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      Genetics, Receptor Binding, Replication, and Mammalian Transmission of H4 Avian Influenza Viruses Isolated from Live Poultry Markets in China

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          ABSTRACT

          H4 avian influenza virus (AIV) is one of the most prevalent influenza virus subtypes in the world. However, whether H4 AIVs pose a threat to public health remains largely unclear. Here, we analyzed the phylogenetic relationships, receptor binding properties, replication, and transmissibility in mammals of H4 AIVs isolated from live poultry markets in China between 2009 and 2012. Genomic sequence analysis of 36 representative H4 viruses revealed 32 different genotypes, indicating that these viruses are undergoing complex and frequent reassortment events. All 32 viruses tested could replicate in the respiratory organs of infected mice without prior adaptation. Receptor binding analysis demonstrated that the H4 AIVs bound to α-2,6-linked glycans, although they retained the binding preference for α-2,3-linked glycans. When we tested the direct-contact transmission of 10 H4 viruses in guinea pigs, we found that three viruses did not transmit to any of the contact animals, one virus transmitted to one of three contact animals, and six viruses transmitted to all three contact animals. When we further tested the respiratory droplet transmissibility of four of the viruses that transmitted efficiently via direct contact, we found that three of them could transmit to one or two of the five exposed animals. Our study demonstrates that the current circulating H4 AIVs can infect, replicate in, and transmit to mammalian hosts, thereby posing a potential threat to human health. These findings emphasize the continual need for enhanced surveillance of H4 AIVs.

          IMPORTANCE Numerous surveillance studies have documented the wide distribution of H4 AIVs throughout the world, yet the biological properties of H4 viruses have not been well studied. In this study, we found that multiple genotypes of H4 viruses are cocirculating in the live poultry markets of China and that H4 viruses can replicate in mice, possess human-type receptor binding specificity, and transmit between guinea pigs via direct contact. Strikingly, some H4 strains also can transmit via respiratory droplet, albeit with limited efficiency. These results clearly show the potential threat posed by H4 viruses to public health.

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          Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus

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            Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin.

            Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and the target for infectivity-neutralizing antibodies. The structures of three conformations of the ectodomain of the 1968 Hong Kong influenza virus HA have been determined by X-ray crystallography: the single-chain precursor, HA0; the metastable neutral-pH conformation found on virus, and the fusion pH-induced conformation. These structures provide a framework for designing and interpreting the results of experiments on the activity of HA in receptor binding, the generation of emerging and reemerging epidemics, and membrane fusion during viral entry. Structures of HA in complex with sialic acid receptor analogs, together with binding experiments, provide details of these low-affinity interactions in terms of the sialic acid substituents recognized and the HA residues involved in recognition. Neutralizing antibody-binding sites surround the receptor-binding pocket on the membrane-distal surface of HA, and the structures of the complexes between neutralizing monoclonal Fabs and HA indicate possible neutralization mechanisms. Cleavage of the biosynthetic precursor HA0 at a prominent loop in its structure primes HA for subsequent activation of membrane fusion at endosomal pH (Figure 1). Priming involves insertion of the fusion peptide into a charged pocket in the precursor; activation requires its extrusion towards the fusion target membrane, as the N terminus of a newly formed trimeric coiled coil, and repositioning of the C-terminal membrane anchor near the fusion peptide at the same end of a rod-shaped molecule. Comparison of this new HA conformation, which has been formed for membrane fusion, with the structures determined for other virus fusion glycoproteins suggests that these molecules are all in the fusion-activated conformation and that the juxtaposition of the membrane anchor and fusion peptide, a recurring feature, is involved in the fusion mechanism. Extension of these comparisons to the soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) protein complex of vesicle fusion allows a similar conclusion.
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              Emergence and pandemic potential of swine-origin H1N1 influenza virus.

              Influenza viruses cause annual epidemics and occasional pandemics that have claimed the lives of millions. The emergence of new strains will continue to pose challenges to public health and the scientific communities. A prime example is the recent emergence of swine-origin H1N1 viruses that have transmitted to and spread among humans, resulting in outbreaks internationally. Efforts to control these outbreaks and real-time monitoring of the evolution of this virus should provide us with invaluable information to direct infectious disease control programmes and to improve understanding of the factors that determine viral pathogenicity and/or transmissibility.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                J Virol
                J. Virol
                jvi
                jvi
                JVI
                Journal of Virology
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                0022-538X
                1098-5514
                18 November 2015
                15 January 2016
                1 February 2016
                15 January 2016
                : 90
                : 3
                : 1455-1469
                Affiliations
                [a ]State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
                [b ]College of Life and Health Sciences, Chubu University, Aichi, Japan
                Author notes
                Address correspondence to Chengjun Li, lichengjun@ 123456caas.cn , or Hualan Chen, chenhualan@ 123456caas.cn .

                L. Liang and G. Deng contributed equally to this article.

                Citation Liang L, Deng G, Shi J, Wang S, Zhang Q, Kong H, Gu C, Guan Y, Suzuki Y, Li Y, Jiang Y, Tian G, Liu L, Li C, Chen H. 2016. Genetics, receptor binding, replication, and mammalian transmission of H4 avian influenza viruses isolated from live poultry markets in China. J Virol 90:1455–1469. doi: 10.1128/JVI.02692-15.

                Article
                02692-15
                10.1128/JVI.02692-15
                4719592
                26581996
                65f30fdf-a7c6-4ad2-8fca-0418141da654
                Copyright © 2016 Liang et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 20 October 2015
                : 12 November 2015
                Page count
                Figures: 5, Tables: 3, Equations: 0, References: 98, Pages: 15, Words: 13973
                Funding
                Funded by: National Science and Technology Major Project
                Award ID: 2012ZX10004214
                Award Recipient : Hualan Chenc
                Funded by: The disease control program of the Ministry of Agriculture, China
                Award Recipient : Hualan Chen
                Funded by: National Natural Science Foundation of China (NSFC) http://dx.doi.org/10.13039/501100001809
                Award ID: 31521005
                Award Recipient : Hualan Chen
                Funded by: National Natural Science Foundation of China (NSFC) http://dx.doi.org/10.13039/501100001809
                Award ID: 31422054
                Award Recipient : Chengjun Li
                Funded by: China Agriculture Research System
                Award ID: CARS-42-G08
                Award Recipient : Guobin Tian
                U.S. National Institutes of Heath provided funding to Hualan Chen under Center for Excellence in Influenza Research and Surveillance (CEIRS) contract number HHSN272201400004C.
                Categories
                Genetic Diversity and Evolution

                Microbiology & Virology
                Microbiology & Virology

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