Genotypic and Phenotypic Study of Antiviral Resistance Mutations in Refractory Cytomegalovirus Infection.

The Journal of Infectious Diseases Pub Date : 2022-11-01 DOI:10.1093/infdis/jiac349

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

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引用次数: 5

Abstract

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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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。

背景:本研究描述了94例临床耐药HCMV患者的新型人类巨细胞病毒(HCMV)遗传变异的基因型和表型特征。方法与结果:94例患者中有25例(26.6%)在UL97、UL54和UL56靶基因中检测到抗病毒耐药突变。基因型-表型相关性研究解决了临床分离株中发现的5个未表征的UL54脱氧核糖核酸聚合酶(G441S、A543V、F460S、R512C、A928T)和2个UL56末端酶(F345L、P800L)突变的状况。A928T对更昔洛韦、膦酸钠和西多福韦具有高的三重耐药，A543V对西多福韦的敏感性降低了10倍。病毒生长试验显示，与野生型AD169 HCMV相比，G441S、A543V、F345L和P800L的病毒生长能力受损。三维模型预测了A543V和A928T表型，但不能预测R512C，这加强了通过重组表型对突变进行个体表征的必要性。结论:扩展突变数据库对于优化治疗和改进对耐药/难治性HCMV感染患者的评估至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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The Journal of Infectious Diseases

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