title: Pathogenesis of acyclovir-resistant herpes simplex type 2 isolates in animal models of genital herpes: models for antiviral evaluations.
abstract: Our understanding of the pathogenesis of acyclovir (ACV)-resistant herpes simplex virus (HSV) is limited, especially with regard to reactivation and recurrent disease. To further explore the pathogenesis of ACV-resistant HSV-2 viruses, we used the guinea pig model of genital HSV-2 infection to evaluate several ACV-resistant isolates of both thymidine kinase (Tk)-altered and Tk-deficient phenotypes obtained from HIV-infected patients. Two plaque-purified workpools from each isolate were initially evaluated. Each produced acute disease and at least one clinical recurrence. The two strains that produced the most severe primary disease and most recurrences, one Tk-deficient virus and one Tk-altered virus, were further evaluated and shown to produce acute and recurrent genital disease similar to that seen with wild-type viruses. Furthermore, the reactivated virus producing recurrent lesions could be a pure population with minimal Tk activity. Finally, we showed that topical foscarnet treatment could alter disease and vaginal virus replication following vaginal inoculation with these two ACV-resistant strains. Using the guinea pig model of genital HSV-2 infection, we found that recurrent disease following infection with markedly Tk-deficient viruses was more common than expected, especially in select isolates. Furthermore, this model should be useful in evaluating potential new therapies for ACV-resistant HSV strains.
authors.affiliation: Children's Hospital Medical Center, Division of Infectious Diseases, Room 1331, 3333 Burnet Avenue, CH-1, Cincinnati, OH 45229-3039, USA. dib@chmcc.org
authors.forename: D I
authors.initials: DI
authors.lastname: Bernstein
authors.forename: J
authors.initials: J
authors.lastname: Ireland
authors.forename: N
authors.initials: N
authors.lastname: Bourne
mesh_terms: D000212:Acyclovir / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial; D005260:Female; D017245:Foscarnet / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D006558:Herpes Genitalis / Q000188:drug therapy / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity*; D006801:Humans; D051379:Mice; D011817:Rabbits; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D014709:Vero Cells; D014775:Virus Activation / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D017245:Foscarnet; D000212:Acyclovir