New locus of drug resistance in the human cytomegalovirus UL56 gene revealed by in vitro exposure to letermovir and ganciclovir

Sunwen Chou, L. Elizabeth Satterwhite, Ronald J. Ercolani

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor recently approved as prophylaxis in stem cell transplant recipients. In further studies of emerging drug resistance, a baseline laboratory CMV strain was serially propagated in cell culture under a combination of letermovir and ganciclovir. In eight experiments, UL56 terminase gene mutations were detected beginning at 10 passages and included novel amino acid substitutions V236A, L328V, and A365S in a region previously associated with letermovir resistance. Outside this region, the UL56 substitution C25F was detected at moderate drug concentrations in two experiments as either the first detected mutation or an addition to a preexisting V231L substitution. In all cases, mutation at UL56 codon 325 conferring absolute letermovir resistance eventually developed at a median of 20 passages. No UL97 kinase or UL54 DNA polymerase mutations relevant to ganciclovir resistance were detected until many passages after the first detection of the UL56 mutations. UL56 substitutions V236A, L328V, and A365S were shown to confer borderline or low-grade letermovir resistance, while C25F conferred a 5.4-fold increase in letermovir resistance (50% effective concentration [EC50]) by itself and a 46-fold increase in combination with V231L. The evolution of resistance mutations sooner in UL56 than in UL54 or UL97 is consistent with prior in vitro observations, and UL56 codon 25 is a genetic locus for letermovir resistance distinct from loci previously described.

Original languageEnglish (US)
Article numbere00922-18
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number9
DOIs
StatePublished - Sep 1 2018

Fingerprint

Ganciclovir
Cytomegalovirus
Drug Resistance
Mutation
Genes
Codon
Genetic Loci
DNA-Directed DNA Polymerase
Amino Acid Substitution
AIC246
In Vitro Techniques
Phosphotransferases
Stem Cells
Cell Culture Techniques
Transplants
Pharmaceutical Preparations

Keywords

  • Cytomegalovirus
  • Drug resistance mechanisms
  • Ganciclovir
  • Letermovir

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

New locus of drug resistance in the human cytomegalovirus UL56 gene revealed by in vitro exposure to letermovir and ganciclovir. / Chou, Sunwen; Satterwhite, L. Elizabeth; Ercolani, Ronald J.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 9, e00922-18, 01.09.2018.

Research output: Contribution to journalArticle

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abstract = "Letermovir is a human cytomegalovirus (CMV) terminase inhibitor recently approved as prophylaxis in stem cell transplant recipients. In further studies of emerging drug resistance, a baseline laboratory CMV strain was serially propagated in cell culture under a combination of letermovir and ganciclovir. In eight experiments, UL56 terminase gene mutations were detected beginning at 10 passages and included novel amino acid substitutions V236A, L328V, and A365S in a region previously associated with letermovir resistance. Outside this region, the UL56 substitution C25F was detected at moderate drug concentrations in two experiments as either the first detected mutation or an addition to a preexisting V231L substitution. In all cases, mutation at UL56 codon 325 conferring absolute letermovir resistance eventually developed at a median of 20 passages. No UL97 kinase or UL54 DNA polymerase mutations relevant to ganciclovir resistance were detected until many passages after the first detection of the UL56 mutations. UL56 substitutions V236A, L328V, and A365S were shown to confer borderline or low-grade letermovir resistance, while C25F conferred a 5.4-fold increase in letermovir resistance (50{\%} effective concentration [EC50]) by itself and a 46-fold increase in combination with V231L. The evolution of resistance mutations sooner in UL56 than in UL54 or UL97 is consistent with prior in vitro observations, and UL56 codon 25 is a genetic locus for letermovir resistance distinct from loci previously described.",
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