Genotypic and phenotypic study of antiviral resistance mutations in refractory cytomegalovirus infection

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...

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Authors: Santos Bravo, Marta, Nicolas Plault, Sánchez-Palomino, Sonsoles, Rodríguez, Cristina, Navarro Gabriel, Mireia, Mosquera, María Mar, Fernández Avilés, Francesc, Suárez-Lledó Grande, María, Rovira, Montserrat, Bodro, Marta, Moreno Camacho, Ma. Asunción, Linares, Laura, Cofán Pujol, Federico, Berengua, Carla, Esteva, Cristina, Cordero, Elisa, Martín Dávila, Pilar, Aranzamendi, Maitane, Pérez Jiménez, Ana Belén, Vidal, Elisa, Fernández Sabé, Núria, Len, Óscar, Hantz, Sebastien, Alain, Sophie, Marcos, Ma. Angeles, Spanish Network for Research in Infectious Diseases (REIPI), Group for the Study of Infection in Transplantation (GESITRA)
Format: article
Status:Versión aceptada para publicación
Publication Date:2022
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/204118
Online Access:https://hdl.handle.net/2445/204118
Access Level:Open access
Keyword:Citomegalovirus
Resistència als medicaments
Cytomegaloviruses
Drug resistance
Description
Summary: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.

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