Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus

Sunwen Chou, Nell S. Lurain, Kenneth D. Thompson, Richard C. Miner, W. Lawrence Drew

Research output: Contribution to journalArticle

153 Citations (Scopus)

Abstract

Certain mutations in the viral DNA polymerase (pol) gene are known to confer drug resistance when transferred to susceptible human cytomegalovirus (CMV) strains, whereas other putative resistance mutations remain unproven. A new marker-transfer technique was used to produce recombinant CMV strains, to determine the drug susceptibility phenotypes conferred by 10 pol mutations (9 observed in clinical isolates). Various degrees of resistance to ganciclovir and cidofovir were conferred by mutations D301N, N410K, D413E, T503I, and L516R, which are located within exonuclease functional domains where D301N and D413E affect highly conserved residues. Mutations A692S, E756K, and E756D, which are not located within recognized functional domains, each conferred foscarnet resistance. This study significantly increases the number of confirmed CMV pol resistance mutations, at both conserved and nonconserved loci, with implications for molecular mechanisms and the genotypic diagnosis of antiviral resistance.

Original languageEnglish (US)
Pages (from-to)32-39
Number of pages8
JournalJournal of Infectious Diseases
Volume188
Issue number1
DOIs
StatePublished - Jul 1 2003

Fingerprint

Viral DNA
DNA-Directed DNA Polymerase
Cytomegalovirus
Drug Resistance
Mutation
Foscarnet
Exonucleases
Ganciclovir
Antiviral Agents
Phenotype
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Immunology

Cite this

Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus. / Chou, Sunwen; Lurain, Nell S.; Thompson, Kenneth D.; Miner, Richard C.; Drew, W. Lawrence.

In: Journal of Infectious Diseases, Vol. 188, No. 1, 01.07.2003, p. 32-39.

Research output: Contribution to journalArticle

Chou, Sunwen ; Lurain, Nell S. ; Thompson, Kenneth D. ; Miner, Richard C. ; Drew, W. Lawrence. / Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus. In: Journal of Infectious Diseases. 2003 ; Vol. 188, No. 1. pp. 32-39.
@article{378f14228567482481a15e298923992b,
title = "Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus",
abstract = "Certain mutations in the viral DNA polymerase (pol) gene are known to confer drug resistance when transferred to susceptible human cytomegalovirus (CMV) strains, whereas other putative resistance mutations remain unproven. A new marker-transfer technique was used to produce recombinant CMV strains, to determine the drug susceptibility phenotypes conferred by 10 pol mutations (9 observed in clinical isolates). Various degrees of resistance to ganciclovir and cidofovir were conferred by mutations D301N, N410K, D413E, T503I, and L516R, which are located within exonuclease functional domains where D301N and D413E affect highly conserved residues. Mutations A692S, E756K, and E756D, which are not located within recognized functional domains, each conferred foscarnet resistance. This study significantly increases the number of confirmed CMV pol resistance mutations, at both conserved and nonconserved loci, with implications for molecular mechanisms and the genotypic diagnosis of antiviral resistance.",
author = "Sunwen Chou and Lurain, {Nell S.} and Thompson, {Kenneth D.} and Miner, {Richard C.} and Drew, {W. Lawrence}",
year = "2003",
month = "7",
day = "1",
doi = "10.1086/375743",
language = "English (US)",
volume = "188",
pages = "32--39",
journal = "Journal of Infectious Diseases",
issn = "0022-1899",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus

AU - Chou, Sunwen

AU - Lurain, Nell S.

AU - Thompson, Kenneth D.

AU - Miner, Richard C.

AU - Drew, W. Lawrence

PY - 2003/7/1

Y1 - 2003/7/1

N2 - Certain mutations in the viral DNA polymerase (pol) gene are known to confer drug resistance when transferred to susceptible human cytomegalovirus (CMV) strains, whereas other putative resistance mutations remain unproven. A new marker-transfer technique was used to produce recombinant CMV strains, to determine the drug susceptibility phenotypes conferred by 10 pol mutations (9 observed in clinical isolates). Various degrees of resistance to ganciclovir and cidofovir were conferred by mutations D301N, N410K, D413E, T503I, and L516R, which are located within exonuclease functional domains where D301N and D413E affect highly conserved residues. Mutations A692S, E756K, and E756D, which are not located within recognized functional domains, each conferred foscarnet resistance. This study significantly increases the number of confirmed CMV pol resistance mutations, at both conserved and nonconserved loci, with implications for molecular mechanisms and the genotypic diagnosis of antiviral resistance.

AB - Certain mutations in the viral DNA polymerase (pol) gene are known to confer drug resistance when transferred to susceptible human cytomegalovirus (CMV) strains, whereas other putative resistance mutations remain unproven. A new marker-transfer technique was used to produce recombinant CMV strains, to determine the drug susceptibility phenotypes conferred by 10 pol mutations (9 observed in clinical isolates). Various degrees of resistance to ganciclovir and cidofovir were conferred by mutations D301N, N410K, D413E, T503I, and L516R, which are located within exonuclease functional domains where D301N and D413E affect highly conserved residues. Mutations A692S, E756K, and E756D, which are not located within recognized functional domains, each conferred foscarnet resistance. This study significantly increases the number of confirmed CMV pol resistance mutations, at both conserved and nonconserved loci, with implications for molecular mechanisms and the genotypic diagnosis of antiviral resistance.

UR - http://www.scopus.com/inward/record.url?scp=0038574429&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038574429&partnerID=8YFLogxK

U2 - 10.1086/375743

DO - 10.1086/375743

M3 - Article

VL - 188

SP - 32

EP - 39

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

SN - 0022-1899

IS - 1

ER -