Microbiology Department, Hospital Clinic of Barcelona, University of Barcelona. Institute for Global Health (ISGlobal), Barcelona, Spain.
Microbiology Department, National Reference Center for Herpesviruses, CHU Limoges, Limoges, France.
J Infect Dis. 2022 Nov 1;226(9):1528-1536. doi: 10.1093/infdis/jiac349.
This study describes the genotypic and phenotypic characterization of novel human cytomegalovirus (HCMV) genetic variants of a cohort of 94 clinically resistant HCMV patients.
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.
Extending mutation databases is crucial to optimize treatments and to improve the assessment of patients with resistant/refractory HCMV infection.
本研究描述了 94 例临床耐药巨细胞病毒（HCMV）患者队列中新型 HCMV 遗传变异的基因和表型特征。
在 94 例患者中的 25 例中检测到 UL97、UL54 和 UL56 靶基因中的抗病毒耐药突变。基因型-表型相关性研究解决了临床分离株中发现的 5 种未表征 UL54 脱氧核糖核酸聚合酶（G441S、A543V、F460S、R512C、A928T）和 2 种 UL56 末端酶（F345L、P800L）突变的状态。A928T 导致更高度的对更昔洛韦、膦甲酸和西多福韦的三重耐药，而 A543V 对西多福韦的敏感性降低了 10 倍。病毒生长测定显示，与野生型 AD169 HCMV 相比，G441S、A543V、F345L 和 P800L 降低了病毒生长能力。三维建模预测了 A543V 和 A928T 表型，但未预测 R512C 表型，这加强了通过重组表型对突变进行单独表征的必要性。
扩展突变数据库对于优化治疗和改善耐药/难治性 HCMV 感染患者的评估至关重要。
