Assessment of UL56 Mutations before Letermovir Therapy in Refractory Cytomegalovirus Transplant Recipients
ABSTRACT De novo mutations in the UL56 terminase subunit and its associated phenotypes were studied in the context of cytomegalovirus (CMV) transplant recipients clinically resistant to DNA-polymerase inhibitors, naive to letermovir. R246C was the only UL56 variant detected by standard and deep sequ...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-04-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.00191-22 |
| _version_ | 1818141896151662592 |
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| author | Marta Santos Bravo Valentin Tilloy Nicolas Plault Sonsoles Sánchez Palomino María Mar Mosquera Mireia Navarro Gabriel Francesc Fernández Avilés María Suárez Lledó Montserrat Rovira Asunción Moreno Laura Linares Marta Bodro Sébastien Hantz Sophie Alain María Ángeles Marcos |
| author_facet | Marta Santos Bravo Valentin Tilloy Nicolas Plault Sonsoles Sánchez Palomino María Mar Mosquera Mireia Navarro Gabriel Francesc Fernández Avilés María Suárez Lledó Montserrat Rovira Asunción Moreno Laura Linares Marta Bodro Sébastien Hantz Sophie Alain María Ángeles Marcos |
| author_sort | Marta Santos Bravo |
| collection | DOAJ |
| description | ABSTRACT De novo mutations in the UL56 terminase subunit and its associated phenotypes were studied in the context of cytomegalovirus (CMV) transplant recipients clinically resistant to DNA-polymerase inhibitors, naive to letermovir. R246C was the only UL56 variant detected by standard and deep sequencing, located within the letermovir-resistance-associated region (residues 230–370). R246C emerged in 2/80 transplant recipients (1 hematopoietic and 1 heart) since first cytomegalovirus replication and responded transiently to various alternative antiviral treatments in vivo. Recombinant phenotyping showed R246C conferred an advanced viral fitness and was sensitive to ganciclovir, cidofovir, foscarnet, maribavir, and letermovir. These results demonstrate a low rate (2.5%) of natural occurring polymorphisms within the letermovir-resistant-associated region before its administration. Identification of high replicative capacity variants in patients not responding to treatment or experiencing relapses could be helpful to guide further therapy and dosing of antiviral molecules. IMPORTANCE We provide comprehensive data on the clinical correlates of both CMV genotypic follow-up by standard and deep sequencing and the clinical outcomes, as well as recombinant phenotypic results of this novel mutation. Our study emphasizes that the clinical follow-up in combination with genotypic and phenotypic studies is essential for the assessment and optimization of patients experiencing HCMV relapses or not responding to antiviral therapy. This information may be important for other researchers and clinicians working in the field to improve the care of transplant patients since drug-resistant CMV infections are an important emerging problem even with the new antiviral development. |
| first_indexed | 2024-12-11T11:07:09Z |
| format | Article |
| id | doaj.art-ba2379023c9c4670a4b4db182ada46c6 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-12-11T11:07:09Z |
| publishDate | 2022-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-ba2379023c9c4670a4b4db182ada46c62022-12-22T01:09:40ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-04-0110210.1128/spectrum.00191-22Assessment of UL56 Mutations before Letermovir Therapy in Refractory Cytomegalovirus Transplant RecipientsMarta Santos Bravo0Valentin Tilloy1Nicolas Plault2Sonsoles Sánchez Palomino3María Mar Mosquera4Mireia Navarro Gabriel5Francesc Fernández Avilés6María Suárez Lledó7Montserrat Rovira8Asunción Moreno9Laura Linares10Marta Bodro11Sébastien Hantz12Sophie Alain13María Ángeles Marcos14Microbiology Department, Hospital Clínic I Provincial de Barcelona, University of Barcelona Institute for Global Health (ISGlobal), Barcelona, SpainNational Reference Center for Herpesviruses, Microbiology Department, CHU Limoges, Limoges, FranceNational Reference Center for Herpesviruses, Microbiology Department, CHU Limoges, Limoges, FranceAIDS Research Group, Institut D’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic I Provincial de Barcelona, University of Barcelona, Barcelona, SpainMicrobiology Department, Hospital Clínic I Provincial de Barcelona, University of Barcelona Institute for Global Health (ISGlobal), Barcelona, SpainMicrobiology