Baloxavir marboxil susceptibility of influenza viruses from the Asia-Pacific, 2012-2018
Baloxavir marboxil susceptibility of influenza viruses from the Asia-Pacific, 2012-2018
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DOI：
10.1016/j.antiviral.2019.02.007
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发表时间：
2019-04-01
影响因子：
7.6
通讯作者：
Hurt, Aeron C.
中科院分区：
文献类型：
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作者：
Koszalka, Paulina;Tilmanis, Danielle;Hurt, Aeron C.
Baloxavir Marboxil (BXM) 是一种流感聚合酶抑制剂抗病毒药物，可与甲型和乙型流感病毒 PA 亚基的核酸内切酶区域结合。为了确定 BXM 获得许可之前流通的病毒的敏感性基线并监测 BXM 使用后的敏感性，开发了一种基于细胞培养的焦点减少测定法，以确定 286 种循环季节性流感病毒、A(H1N1)pdm09、A(H3N2)、B（山形/维多利亚）谱系病毒，包括神经氨酸酶抑制剂 (NAI) 抗性病毒对巴洛沙韦的敏感性酸 (BXA)，BXM 的活性代谢形式。 BXA 对所有测试的流感亚型均有效，平均 EC50 值（最小值-最大值）为 0.7 +/- 0.5 nM (0.1-2.1 nM)、1.2 +/- 0.6 nM (0.1-2.4)、7.2 +/- 3.5 nM (0.7-14.8) 和 5.8 +/- 4.5 nM (1.8-15.5) 分别针对 A(H1N1)pdm09、A(H3N2)、B（维多利亚系）和 B（山形系）流感病毒获得。使用反向遗传学，将已知会改变 BXA 敏感性的氨基酸替换引入 PA 蛋白中，导致 EC50 倍数变化增加 2 至 65 倍。我们的研究表明，当前流行的病毒对 BXA 敏感，并且新开发的焦点减少测定非常适合参考实验室的敏感性监测。
Baloxavir Marboxil (BXM) is an influenza polymerase inhibitor antiviral that binds to the endonuclease region in the PA subunit of influenza A and B viruses. To establish the baseline susceptibility of viruses circulating prior to licensure of BXM and to monitor for susceptibility post-BXM use, a cell culture-based focus reduction assay was developed to determine the susceptibility of 286 circulating seasonal influenza viruses, A(H1N1)pdm09, A(H3N2), B (Yamagata/Victoria) lineage viruses, including neuraminidase inhibitor (NAI) resistant viruses, to Baloxavir Acid (BXA), the active metabolic form of BXM. BXA was effective against all influenza subtypes tested with mean EC50 values (minimum-maximum) of 0.7 +/- 0.5 nM (0.1-2.1 nM), 1.2 +/- 0.6 nM (0.1-2.4), 7.2 +/- 3.5 nM (0.7-14.8), and 5.8 +/- 4.5 nM (1.8-15.5) obtained for A(H1N1)pdm09, A(H3N2), B(Victoria lineage), and B(Yamagata lineage) influenza viruses, respectively. Using reverse genetics, amino acid substitutions known to alter BXA susceptibility were introduced into the PA protein resulting in EC50 fold change increases that ranged from 2 to 65. Our study demonstrates that currently circulating viruses are susceptible to BXA and that the newly developed focus reduction assay is well suited to susceptibility monitoring in reference laboratories.