Si Youhui, Li Jianguo, Niu Yuqiang, Liu Xiuying, Ren Lili, Guo Li, Cheng Min, Zhou Hongli, Wang Jianwei, Jin Qi, Yang Wei
Ministry of Health Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
PLoS One. 2014 Sep 15;9(9):e107235. doi: 10.1371/journal.pone.0107235. eCollection 2014.
The recently identified human infections with a novel avian influenza H7N9 virus in China raise important questions regarding possible risk to humans. However, the entry properties and tropism of this H7N9 virus were poorly understood. Moreover, neuraminidase inhibitor resistant H7N9 isolates were recently observed in two patients and correlated with poor clinical outcomes. In this study, we aimed to elucidate the entry properties of H7N9 virus, design and evaluate inhibitors for H7N9 virus entry. We optimized and developed an H7N9-pseudotyped particle system (H7N9pp) that could be neutralized by anti-H7 antibodies and closely mimicked the entry process of the H7N9 virus. Avian, human and mouse-derived cultured cells showed high, moderate and low permissiveness to H7N9pp, respectively. Based on influenza virus membrane fusion mechanisms, a potent anti-H7N9 peptide (P155-185-chol) corresponding to the C-terminal ectodomain of the H7N9 hemagglutinin protein was successfully identified. P155-185-chol demonstrated H7N9pp-specific inhibition of infection with IC50 of 0.19 µM. Importantly, P155-185-chol showed significant suppression of A/Anhui/1/2013 H7N9 live virus propagation in MDCK cells and additive effects with NA inhibitors Oseltamivir and Zanamivir. These findings expand our knowledge of the entry properties of the novel H7N9 viruses, and they highlight the potential for developing a new class of inhibitors targeting viral entry for use in the next pandemic.
近期在中国发现的人类感染新型H7N9禽流感病毒事件引发了关于对人类潜在风险的重要问题。然而，对这种H7N9病毒的进入特性和嗜性了解甚少。此外，最近在两名患者中观察到对神经氨酸酶抑制剂耐药的H7N9分离株，且与不良临床结果相关。在本研究中，我们旨在阐明H7N9病毒的进入特性，设计并评估针对H7N9病毒进入的抑制剂。我们优化并开发了一种可被抗H7抗体中和且紧密模拟H7N9病毒进入过程的H7N9假型颗粒系统（H7N9pp）。禽类、人类和小鼠来源的培养细胞对H7N9pp的易感性分别为高、中、低。基于流感病毒膜融合机制，成功鉴定出一种对应于H7N9血凝素蛋白C末端胞外域的强效抗H7N9肽（P155 - 185 - chol）。P155 - 185 - chol对感染的抑制表现出H7N9pp特异性，IC50为0.19 μM。重要的是，P155 - 185 - chol在MDCK细胞中对A/安徽/1/2013 H7N9活病毒的增殖显示出显著抑制作用，并且与神经氨酸酶抑制剂奥司他韦和扎那米韦具有相加效应。这些发现扩展了我们对新型H7N9病毒进入特性的认识，并突出了开发一类针对病毒进入的新型抑制剂以应对下一次大流行的潜力。
