Mutation in region III of the DNA polymerase gene associated with dual ganciclovir-foscarnet resistance in cytomegalovirus (CMV) isolates from three subjects receiving prolonged antiviral therapy

Sunwen Chou, G. Marousek, D. Parenti, J. Lalezari, R. Miner, L. Drew

Research output: Contribution to journalArticle

Abstract

Most ganciclovir (GCV) resistant clinical CMV isolates have well defined mutations in the UL97 phosphotransferase sequence. CMV DNA polymerase (Pol) mutations also confer various drug resistance phenotypes but are less well characterized. Buffy coat CMV isolates from 3 HIV-infected subjects showing dual GCV and foscarnet (FOS) resistance (IC50 9.8-16.7 μM and 530-1020 μM respectively) after prolonged therapy were sequenced. In each case, as expected, a known GCV-resistance mutation was observed in UL97 (V594 and/or S595). A Pol mutation (Ala to Val at codon 809, V809) in conserved region III was also detected in each subject. Serial isolates in 2 cases showed that the appearance of V809 correlated with FOS resistance. A segment of Pol containing V809, from one of the clinical isolates, was transferred to laboratory CMV strain AD169. The recombinant virus showed 2.6-fold increased GCV and 6.3-fold increased FOS resistance (IC50 = 7.8 μM and 410 μM respectively) as compared to parental virus. We conclude that the V809 mutation contributed to resistance to both drugs in isolates from all 3 subjects and appears to be a clinically significant resistance marker.

Original languageEnglish (US)
Pages (from-to)449
Number of pages1
JournalClinical Infectious Diseases
Volume25
Issue number2
StatePublished - 1997
Externally publishedYes

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DNA Polymerase III
Foscarnet
Ganciclovir
Cytomegalovirus
Antiviral Agents
Mutation
Genes
Inhibitory Concentration 50
Viruses
Therapeutics
DNA-Directed DNA Polymerase
Drug Resistance
Codon
Phosphotransferases
HIV
Phenotype
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Immunology

Cite this

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title = "Mutation in region III of the DNA polymerase gene associated with dual ganciclovir-foscarnet resistance in cytomegalovirus (CMV) isolates from three subjects receiving prolonged antiviral therapy",
abstract = "Most ganciclovir (GCV) resistant clinical CMV isolates have well defined mutations in the UL97 phosphotransferase sequence. CMV DNA polymerase (Pol) mutations also confer various drug resistance phenotypes but are less well characterized. Buffy coat CMV isolates from 3 HIV-infected subjects showing dual GCV and foscarnet (FOS) resistance (IC50 9.8-16.7 μM and 530-1020 μM respectively) after prolonged therapy were sequenced. In each case, as expected, a known GCV-resistance mutation was observed in UL97 (V594 and/or S595). A Pol mutation (Ala to Val at codon 809, V809) in conserved region III was also detected in each subject. Serial isolates in 2 cases showed that the appearance of V809 correlated with FOS resistance. A segment of Pol containing V809, from one of the clinical isolates, was transferred to laboratory CMV strain AD169. The recombinant virus showed 2.6-fold increased GCV and 6.3-fold increased FOS resistance (IC50 = 7.8 μM and 410 μM respectively) as compared to parental virus. We conclude that the V809 mutation contributed to resistance to both drugs in isolates from all 3 subjects and appears to be a clinically significant resistance marker.",
author = "Sunwen Chou and G. Marousek and D. Parenti and J. Lalezari and R. Miner and L. Drew",
year = "1997",
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journal = "Clinical Infectious Diseases",
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TY - JOUR

T1 - Mutation in region III of the DNA polymerase gene associated with dual ganciclovir-foscarnet resistance in cytomegalovirus (CMV) isolates from three subjects receiving prolonged antiviral therapy

AU - Chou, Sunwen

AU - Marousek, G.

AU - Parenti, D.

AU - Lalezari, J.

AU - Miner, R.

AU - Drew, L.

PY - 1997

Y1 - 1997

N2 - Most ganciclovir (GCV) resistant clinical CMV isolates have well defined mutations in the UL97 phosphotransferase sequence. CMV DNA polymerase (Pol) mutations also confer various drug resistance phenotypes but are less well characterized. Buffy coat CMV isolates from 3 HIV-infected subjects showing dual GCV and foscarnet (FOS) resistance (IC50 9.8-16.7 μM and 530-1020 μM respectively) after prolonged therapy were sequenced. In each case, as expected, a known GCV-resistance mutation was observed in UL97 (V594 and/or S595). A Pol mutation (Ala to Val at codon 809, V809) in conserved region III was also detected in each subject. Serial isolates in 2 cases showed that the appearance of V809 correlated with FOS resistance. A segment of Pol containing V809, from one of the clinical isolates, was transferred to laboratory CMV strain AD169. The recombinant virus showed 2.6-fold increased GCV and 6.3-fold increased FOS resistance (IC50 = 7.8 μM and 410 μM respectively) as compared to parental virus. We conclude that the V809 mutation contributed to resistance to both drugs in isolates from all 3 subjects and appears to be a clinically significant resistance marker.

AB - Most ganciclovir (GCV) resistant clinical CMV isolates have well defined mutations in the UL97 phosphotransferase sequence. CMV DNA polymerase (Pol) mutations also confer various drug resistance phenotypes but are less well characterized. Buffy coat CMV isolates from 3 HIV-infected subjects showing dual GCV and foscarnet (FOS) resistance (IC50 9.8-16.7 μM and 530-1020 μM respectively) after prolonged therapy were sequenced. In each case, as expected, a known GCV-resistance mutation was observed in UL97 (V594 and/or S595). A Pol mutation (Ala to Val at codon 809, V809) in conserved region III was also detected in each subject. Serial isolates in 2 cases showed that the appearance of V809 correlated with FOS resistance. A segment of Pol containing V809, from one of the clinical isolates, was transferred to laboratory CMV strain AD169. The recombinant virus showed 2.6-fold increased GCV and 6.3-fold increased FOS resistance (IC50 = 7.8 μM and 410 μM respectively) as compared to parental virus. We conclude that the V809 mutation contributed to resistance to both drugs in isolates from all 3 subjects and appears to be a clinically significant resistance marker.

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