Characterization of acyclovir-resistant and -sensitive herpes simplex viruses isolated from a patient with an...

Several different genital and non-genital HSV isolates were obtained from a patient with an acquired immune deficiency of unknown aetiology. The patient was initially treated with topical acyclovir (ACV) and later with topical and intravenous ACV. In spite of treatment with antiviral drugs the patient continued to shed virus and to have extensive genital ulcerations. Restriction endonuclease (RE) analyses of the viral DNA revealed that all the isolates had characteristic HSV-2 patterns and that there were three genetically distinct virus groups among the ten isolates tested. Three post-therapy isolates, with the same RE pattern, were found to be devoid of thymidine kinase activity (TKD), highly resistant to ACV in cell culture, but sensitive to vidarabine (ara-A), phosphonoacetate and phosphonoformate. Two of these TKD isolates were obtained during and after topical ACV therapy and before intravenous treatment. Mice inoculated intracerebrally with a lethal dose of each of the three TKD viruses were refractory to ACV, but responded to vidarabine or a combination of ACV and ara-A. Mice inoculated with the TK+ viruses (including the pre-therapy isolate) responded to ACV and/or ara-A treatment. The results indicate that: (i) TKD variants may be produced in humans after topical ACV therapy; (ii) different ACV-resistant or sensitive HSV-2 variants can establish latency at different body sites and reactivate; and (iii) when drug-resistant viruses are isolated from patients with multiple reactivations, the drug in question should not be discontinued, since the patients may also be shedding drug-sensitive virus at a different body site.