) to more s evere attenuation. Following corneal inoculation, three polymerase mut ants exhibited modest deficits (relative to those of thymidine kinase negative mutants) in their abilities to replicate acutely in the gangl ion and reactivate from latency. For mutant AraA(r)13, the deficit in ganglionic replication was shown to be due to its polymerase mutation by analysis of recombinant viruses derived by marker rescue. These res ults may have implications for issues of penciclovir action and resist ance,for drug resistance in the clinic, and for the interactions of he rpes viruses with the peripheral and central nervous systems. (C) 1998 Elsevier Science B.V.