TY - JOUR
T1 - Relative frequency of cytomegalovirus UL56 gene mutations detected in genotypic letermovir resistance testing
AU - Chou, Sunwen
AU - Kleiboeker, Steven
N1 - Funding Information:
Letermovir (LMV) is the first human cytomegalovirus (CMV) terminase complex inhibitor approved for clinical use. Against wild type CMV, it has impressive inhibitory potency, with low nanomolar effective concentrations for 50% reduction of viral growth (EC50) (Lischka et al., 2010). A phase 3 clinical trial showing efficacy and safety in prevention of CMV infection in hematopoietic cell transplant recipients supported the original FDA approval for this indication (Marty et al., 2017). Breakthrough CMV infection and drug resistance during LMV prophylaxis was uncommon in those with verified absence of infection at baseline (Douglas et al., 2020), and drug resistance is unexpected during prophylaxis. Because of the lack of cross-resistance, LMV has been used off-label for the salvage treatment of CMV infection resistant to standard approved therapies, with case reports documenting genotypic LMV resistance (Cherrier et al., 2018; Piret and Boivin, 2019; Turner et al., 2019). This complication was anticipated by in vitro selection experiments, with mutations mapping to genes UL56, UL89 and UL51 (Chou, 2015, 2017a, b; Goldner et al., 2014), but most commonly to UL56 codons 229 to 369. The objective of the current study was to assess the relative frequency of LMV resistance mutations in clinical diagnostic practice using a large dataset, and to phenotype newly identified mutations potentially affecting LMV susceptibility.This work was supported by National Institutes of Health grant R01-AI116635 and use of Department of Veterans Affairs facilities and resources.
Funding Information:
This work was supported by National Institutes of Health grant R01-AI116635 and use of Department of Veterans Affairs facilities and resources.
Publisher Copyright:
© 2022
PY - 2022/11
Y1 - 2022/11
N2 - Genotypic testing for letermovir (LMV) resistance was performed by Sanger sequencing of cytomegalovirus terminase gene UL56 (codons 202–412) in 1165 diagnostic specimens, disclosing 36 sequence variants among 173 (14.8%) of the specimens, including one or more LMV resistance mutations in 134 specimens. Codon 325 mutations (C325Y/F/W/R) were the most common (108 specimens), followed by those at codon 369 (R369 S/G/T/K, 13 specimens) and V236M (11 specimens). Mutations V231L, N232Y, Q234R, L257F and V363I were detected in 1–3 specimens each. Combinations of codon 325 mutation and those at codons 236 or 369 were found in 6 specimens. Eleven novel sequence variants were phenotyped, validating Q234R, V363I and R369K as conferring 2- to 5-fold increased LMV 50% inhibitory concentrations (EC50). These findings indicate that UL56 codon 325 mutations conferring >3000-fold LMV EC50 are detected much more frequently in clinical practice than those conferring lower grade resistance, and suggest that a single step mutation to absolute LMV resistance is an ongoing concern in its therapeutic use.
AB - Genotypic testing for letermovir (LMV) resistance was performed by Sanger sequencing of cytomegalovirus terminase gene UL56 (codons 202–412) in 1165 diagnostic specimens, disclosing 36 sequence variants among 173 (14.8%) of the specimens, including one or more LMV resistance mutations in 134 specimens. Codon 325 mutations (C325Y/F/W/R) were the most common (108 specimens), followed by those at codon 369 (R369 S/G/T/K, 13 specimens) and V236M (11 specimens). Mutations V231L, N232Y, Q234R, L257F and V363I were detected in 1–3 specimens each. Combinations of codon 325 mutation and those at codons 236 or 369 were found in 6 specimens. Eleven novel sequence variants were phenotyped, validating Q234R, V363I and R369K as conferring 2- to 5-fold increased LMV 50% inhibitory concentrations (EC50). These findings indicate that UL56 codon 325 mutations conferring >3000-fold LMV EC50 are detected much more frequently in clinical practice than those conferring lower grade resistance, and suggest that a single step mutation to absolute LMV resistance is an ongoing concern in its therapeutic use.
KW - Cytomegalovirus
KW - Genotypic resistance testing
KW - Letermovir
KW - UL56
UR - http://www.scopus.com/inward/record.url?scp=85139023451&partnerID=8YFLogxK
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U2 - 10.1016/j.antiviral.2022.105422
DO - 10.1016/j.antiviral.2022.105422
M3 - Article
C2 - 36170912
AN - SCOPUS:85139023451
VL - 207
JO - Antiviral Research
JF - Antiviral Research
SN - 0166-3542
M1 - 105422
ER -