Growth activation of influenza virus by trypsin and effect of T-705 (favipiravir) on trypsin-optimized growth condition
Growth activation of influenza virus by trypsin and effect of T-705 (favipiravir) on trypsin-optimized growth condition
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DOI：
10.4149/av_2019_311
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发表时间：
2019-01-01
期刊：
影响因子：
1.7
通讯作者：
ShirakI, K.
中科院分区：
文献类型：
--
作者：
Daikokui, T.;Okuda, T.;ShirakI, K.
流感病毒通过胰酶对血凝素的蛋白水解性裂解而被激活。在确定最适胰酶浓度后，比较了T-705(法维拉韦)和GS 4071(奥司他韦的活性形式)处理的细胞内和细胞外流感A/PR/8/34(H1N1)和A/Victoria/361/2011(H3N2)病毒的产量。虽然两种药物均以剂量依赖的方式有效地抑制细胞外病毒RNA的释放，但T-705将其抑制到未经胰酶处理的接种物的水平，而GS 4071的最终抑制水平是未经胰酶处理的10倍。在胰酶处理和未处理的细胞中，T-705都将细胞内病毒RNA的产生抑制到输入病毒的水平。相反，GS 4071剂量依赖地抑制胰酶处理的细胞内病毒RNA的产生，但允许病毒RNA的合成。GS 4071的最大抑制水平是不加胰酶细胞的10倍，是不加胰酶细胞接种量的1,000倍。T-705对细胞内和细胞外病毒产生的抑制作用分别是GS 4071的1000倍和10倍。T-705在没有胰酶的情况下，甚至在胰酶优化的生长条件下都有很强的抗流感活性，提示T-705在治疗流感合并细菌性肺炎方面具有一定的治疗优势。
Influenza virus is activated by proteolytic cleavage of hemagglutinin by trypsin. After determining the optimal trypsin concentration, intracellular and extracellular influenza A/PR/8/34 (H1N1) and A/Victoria/361/2011 (H3N2) virus productions were compared in cultures treated with T-705 (favipiravir) and GS 4071 (an active form of oseltamivir). Although both drugs efficiently inhibited extracellular viral RNA release in a dose-dependent manner, T-705 inhibited it to the level of the inoculum without trypsin treatment, while GS 4071 inhibited it to a final level 10 times higher than that without trypsin. T-705 inhibited intracellular viral RNA production to the level of input virus in both trypsin-treated and untreated cells. In contrast, GS 4071 dose-dependently inhibited intracellular viral RNA production in cells treated with trypsin but allowed viral RNA synthesis. The level of maximum inhibition by GS 4071was 10 times higher than that of cells without trypsin and 1,000 times greater than the inoculum titer in cells without trypsin. T-705 inhibited both intracellular and extracellular virus production 1,000 and 10 times more strongly, respectively, than GS 4071. T-705 has powerful anti-influenza activity in the absence of trypsin and even in the trypsin-optimized growth condition, suggesting the therapeutic advantage in treatment of influenza complicated with bacterial pneumonia.