Genotypic and Phenotypic Study of Antiviral Resistance Mutations in Refractory Cytomegalovirus Infection
Por:
Santos Bravo M, Plault N, Sánchez-Palomino S, Rodríguez C, Navarro Gabriel M, Mosquera MM, Fernández Avilés F, Suarez-Lledó M, Rovira M, Bodro M, Moreno A, Linares L, Cofan F, Berengua C, Esteva-Afonso C, Cordero E, Martin-Davila P, Aranzamendi M, Pérez Jiménez AB, Vidal E, Fernández Sabé N, Len O, Hantz S, Alain S and Marcos MÁ
Publicada:
1 nov 2022
Ahead of Print:
1 sep 2022
Resumen:
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.
Genotype-phenotype correlation study resolved the status of UL54 A928T high triple-resistant mutation to ganciclovir, foscarnet, and cidofovir and UL54 A543V-resistant mutation to cidofovir found in clinical isolates. Moreover, UL54 G441S, A543V and UL56 F345L, P800L impaired viral growth capacities.
Filiaciones:
Santos Bravo M:
Microbiology Department, Hospital Clinic of Barcelona, University of Barcelona. Institute for Global Health (ISGlobal), Barcelona, Spain
Plault N:
National Reference Center for Herpesviruses, Microbiology Department, CHU Limoges, Limoges, France
UMR Inserm 1092, University of Limoges, Limoges, France
Sánchez-Palomino S:
AIDS Research Group, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic I Provincial de Barcelona, University of Barcelona, Barcelona, Spain
Rodríguez C:
Microbiology Department, Hospital Clinic of Barcelona, University of Barcelona. Institute for Global Health (ISGlobal), Barcelona, Spain
Navarro Gabriel M:
Microbiology Department, Hospital Clinic of Barcelona, University of Barcelona. Institute for Global Health (ISGlobal), Barcelona, Spain
Mosquera MM:
Microbiology Department, Hospital Clinic of Barcelona, University of Barcelona. Institute for Global Health (ISGlobal), Barcelona, Spain
Fernández Avilés F:
Bone Marrow Transplant Unit, Hematology Department, Clinical Institute of Hematological and Oncological Diseases (ICMHO) Hospital Clinic of Barcelona, , Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Suarez-Lledó M:
Bone Marrow Transplant Unit, Hematology Department, Clinical Institute of Hematological and Oncological Diseases (ICMHO) Hospital Clinic of Barcelona, , Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Rovira M:
Bone Marrow Transplant Unit, Hematology Department, Clinical Institute of Hematological and Oncological Diseases (ICMHO) Hospital Clinic of Barcelona, , Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Bodro M:
Infectious Diseases Department, Hospital Clinic of Barcelona, Barcelona, Spain
Moreno A:
Infectious Diseases Department, Hospital Clinic of Barcelona, Barcelona, Spain
Linares L:
Infectious Diseases Department, Hospital Clinic of Barcelona, Barcelona, Spain
Cofan F:
Renal Transplantation Unit, Department of Nephrology. Hospital Clinic of Barcelona, Barcelona, Spain
Berengua C:
Microbiology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Esteva-Afonso C:
Molecular Microbiology Unit, Hospital Universitari Sant Joan de Déu, Barcelona, Spain. Malalties Prevenibles amb Vacunes, Institut de Recerca Sant Joan de Déu, Universitat de Barcelona. Centre of Biomedical Research for Epidemiology and Public Health (CIBERESP), Barcelona, Spain
Cordero E:
Clinical Unit of Infectious Diseases, Microbiology, and Preventive Medicine. Viral and Infectious Diseases in Immunodeficient Group. Institute of Biomedicine of Seville (IBiS). Virgen del Rocio University Hospital. University of Seville. Seville, Spain
Martin-Davila P:
Infectious Diseases Department. Hospital Ramon y Cajal, Madrid, Spain
Aranzamendi M:
Microbiology Department. Hospital Universitario de Cruces, Donostia, Gipuzkoa, Spain
Pérez Jiménez AB:
Microbiology Unit, Hospital Universitario Reina Sofía, Intituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain. Centre of Biomedical Research for Infectious Diseases (CIBERINFEC), Intitute of Carlos III, Madrid, Spain
Vidal E:
Microbiology Unit, Hospital Universitario Reina Sofía, Intituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain. Centre of Biomedical Research for Infectious Diseases (CIBERINFEC), Intitute of Carlos III, Madrid, Spain
Fernández Sabé N:
Department of Infectious Diseases, Bellvitge University Hospital, Insitut D'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
Len O:
Department of Infectious Diseases, Hospital Universitari Vall d'Hebrón, Universitat Autónoma de Barcelona, Barcelona, Spain
Hantz S:
National Reference Center for Herpesviruses, Microbiology Department, CHU Limoges, Limoges, France
UMR Inserm 1092, University of Limoges, Limoges, France
Alain S:
National Reference Center for Herpesviruses, Microbiology Department, CHU Limoges, Limoges, France
UMR Inserm 1092, University of Limoges, Limoges, France
Marcos MÁ:
Microbiology Department, Hospital Clinic of Barcelona, University of Barcelona. Institute for Global Health (ISGlobal), Barcelona, Spain
Green Accepted, Green Submitted
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