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

Xiaonan Zhang, Zhigang Song, Jing He, Hui-Ling Yen, Jianhua Li, Zhaoqin Zhu, Di Tian, Wei Wang, Lei Xu, Wencai Guan, Yi Liu, Sen Wang, Bisheng Shi, Wanju Zhang, Boyin Qin, Jialin Cai, Yanmin Wan, Chunhua Xu, Xiaonan Ren, Haili ChenLu Liu, Yuqin Yang, Xiaohui Zhou, Wenjiang Zhou, Jianqing Xu, Xiaoyan Zhang, Malik Peiris, Yunwen Hu, Zhenghong Yuan

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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.

Original languageEnglish
Article numbere78
Pages (from-to)1-9
Number of pages9
JournalEmerging Microbes and Infections
Issue number11
Publication statusPublished - Nov 2014
Externally publishedYes


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