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Emerging Microbes & Infections Volume 3, 2014 - Issue 1
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Original Articles

Drug susceptibility profile and pathogenicity of H7N9 influenza virus (Anhui1 lineage) with R292K substitution

Xiaonan ZhangDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Zhigang SongDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Jing HeDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Hui-Ling YenState Key Laboratory of Emerging Infectious Disease, School of Public Health, University of Hong Kong, Hong Kong, China
,
Jianhua LiKey Lab of Medical Molecular Virology, School of Basic Medical Science, Fudan University, Shanghai 200032, China
,
Zhaoqin ZhuDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Di TianDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Wei WangDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Lei XuDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Wencai GuanDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Yi LiuDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Sen WangDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China;Key Lab of Medical Molecular Virology, School of Basic Medical Science, Fudan University, Shanghai 200032, China
,
Bisheng ShiDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Wanju ZhangDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Boyin QinAnimal Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Jialin CaiAnimal Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Yanmin WanScientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Chunhua XuAnimal Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Xiaonan RenAnimal Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Haili ChenDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Lu LiuScientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Yuqin YangAnimal Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Xiaohui ZhouAnimal Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Wenjiang ZhouAnimal Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Jianqing XuKey Lab of Medical Molecular Virology, School of Basic Medical Science, Fudan University, Shanghai 200032, China;Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Xiaoyan ZhangKey Lab of Medical Molecular Virology, School of Basic Medical Science, Fudan University, Shanghai 200032, China;Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
,
Malik PeirisState Key Laboratory of Emerging Infectious Disease, School of Public Health, University of Hong Kong, Hong Kong, China
,
Yunwen HuDepartment of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, ChinaCorrespondence[email protected] [email protected]
&
Zhenghong YuanKey Lab of Medical Molecular Virology, School of Basic Medical Science, Fudan University, Shanghai 200032, ChinaCorrespondence[email protected] [email protected]
 show all
Pages 1-9 | Received 23 Sep 2015, Accepted 02 Nov 2015, Published online: 25 Jan 2019
 
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Abstract

Neuraminidase inhibitors (NAIs) are the only available licensed therapeutics against human H7N9 influenza virus infections. The emergence of NAI-resistant variants of H7N9viruses with an NA R292K mutation poses a therapeutic challenge. A comprehensive understanding of the susceptibility of these viruses to clinically available NAIs, non-NAIs and their combinations is crucial for effective treatment. In this study, by using limited serial passage and plaque purification, an R292K variant of the Anhui1 lineage was isolated from a patient with clinical evidence of resistance to oseltamivir. In vitro and cell-based assays confirmed a high level of resistance conferred by the R292K mutation to oseltamivir carboxylate and a moderate level of resistance to zanamivir and peramivir. Non-NAI antivirals, such as T-705, ribavirin and NT-300, efficiently inhibited both the variant and the wild-type in cell-based assays. A combination of NAIs and non-NAIs did not exhibit a marked synergistic effect against the R292K variant. However, the combination of two non-NAIs (T-705 and ribavirin) exhibited significant synergism against the mutant virus. In experimentally infected mice, the variant showed delayed onset of symptoms, a reduced viral load and attenuated lethality compared with the wild-type. Our study suggested non-NAIs should be tested clinically for H7N9 patients with a sustained high viral load. Possible drug combination regimens, such as T-705 plus ribavirin, should be further tested in animal models. The pathogenicity and transmissibility of the R292K H7N9 variant should be further assessed with genetically well-characterized pairs of viruses and, most-desirably, with competitive fitness experiments.

This research was supported by the National Megaprojects of China for Infectious Disease (2012ZX10004211 and 2014ZX10004002-003-004), National Natural Science Foundation of China (81341004), Ministry of Science and Technology (KJYJ-2013-01-01) and Shanghai Municipal Health and Family Planning Commission (2013QLG002).

Supplementary Information for this article can be found on Emerging Microbes and Infections' website (http://www.nature.com/emi/).

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