Human infections with novel reassortant H5N6 avian influenza viruses in China

Zhang, Ye; Chen, Minmei; Huang, Yiwei; Zhu, Wenfei; Yang, Lei; Gao, Lidong; Li, Xiaodan; FuYin, Bi; Huang, Chaoyang; Ning, Kang; Zhang, Hengjiao; Li, Zi; Bo, Hong; Wang, Dayan; Shu, Yuelong

doi:10.1038/emi.2017.38

Cited by 25 publications

(23 citation statements)

References 7 publications

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“…Among them, currently, H5N1, H5N6, H9N2, and H7N9 AIVs are the most prevalent subtypes in many Chinese regions [105,106]. It is noteworthy that all these subtypes not only cause substantial economic losses to poultry farming but also pose a potential threat to public health [106][107][108][109][110][111][112]. To find potential clues about the various effects of PA-X on the modulation of viral virulence, we systematically analyzed the PA-X polymorphisms in four prevalent AIV subtypes.…”

Section: Polymorphism In Pa-x In Influenza Viruses As a Threat To Pubmentioning

confidence: 99%

PA-X: a key regulator of influenza A virus pathogenicity and host immune responses

Liu

2018

Med Microbiol Immunol

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PA-X, a fusion protein belonging to influenza A viruses (IAVs), integrating the N-terminal 191 amino acids of PA gene and the ribosomal frame-shifting product that lengthens out to 41 or 61 amino acids. Since its discovery in 2012, multiple functions have been attributed to this small protein, including a process, where wide-spread protein synthesis in infected host cells is shut down (called host shutoff), and viral replication, polymerase activity, viral-induced cell apoptosis, PA nuclear localization, and virulence are modulated. However, many of its proposed functions may be specific to strain, subtype, host, or cell line. In this review, we start by describing the well-defined global host-shutoff ability of PA-X and the potential mechanisms underlying it. We move on to the role played by PA-X in modulating innate and acquired immune responses in the host. We then systematically discuss the role played by PA-X in modulating the virulence of influenza viruses of different subtypes and host origins, and finish with a general overview of the research advances made in identifying the host cell partners that interact with PA-X. To uncover possible clues about the differential effects of PA-X in modulating viral virulence, we focus on systemically evaluating polymorphisms in PA-X from various viral subtypes and hosts, including avian and human H5N1, H5N6, H9N2, and H7N9 viruses. Finally, we conclude with a proposition regarding the possible future research directions for this important protein.

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Section: Polymorphism In Pa-x In Influenza Viruses As a Threat To Pubmentioning

confidence: 99%

PA-X: a key regulator of influenza A virus pathogenicity and host immune responses

Liu

2018

Med Microbiol Immunol

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“…Screening for NAI resistance-associated markers in AIV of the N6 NA subtype. The N6 subtype of influenza viruses, in combination with highly pathogenic (HP) AIVs of the H5 subtype, have been recently reported to infect humans in China (16,23). Although there have been no recent reports of NAI resistance in the N6 subtype (24), the fatality risk of A(H5N6) human cases has been found to be similar to or higher than those of HPAI A(H5N1) and A(H7N9) infections (17).…”

mentioning

confidence: 99%

Screening for Neuraminidase Inhibitor Resistance Markers among Avian Influenza Viruses of the N4, N5, N6, and N8 Neuraminidase Subtypes

Choi

Jeong

Kwon

et al. 2018

J Virol

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Several subtypes of avian influenza viruses (AIVs) are emerging as novel human pathogens, and the frequency of related infections has increased in recent years. Although neuraminidase (NA) inhibitors (NAIs) are the only class of antiviral drugs available for therapeutic intervention for AIV-infected patients, studies on NAI resistance among AIVs have been limited, and markers of resistance are poorly understood. Previously, we identified unique NAI resistance substitutions in AIVs of the N3, N7, and N9 NA subtypes. Here, we report profiles of NA substitutions that confer NAI resistance in AIVs of the N4, N5, N6, and N8 NA subtypes using gene-fragmented random mutagenesis. We generated libraries of mutant influenza viruses using reverse genetics (RG) and selected resistant variants in the presence of the NAIs oseltamivir carboxylate and zanamivir in MDCK cells. In addition, two substitutions, H274Y and R292K (N2 numbering), were introduced into each NA gene for comparison. We identified 37 amino acid substitutions within the NA gene, 16 of which (4 in N4, 4 in N5, 4 in N6, and 4 in N8) conferred resistance to NAIs (oseltamivir carboxylate, zanamivir, or peramivir) as determined using a fluorescence-based NA inhibition assay. Substitutions conferring NAI resistance were mainly categorized as either novel NA subtype specific (G/N147V/I, A246V, and I427L) or previously reported in other subtypes (E119A/D/V, Q136K, E276D, R292K, and R371K). Our results demonstrate that each NA subtype possesses unique NAI resistance markers, and knowledge of these substitutions in AIVs is important in facilitating antiviral susceptibility monitoring of NAI resistance in AIVs. The frequency of human infections with avian influenza viruses (AIVs) has increased in recent years. Despite the availability of vaccines, neuraminidase inhibitors (NAIs), as the only available class of drugs for AIVs in humans, have been constantly used for treatment, leading to the inevitable emergence of drug-resistant variants. To screen for substitutions conferring NAI resistance in AIVs of N4, N5, N6, and N8 NA subtypes, random mutations within the target gene were generated, and resistant viruses were selected from mutant libraries in the presence of individual drugs. We identified 16 NA substitutions conferring NAI resistance in the tested AIV subtypes; some are novel and subtype specific, and others have been previously reported in other subtypes. Our findings will contribute to an increased and more comprehensive understanding of the mechanisms of NAI-induced inhibition of influenza virus and help lead to the development of drugs that bind to alternative interaction motifs.

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“…In 2016, two H5N6 viruses were isolated from two patients in China. The internal gene cassettes of these two strains differ from those reported previously, representing two novel genotypes of H5N6 viruses (Zhang et al 2017b). Another novel influenza H5N6 virus with a unique internal gene cassette was isolated from a patient in Jiangsu province in China in 2018 (unpubl.…”

Section: Hpai H5n6 Virusesmentioning

confidence: 86%

The Epidemiology, Virology, and Pathogenicity of Human Infections with Avian Influenza Viruses

Wang

Zhu

Yang

et al. 2020

Cold Spring Harb Perspect Med

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Human infections with novel reassortant H5N6 avian influenza viruses in China

Cited by 25 publications

References 7 publications

PA-X: a key regulator of influenza A virus pathogenicity and host immune responses

PA-X: a key regulator of influenza A virus pathogenicity and host immune responses

Screening for Neuraminidase Inhibitor Resistance Markers among Avian Influenza Viruses of the N4, N5, N6, and N8 Neuraminidase Subtypes

The Epidemiology, Virology, and Pathogenicity of Human Infections with Avian Influenza Viruses

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