Ganciclovir-resistant cytomegalovirus disease after allogeneic stem cell transplantation: pitfalls of phenotypic diagnosis by in vitro selection of an UL97 mutant strain.
A 9-month posttransplantation course of an allogeneic stem-cell transplant recipient (human cytomegalovirus [HCMV] serostatus, donor positive/recipient negative), in whom ganciclovir (GCV) resistance developed (UL97 mutations M460V, L595S, and C603W) on day 164 after transplantation and who developed HCMV retinitis and fatal HCMV encephalitis is presented. Virus strains isolated from secondary cultures were analyzed by UL97 restriction assays and sequencing and were compared with primary DNA extracts of the same specimens, which resulted in molecular proof of an initial HCMV strain-specific in vitro selection of the in vivo nondominant UL97 L595S-C603 mutant strain from 3 viral variants present in vivo. In addition, compartmentalization of virus present in blood and cerebrospinal fluid was found. The influence of rapidly increasing plasma virus load (to >10(6) copies/mL) and oral administration of GCV on the emergence of GCV resistance is shown. These findings have strong implications for the diagnosis of HCMV drug resistance.
Hamprecht
Klaus
K
Institute of Medical Virology, University Hospital of Tübingen, Germany. kshampre@med.uni-tuebingen.de
Eckle
Tobias
T
Prix
Lothar
L
Faul
Christoph
C
Einsele
Hermann
H
Jahn
Gerhard
G
D000998:Antiviral Agents / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000178:diet therapy* / Q000821:virology; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D024882:Drug Resistance, Viral; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D014184:Transplantation, Homologous; D019562:Viral Load; D014764:Viral Proteins
D000998:Antiviral Agents; C109367:UL54 protein, Human herpesvirus 5; D014764:Viral Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D004259:DNA-Directed DNA Polymerase; D015774:Ganciclovir