Highly pathogenic avian influenza H7N9 viruses with reduced susceptibility to neuraminidase inhibitors showed comparable replication capacity to their sensitive counterparts

Li Xin,Jing Tang,Yanhui Cheng,Dayan Wang,Shumei Zou,Xiyan Li,Lei Yang,Weijuan Huang,Wenfei Zhu,Jianfang Zhou,Jing Zhang,Hejiang Wei

doi:10.1186/s12985-019-1194-9

Abstract

BackgroundHuman infection with avian influenza H7N9 virus was first reported in 2013. Since the fifth epidemic, a highly pathogenic avian influenza (HPAI) H7N9 virus has emerged and caused 33 human infections. Several potential NAI resistance sites have been found in human cases. However, the drug susceptibility and replication ability of HPAI H7N9 virus with such substitutions have not yet been studied.MethodsThirty-three HPAI H7N9 virus strains were isolated from human cases in China, and then sequences were analyzed to identify potential NAI resistance sites. Recombinant influenza viruses were generated to evaluate the effect of NA amino acid substitutions on NAI (oseltamivir or zanamivir) susceptibility and viral replication efficiency in MDCK cells.ResultsFour potential NAI resistance sites, R292 K, E119V, A246T or H274Y, were screened. All four substitutions conferred either reduced or highly reduced susceptibility to oseltamivir or zanamivir. 292 K not only highly reduced the susceptibility of HPAI H7N9 to oseltamivir but also induced an increase in the IC50 of zanamivir. 119 V or 274Y conferred reduced susceptibility of HPAI H7N9 to oseltamivir. Additionally, 246 T conferred reduced susceptibility to zanamivir. All tested NAI-resistant viruses were capable of replication in MDCK cells. The virus yields of rg006-NA292K were lower than those of rg006-NA292R at 24, 48, 72 and 96 h postinfection (P<0.05). Rg006-NA119V, rg006-NA246T or rg006-NA274Y showed comparable replication capacity to wild-type virus (except for rg006-NA274Y at 96 h, P<0.05).ConclusionsAll 4 amino acid substitutions (R292 K, E119V, A246T or H274Y) in NA reduced the susceptibility of HPAI H7N9 to NAIs. The NAI-resistant mutations in HPAI H7N9, in most cases, did not reduce the replication ability of the virus in mammalian cells. Special attention needs to be paid to these mutations, and the development of new anti-H7N9 drugs is of great importance.

Highlights

Human infection with avian influenza Low pathogenic avian influenza H7N9 (H7N9) virus was first reported in 2013
All 4 amino acid substitutions (R292 K, E119V, A246T or H274Y) in NA reduced the susceptibility of highly pathogenic avian influenza (HPAI) H7N9 to neuraminidase inhibitors (NAIs)
Special attention needs to be paid to these mutations, and the development of new anti-H7N9 drugs is of great importance

Summary

Introduction

Human infection with avian influenza H7N9 virus was first reported in 2013. A highly pathogenic avian influenza (HPAI) H7N9 virus has emerged and caused 33 human infections. In March 2013, China reported the first human infection with a novel reassortant avian influenza H7N9 virus [1]. Multiple basic amino acid insertions in the cleavage site of hemagglutinin have been observed since the fifth wave, which supported the emergence of HPAI H7N9 viruses [3,4,5]. HPAI H7N9 viruses, which are lethal in chickens, were detected in poultry in wave five [6]. Human and poultry infections by HPAI H7N9 viruses across China pose a great challenge to disease prevention and control

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