Department, Hospital Clínic I Provincial de Barcelona, University of Barcelona Institute for Global Health (ISGlobal), Barcelona, SpainBone Marrow Transplant Unit, Hematology Department, Hospital Clínic I Provincial de Barcelona, Barcelona, SpainBone Marrow Transplant Unit, Hematology Department, Hospital Clínic I Provincial de Barcelona, Barcelona, SpainBone Marrow Transplant Unit, Hematology Department, Hospital Clínic I Provincial de Barcelona, Barcelona, SpainInfectious Diseases Department, Hospital Clínic I Provincial de Barcelona, Barcelona, SpainInfectious Diseases Department, Hospital Clínic I Provincial de Barcelona, Barcelona, SpainInfectious Diseases Department, Hospital Clínic I Provincial de Barcelona, Barcelona, SpainNational Reference Center for Herpesviruses, Microbiology Department, CHU Limoges, Limoges, FranceNational Reference Center for Herpesviruses, Microbiology Department, CHU Limoges, Limoges, FranceMicrobiology Department, Hospital Clínic I Provincial de Barcelona, University of Barcelona Institute for Global Health (ISGlobal), Barcelona, SpainABSTRACT De novo mutations in the UL56 terminase subunit and its associated phenotypes were studied in the context of cytomegalovirus (CMV) transplant recipients clinically resistant to DNA-polymerase inhibitors, naive to letermovir. R246C was the only UL56 variant detected by standard and deep sequencing, located within the letermovir-resistance-associated region (residues 230–370). R246C emerged in 2/80 transplant recipients (1 hematopoietic and 1 heart) since first cytomegalovirus replication and responded transiently to various alternative antiviral treatments in vivo. Recombinant phenotyping showed R246C conferred an advanced viral fitness and was sensitive to ganciclovir, cidofovir, foscarnet, maribavir, and letermovir. These results demonstrate a low rate (2.5%) of natural occurring polymorphisms within the letermovir-resistant-associated region before its administration. Identification of high replicative capacity variants in patients not responding to treatment or experiencing relapses could be helpful to guide further therapy and dosing of antiviral molecules. IMPORTANCE We provide comprehensive data on the clinical correlates of both CMV genotypic follow-up by standard and deep sequencing and the clinical outcomes, as well as recombinant phenotypic results of this novel mutation. Our study emphasizes that the clinical follow-up in combination with genotypic and phenotypic studies is essential for the assessment and optimization of patients experiencing HCMV relapses or not responding to antiviral therapy. This information may be important for other researchers and clinicians working in the field to improve the care of transplant patients since drug-resistant CMV infections are an important emerging problem even with the new antiviral development.https://journals.asm.org/doi/10.1128/spectrum.00191-22cytomegalovirusletermovirbaseline mutationstransplant recipientsphenotype |
| spellingShingle | Marta Santos Bravo Valentin Tilloy Nicolas Plault Sonsoles Sánchez Palomino María Mar Mosquera Mireia Navarro Gabriel Francesc Fernández Avilés María Suárez Lledó Montserrat Rovira Asunción Moreno Laura Linares Marta Bodro Sébastien Hantz Sophie Alain María Ángeles Marcos Assessment of UL56 Mutations before Letermovir Therapy in Refractory Cytomegalovirus Transplant Recipients Microbiology Spectrum cytomegalovirus letermovir baseline mutations transplant recipients phenotype |
| title | Assessment of UL56 Mutations before Letermovir Therapy in Refractory Cytomegalovirus Transplant Recipients |
| title_full | Assessment of UL56 Mutations before Letermovir Therapy in Refractory Cytomegalovirus Transplant Recipients |
| title_fullStr | Assessment of UL56 Mutations before Letermovir Therapy in Refractory Cytomegalovirus Transplant Recipients |
| title_full_unstemmed | Assessment of UL56 Mutations before Letermovir Therapy in Refractory Cytomegalovirus Transplant Recipients |
| title_short | Assessment of UL56 Mutations before Letermovir Therapy in Refractory Cytomegalovirus Transplant Recipients |
| title_sort | assessment of ul56 mutations before letermovir therapy in refractory cytomegalovirus transplant recipients |
| topic | cytomegalovirus letermovir baseline mutations transplant recipients phenotype |
| url | https://journals.asm.org/doi/10.1128/spectrum.00191-22 |
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