Assessment of UL56 Mutations before Letermovir Therapy in Refractory Cytomegalovirus Transplant Recipients

Microbiology Spectrum

Sonsoles Sánchez Palomino¹  Francesc Fernández Avilés²  María Suárez Lledó²  Montserrat Rovira²  Marta Bodro³  Asunción Moreno³  Laura Linares³  Mireia Navarro Gabriel⁴  Marta Santos Bravo⁴  María Ángeles Marcos⁴  María Mar Mosquera⁴  Sébastien Hantz⁵  Nicolas Plault⁵  Sophie Alain⁵  Valentin Tilloy⁵ 

[1] AIDS Research Group, Institut D’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic I Provincial de Barcelona, University of Barcelona, Barcelona, Spain;Bone Marrow Transplant Unit, Hematology Department, Hospital Clínic I Provincial de Barcelona, Barcelona, Spain;Infectious Diseases Department, Hospital Clínic I Provincial de Barcelona, Barcelona, Spain;Microbiology Department, Hospital Clínic I Provincial de Barcelona, University of Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain;National Reference Center for Herpesviruses, Microbiology Department, CHU Limoges, Limoges, France;

关键词: cytomegalovirus;    letermovir;    baseline mutations;    transplant recipients;    phenotype;   

DOI  :  10.1128/spectrum.00191-22

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown