Biological and biochemical characterization of clinical isolates of herpes simplex virus type 2 resistant to acyclovir

A series of clinical isolates of herpes simplex virus type 2 were taken from a patient with chronic lymphocytic leukemia. Acyclovir (ACV) susceptibility assays revealed that some isolates were resistant to ACV and cross-resistant to ganciclovir but not to phosphonoacetic acid. The nature of the resistance was examined further. A number of cloned variants were generated, and thymidine kinase and DNA polymerase assays were carried out. Variants that were resistant to ACV were found to be thymidine kinase deficient. Evidence for alteration in the DNA polymerase was not found when ACV triphosphate or phosphonoacetic acid was used as the inhibitor. In vivo studies with the plaque-purified viruses showed that ACV resistance was associated with a reduced neurovirulence. In a zosteriform model, virus resistant to ACV was unable to induce secondary spread in the same dermatome, to invade the peripheral nervous system or the central nervous system, or to establish latent infections.