Genotypic and Phenotypic Study of Antiviral Resistance Mutations in Refractory Cytomegalovirus Infection.
antiviral drugs
cytomegalovirus
genotype
phenotype
resistant mutations
Journal
The Journal of infectious diseases
ISSN: 1537-6613
Titre abrégé: J Infect Dis
Pays: United States
ID NLM: 0413675
Informations de publication
Date de publication:
01 11 2022
01 11 2022
Historique:
received:
16
06
2022
accepted:
18
08
2022
pubmed:
23
8
2022
medline:
4
11
2022
entrez:
22
8
2022
Statut:
ppublish
Résumé
This study describes the genotypic and phenotypic characterization of novel human cytomegalovirus (HCMV) genetic variants of a cohort of 94 clinically resistant HCMV patients. Antiviral-resistant mutations were detected in the UL97, UL54, and UL56 target genes of 25 of 94 (26.6%) patients. The genotype-phenotype correlation study resolved the status of 5 uncharacterized UL54 deoxyribonucleic acid polymerase (G441S, A543V, F460S, R512C, A928T) and 2 UL56 terminase (F345L, P800L) mutations found in clinical isolates. A928T conferred high, triple resistance to ganciclovir, foscarnet, and cidofovir, and A543V had 10-fold reduced susceptibility to cidofovir. Viral growth assays showed G441S, A543V, F345L, and P800L impaired viral growth capacities compared with wild-type AD169 HCMV. Three-dimensional modeling predicted A543V and A928T phenotypes but not R512C, reinforcing the need for individual characterization of mutations by recombinant phenotyping. Extending mutation databases is crucial to optimize treatments and to improve the assessment of patients with resistant/refractory HCMV infection.
Sections du résumé
BACKGROUND
This study describes the genotypic and phenotypic characterization of novel human cytomegalovirus (HCMV) genetic variants of a cohort of 94 clinically resistant HCMV patients.
METHODS AND RESULTS
Antiviral-resistant mutations were detected in the UL97, UL54, and UL56 target genes of 25 of 94 (26.6%) patients. The genotype-phenotype correlation study resolved the status of 5 uncharacterized UL54 deoxyribonucleic acid polymerase (G441S, A543V, F460S, R512C, A928T) and 2 UL56 terminase (F345L, P800L) mutations found in clinical isolates. A928T conferred high, triple resistance to ganciclovir, foscarnet, and cidofovir, and A543V had 10-fold reduced susceptibility to cidofovir. Viral growth assays showed G441S, A543V, F345L, and P800L impaired viral growth capacities compared with wild-type AD169 HCMV. Three-dimensional modeling predicted A543V and A928T phenotypes but not R512C, reinforcing the need for individual characterization of mutations by recombinant phenotyping.
CONCLUSIONS
Extending mutation databases is crucial to optimize treatments and to improve the assessment of patients with resistant/refractory HCMV infection.
Identifiants
pubmed: 35993155
pii: 6672993
doi: 10.1093/infdis/jiac349
doi:
Substances chimiques
Cidofovir
JIL713Q00N
DNA-Directed DNA Polymerase
EC 2.7.7.7
Viral Proteins
0
Ganciclovir
P9G3CKZ4P5
Antiviral Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1528-1536Investigateurs
Francisco López-Medrano
(F)
Jose María Agüado
(JM)
Cecilia Martin-Gandul
(C)
Jordi Carratalá
(J)
Jordí Niubó
(J)
Carlos Cervera
(C)
Patricia Muñoz
(P)
María Carmen Fariñas
(MC)
Andrés Antón
(A)
Miguel Montejo
(M)
Pilar Pérez-Romero
(P)
Julián Torres-Cisneros
(J)
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Déclaration de conflit d'intérêts
Potential conflict of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Conflicts of Interest.