Research Center in Infectious Diseases of the CHU of Québec and Laval University, Québec City, Québec, Canada.
Research Center in Infectious Diseases of the CHU of Québec and Laval University, Québec City, Québec, Canada.
Antiviral Res. 2019 Oct;170:104561. doi: 10.1016/j.antiviral.2019.104561. Epub 2019 Jul 16.
As part of a 2015-2018 clinical trial of peramivir treatment for acute influenza infections in the elderly, an influenza B/Yamagata/16/1988-like isolate harbouring a Val430Ile neuraminidase (NA) substitution was recovered from a single patient. This substitution was detected in respiratory samples collected before and during peramivir treatment. In NA inhibition assays, oseltamivir, zanamivir and peramivir IC50s of the Val430Ile isolate were 4-, 15- and 16-fold higher compared to a wild-type (WT) strain. In reverse genetics experiments, the Ile430Val reversion restored the drug susceptible phenotype. The Val430Ile mutant and the WT strain had comparable replication kinetics in ST6GalI-MDCK cells and the NA mutation was stable after four passages in that cell line. Molecular dynamics simulations suggested that Val430Ile impacts the NA binding through a mechanism involving the catalytic Arg116 residue. The potential of some NA mutations not part of the active site to alter the susceptibility to NA inhibitors highlights the need to develop novel antiviral strategies against influenza B infections.
在 2015-2018 年期间，一项针对老年人急性流感感染的帕拉米韦治疗的临床试验中，从一名患者中分离出一株携带 Val430Ile 神经氨酸酶（NA）取代的乙型流感/Yamagata/16/1988 样分离株。该取代在帕拉米韦治疗前和治疗期间采集的呼吸道样本中被检测到。在 NA 抑制测定中，与野生型（WT）株相比，Val430Ile 分离株的奥司他韦、扎那米韦和帕拉米韦 IC50 分别高出 4 倍、15 倍和 16 倍。在反向遗传学实验中，Ile430Val 的回复恢复了药物敏感性表型。Val430Ile 突变体和 WT 株在 ST6GalI-MDCK 细胞中的复制动力学相当，并且该 NA 突变在该细胞系中传代 4 次后仍然稳定。分子动力学模拟表明，Val430Ile 通过涉及催化 Arg116 残基的机制影响 NA 的结合。一些不在活性位点的 NA 突变改变对 NA 抑制剂的敏感性的潜力突出了开发针对乙型流感感染的新型抗病毒策略的必要性。
