PMID- 18952495
OWN - NLM
STAT- MEDLINE
DCOM- 20090310
LR  - 20131121
IS  - 1386-6532 (Print)
IS  - 1386-6532 (Linking)
VI  - 44
IP  - 1
DP  - 2009 Jan
TI  - Human herpesvirus 6 ganciclovir-resistant strain with amino acid substitutions 
      associated with the death of an allogeneic stem cell transplant recipient.
PG  - 15-9
LID - 10.1016/j.jcv.2008.09.002 [doi]
AB  - BACKGROUND: Viral resistance to antiviral drugs can cause serious complications 
      in immunosuppressed patients. We isolated from an allogeneic stem cell transplant 
      (SCT) recipient an antiviral-resistant human herpesvirus 6 (HHV-6) strain with 
      mutations that caused amino acid substitutions. OBJECTIVE: To study the impact of 
      mutations in the U38 and U69 genes of the ganciclovir (GCV)-resistant HHV-6 
      strain associated with the death of the SCT recipient. STUDY DESIGN: Viruses were 
      obtained from blood taken during symptomatic disease. Mutations in the genes for 
      U69 protein kinase and U38 DNA polymerase were analyzed and the effects of the 
      U69 mutations on GCV resistance were assayed using a recombinant baculovirus 
      system. RESULTS: Increasing HHV-6 antigenemia occurred after 2-3 months of 
      preemptive GCV therapy, followed by symptomatic HHV-6 disease that ended in fatal 
      fungus-related septic shock. The HHV-6 strain isolated from the patient was 
      100-fold more resistant to GCV than was a wild-type strain. New mutations were 
      found in HHV-6 genes U38 (P462S and A565V) and U69 (L202I and L213I). The 
      mutation of U38 P462S corresponds to a mutation in the UL54 gene (P522S) of a 
      GCV-resistant HCMV. The U69 mutations did not alter GCV sensitivity in 
      baculovirus GCV-resistant assay system. CONCLUSIONS: Drug-resistant mutations 
      arising during preemptive therapy may complicate post-transplant HHV-6 disease in 
      SCT recipients. The increased copy number during GCV treatment of this new 
      GCV-resistant HHV-6 strain correlated with mutations in the U69 and U38 genes. 
      Since the kinase mutation did not alter sensitivity to GCV when tested in the in 
      vitro system, it is likely that the substitutions in the polymerase related to 
      GCV resistance.
FAU - Isegawa, Yuji
AU  - Isegawa Y
AD  - Department of Infectious Disease Control, Graduate School of Medicine, Osaka 
      University, G-5, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. 
      isegawa@bact.med.osaka-u.ac.jp
FAU - Hara, Junichi
AU  - Hara J
FAU - Amo, Kiyoko
AU  - Amo K
FAU - Osugi, Yuko
AU  - Osugi Y
FAU - Takemoto, Masaya
AU  - Takemoto M
FAU - Yamanishi, Koichi
AU  - Yamanishi K
FAU - Fukunaga, Rikiro
AU  - Fukunaga R
FAU - Shibata, Mari
AU  - Shibata M
FAU - Ohshima, Atsushi
AU  - Ohshima A
FAU - Horiguchi, Yasuhiko
AU  - Horiguchi Y
FAU - Sugimoto, Nakaba
AU  - Sugimoto N
LA  - eng
SI  - GENBANK/AB283020
SI  - GENBANK/AB283021
SI  - GENBANK/AB283022
SI  - GENBANK/AB283023
SI  - GENBANK/AB283024
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081025
PL  - Netherlands
TA  - J Clin Virol
JT  - Journal of clinical virology : the official publication of the Pan American 
      Society for Clinical Virology
JID - 9815671
RN  - 0 (Antiviral Agents)
RN  - 0 (DNA, Viral)
RN  - 0 (Viral Nonstructural Proteins)
RN  - P9G3CKZ4P5 (Ganciclovir)
SB  - IM
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution/genetics
MH  - Animals
MH  - Antiviral Agents/*pharmacology
MH  - Baculoviridae/genetics
MH  - Cell Line
MH  - Child, Preschool
MH  - DNA, Viral/chemistry/genetics
MH  - *Drug Resistance, Viral
MH  - Fatal Outcome
MH  - Ganciclovir/*pharmacology
MH  - Herpesvirus 6, Human/*drug effects/genetics/*isolation & purification
MH  - Humans
MH  - Male
MH  - Molecular Sequence Data
MH  - Mutation, Missense
MH  - Roseolovirus Infections/*virology
MH  - Sequence Alignment
MH  - Sequence Analysis, DNA
MH  - Stem Cell Transplantation/adverse effects
MH  - Transplantation
MH  - Viral Nonstructural Proteins/genetics
EDAT- 2008/10/28 09:00
MHDA- 2009/03/11 09:00
CRDT- 2008/10/28 09:00
PHST- 2008/01/08 00:00 [received]
PHST- 2008/08/14 00:00 [revised]
PHST- 2008/09/04 00:00 [accepted]
PHST- 2008/10/28 09:00 [pubmed]
PHST- 2009/03/11 09:00 [medline]
PHST- 2008/10/28 09:00 [entrez]
AID - S1386-6532(08)00326-0 [pii]
AID - 10.1016/j.jcv.2008.09.002 [doi]
PST - ppublish
SO  - J Clin Virol. 2009 Jan;44(1):15-9. doi: 10.1016/j.jcv.2008.09.002. Epub 2008 Oct 
      25.