RECURRENT ACYCLOVIR-RESISTANT HERPES-SIMPLEX IN AN IMMUNOCOMPROMISED PATIENT - CAN STRAIN DIFFERENCES COMPENSATE FOR LOSS OF THYMIDINE KINASE IN PATHOGENESIS

To investigate how acyclovir-resistant (ACV(r)) herpes simplex virus ( HSV) evades drug therapy and causes disease, HSV-1 isolates from a bon e marrow transplant (BMT) patient were studied. The patient developed ACV(r) disease after an initial BMT and, following a second BMT, react ivated ACV(r) HSV despite high-dose acyclovir prophylaxis. ACV(r) isol ates from each episode contained the same point mutation in the viral thymidine kinase (tk) gene, documenting the emergence, latency, and re activation of this mutant. The mutants were exceedingly impaired for T K activity in sensitive enzyme, plaque autoradiography, and drug-susce ptibility assays. Nevertheless, these mutants and a tk deletion mutant constructed in the same genetic background reactivated from latency i n mouse trigeminal ganglia, in contrast to similar mutants from labora tory strains. It is hypothesized that alleles in the clinical isolate compensate for the loss of TK in this animal model, Such genetic varia bility may be important for ACV(r) disease in humans.