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 (ACVr) herpes simplex virus (HSV) evades drug therapy and causes disease, HSV-1 isolates from a bone marrow transplant (BMT) patient were studied. The patient developed ACVr disease after an initial BMT and, following a second BMT, reactivated ACVr HSV despite high-dose acyclovir prophylaxis. ACVr isolates from each episode contained the same point mutation in the viral thymidine kinase (tk) gene, documenting the emergence, latency, and reactivation of this mutant. The mutants were exceedingly impaired for TK activity in sensitive enzyme, plaque autoradiography, and drug-susceptibility assays. Nevertheless, these mutants and a tk deletion mutant constructed in the same genetic background reactivated from latency in mouse trigeminal ganglia, in contrast to similar mutants from laboratory strains. It is hypothesized that alleles in the clinical isolate compensate for the loss of TK in this animal model. Such genetic variability may be important for ACVr disease in humans.
Horsburgh
B C
BC
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Chen
S H
SH
Hu
A
A
Mulamba
G B
GB
Burns
W H
WH
Coen
D M
DM
D000212:Acyclovir / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001345:Autoradiography; D016026:Bone Marrow Transplantation / Q000276:immunology; D002522:Chlorocebus aethiops; D004352:Drug Resistance, Microbial; D006561:Herpes Simplex / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D006801:Humans; D016867:Immunocompromised Host; D051379:Mice; D017354:Point Mutation; D012008:Recurrence; D013045:Species Specificity; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014709:Vero Cells; D010948:Viral Plaque Assay; D014775:Virus Activation
D000998:Antiviral Agents; D013937:Thymidine Kinase; D000212:Acyclovir