Marta Santos Bravo, Nicolas Plault, Sonsoles Sánchez-Palomino, Cristina Rodríguez, Mireia Navarro Gabriel, María Mar Mosquera, Francesc Fernández Avilés, María Suarez-Lledó, Montserrat Rovira, Marta Bodro, Asunción Moreno, Laura Linares, Frederic Cofan, Carla Berengua, Cristina Esteva, Elisa Cordero, Pilar Martin-Davila, Maitane Aranzamendi, Ana Belén Pérez Jiménez, Elisa Vidal, Nuria Fernández Sabé, Oscar Len, Sebastien Hantz, Sophie Alain, María Ángeles Marcos
{"title":"难治性巨细胞病毒感染抗病毒耐药突变的基因型和表型研究。","authors":"Marta Santos Bravo, Nicolas Plault, Sonsoles Sánchez-Palomino, Cristina Rodríguez, Mireia Navarro Gabriel, María Mar Mosquera, Francesc Fernández Avilés, María Suarez-Lledó, Montserrat Rovira, Marta Bodro, Asunción Moreno, Laura Linares, Frederic Cofan, Carla Berengua, Cristina Esteva, Elisa Cordero, Pilar Martin-Davila, Maitane Aranzamendi, Ana Belén Pérez Jiménez, Elisa Vidal, Nuria Fernández Sabé, Oscar Len, Sebastien Hantz, Sophie Alain, María Ángeles Marcos","doi":"10.1093/infdis/jiac349","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>This study describes the genotypic and phenotypic characterization of novel human cytomegalovirus (HCMV) genetic variants of a cohort of 94 clinically resistant HCMV patients.</p><p><strong>Methods and results: </strong>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.</p><p><strong>Conclusions: </strong>Extending mutation databases is crucial to optimize treatments and to improve the assessment of patients with resistant/refractory HCMV infection.</p>","PeriodicalId":509652,"journal":{"name":"The Journal of Infectious Diseases","volume":" ","pages":"1528-1536"},"PeriodicalIF":0.0000,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"5","resultStr":"{\"title\":\"Genotypic and Phenotypic Study of Antiviral Resistance Mutations in Refractory Cytomegalovirus Infection.\",\"authors\":\"Marta Santos Bravo, Nicolas Plault, Sonsoles Sánchez-Palomino, Cristina Rodríguez, Mireia Navarro Gabriel, María Mar Mosquera, Francesc Fernández Avilés, María Suarez-Lledó, Montserrat Rovira, Marta Bodro, Asunción Moreno, Laura Linares, Frederic Cofan, Carla Berengua, Cristina Esteva, Elisa Cordero, Pilar Martin-Davila, Maitane Aranzamendi, Ana Belén Pérez Jiménez, Elisa Vidal, Nuria Fernández Sabé, Oscar Len, Sebastien Hantz, Sophie Alain, María Ángeles Marcos\",\"doi\":\"10.1093/infdis/jiac349\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>This study describes the genotypic and phenotypic characterization of novel human cytomegalovirus (HCMV) genetic variants of a cohort of 94 clinically resistant HCMV patients.</p><p><strong>Methods and results: </strong>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.</p><p><strong>Conclusions: </strong>Extending mutation databases is crucial to optimize treatments and to improve the assessment of patients with resistant/refractory HCMV infection.</p>\",\"PeriodicalId\":509652,\"journal\":{\"name\":\"The Journal of Infectious Diseases\",\"volume\":\" \",\"pages\":\"1528-1536\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2022-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"5\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Infectious Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/infdis/jiac349\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/infdis/jiac349","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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 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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