title: Compartmentalization of acyclovir-resistant varicella zoster virus: implications for sampling in molecular diagnostics.
abstract: BACKGROUND
  Acyclovir resistance of varicella zoster virus (VZV) may arise in stem cell transplant (SCT) recipients with VZV disease and is usually a result of mutations in VZV thymidine kinase (TK), which is the target protein of acyclovir. Early detection of such mutations is necessary to enable timely therapy adaptation, for example, to foscarnet. We aimed to investigate whether TK mutations arise over time, and what sample types might be the most useful for this method.
  
  
  METHODS
  Spatially and temporally distinct samples from 3 SCT recipients with VZV disease unresponsive to acyclovir treatment were retrospectively investigated for the presence of TK mutations by polymerase chain reaction and sequence analysis.
  
  
  RESULTS
  In all 3 patients, a mutation in the VZV TK coding region was found resulting in an amino acid substitution. TK mutations were not only temporally but also spatially compartmentalized. In particular, plasma samples frequently showed wild-type TK sequences, whereas cerebrospinal fluid or skin vesicle fluid acquired on the same day contained mutant sequences.
  
  
  CONCLUSIONS
  This study shows the importance of careful sampling for molecular diagnostics of acyclovir resistance in VZV disease. All affected body sites should be sampled and plasma samples may not be representative for the viral mutation status.
authors: Department of Medical Microbiology, Maastricht University Medical Center, Maastricht, The Netherlands. aatp.brink@mumc.nl
authors: Antoinette A T P
authors: AA
authors: Brink
authors: Michel
authors: M
authors: van Gelder
authors: Petra F
authors: PF
authors: Wolffs
authors: Cathrien A
authors: CA
authors: Bruggeman
authors: Inge H M
authors: IH
authors: van Loo
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage* / Q000494:pharmacology*; D000328:Adult; D024882:Drug Resistance, Viral; D020804:Encephalitis, Varicella Zoster / Q000188:drug therapy / Q000821:virology*; D005260:Female; D006562:Herpes Zoster / Q000188:drug therapy / Q000821:virology*; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000302:isolation & purification*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests / Q000379:methods; D008875:Middle Aged; D020125:Mutation, Missense; D057089:Pathology, Molecular / Q000379:methods; D016133:Polymerase Chain Reaction; D013937:Thymidine Kinase / Q000235:genetics; D014180:Transplantation; D014764:Viral Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D014764:Viral Proteins; D013937:Thymidine Kinase; D000212:Acyclovir