Pathogenesis of acyclovir-resistant herpes simplex type 2 isolates in animal models of genital herpes: models for antiviral evaluations

Our understanding of the pathogenesis of acyclovir (ACV)-resistant herpes s implex virus (HSV) is limited, especially with regard to reactivation and r ecurrent disease. To further explore the pathogenesis of ACV-resistant HSV- 2 viruses, we used the guinea pig model of genital HSV-2 infection to evalu ate several ACV-resistant isolates of both thymidine kinase (Tk)-altered an d Tk-deficient phenotypes obtained from HIV-infected patients. Two plaque-p urified workpools from each isolate were initially evaluated. Each produced acute disease and at least one clinical recurrence. The two strains that p roduced the most severe primary disease and most recurrences, one Tk-defici ent virus and one Tk-altered virus, were further evaluated and shown to pro duce acute and recurrent genital disease similar to that seen with wild-typ e viruses. Furthermore, the reactivated virus producing recurrent lesions c ould be a pure population with minimal Tk activity. Finally, we showed that topical foscarnet treatment could alter disease and vaginal virus replicat ion following vaginal inoculation with these two ACV-resistant strains. Usi ng the guinea pig model of genital HSV-2 infection, we found that recurrent disease following infection with markedly Tk-deficient viruses was more co mmon than expected, especially in select isolates. Furthermore, this model should be useful in evaluating potential new therapies for ACV-resistant HS V strains. (C) 2000 Elsevier Science B.V. All rights reserved.