Development of clinical resistance to acyclovir in herpes simplex virus-infected mice receiving oral therapy

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Abstract
Mice inoculated in the ear pinna with herpes simplex virus were treated effectively by including 1 mg of acyclovir per ml in the drinking water. During a 5-day course of treatment the development of resistance was not readily apparent. However, when a suboptimal therapeutic dose was used and virus was repeatedly inoculated into further mice undergoing therapy, the infection became completely refractory to treatment by passage 4. Some of the viruses isolated exhibited reduced ability to induce thymidine kinase, and this appeared to account at least in part for the development of resistance. However, the viruses isolated from the tissues of such mice comprised complex mixtures of strains with widely differing in vitro susceptibilities to acyclovir. The properties of these virus yields gave an indication of the likely nature of resistance to nucleoside analogs in humans and suggested some difficulties which may be encountered when clinical specimens are analyzed.