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      Changes in the hemagglutinin of H5N1 viruses during human infection – Influence on receptor binding

      research-article

      a , b , 1 , 2 , c , 2 , 3 , d , e , 2 , d , 2 , d , 2 , c , c , c , 4 , c , f , c , 5 , c , g , a , a , g , a , a , g , h , i , c , d , c , c , a , j , a , b , * , d , **

      Virology

      Academic Press

      H5N1 influenza infection, Pyrosequencing, Hemagglutinin, Receptor specificity, Hemagglutination assays, Receptor binding, Carbohydrate microarray, Biolayer interferometry, Synthetic sialylglycopolymers, Hemagglutinin X-ray crystal structure

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          Abstract

          As avian influenza A(H5N1) viruses continue to circulate in Asia and Africa, global concerns of an imminent pandemic persist. Recent experimental studies suggest that efficient transmission between humans of current H5N1 viruses only requires a few genetic changes. An essential step is alteration of the virus hemagglutinin from preferential binding to avian receptors for the recognition of human receptors present in the upper airway. We have identified receptor-binding changes which emerged during H5N1 infection of humans, due to single amino acid substitutions, Ala134Val and Ile151Phe, in the hemagglutinin. Detailed biological, receptor-binding, and structural analyses revealed reduced binding of the mutated viruses to avian-like receptors, but without commensurate increased binding to the human-like receptors investigated, possibly reflecting a receptor-binding phenotype intermediate in adaptation to more human-like characteristics. These observations emphasize that evolution in nature of avian H5N1 viruses to efficient binding of human receptors is a complex multistep process.

          Highlights

          • Changes in receptor binding of HA during H5N1 human infection were identified.

          • Single A134V and L151F substitutions caused reduced affinity for avian receptors.

          • Glycan array analyses were used to identify changes in receptor binding specificity.

          • Structural basis for altered receptor binding was examined by X-ray crystallography.

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          Most cited references 35

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          Avian influenza A (H5N1) infection in humans.

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            Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses.

             M Hatta (2001)
            In 1997, an H5N1 influenza A virus was transmitted from birds to humans in Hong Kong, killing 6 of the 18 people infected. When mice were infected with the human isolates, two virulence groups became apparent. Using reverse genetics, we showed that a mutation at position 627 in the PB2 protein influenced the outcome of infection in mice. Moreover, high cleavability of the hemagglutinin glycoprotein was an essential requirement for lethal infection.
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              Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals.

              Interspecies transmission of influenza A viruses circulating in wild aquatic birds occasionally results in influenza outbreaks in mammals, including humans. To identify early changes in the receptor binding properties of the avian virus hemagglutinin (HA) after interspecies transmission and to determine the amino acid substitutions responsible for these alterations, we studied the HAs of the initial isolates from the human pandemics of 1957 (H2N2) and 1968 (H3N2), the European swine epizootic of 1979 (H1N1), and the seal epizootic of 1992 (H3N3), all of which were caused by the introduction of avian virus HAs into these species. The viruses were assayed for their ability to bind the synthetic sialylglycopolymers 3'SL-PAA and 6'SLN-PAA, which contained, respectively, 3'-sialyllactose (the receptor determinant preferentially recognized by avian influenza viruses) and 6'-sialyl(N-acetyllactosamine) (the receptor determinant for human viruses). Avian and seal viruses bound 6'SLN-PAA very weakly, whereas the earliest available human and swine epidemic viruses bound this polymer with a higher affinity. For the H2 and H3 strains, a single mutation, 226Q-->L, increased binding to 6'SLN-PAA, while among H1 swine viruses, the 190E-->D and 225G-->E mutations in the HA appeared important for the increased affinity of the viruses for 6'SLN-PAA. Amino acid substitutions at positions 190 and 225 with respect to the avian virus consensus sequence are also present in H1 human viruses, including those that circulated in 1918, suggesting that substitutions at these positions are important for the generation of H1 human pandemic strains. These results show that the receptor-binding specificity of the HA is altered early after the transmission of an avian virus to humans and pigs and, therefore, may be a prerequisite for the highly effective replication and spread which characterize epidemic strains.
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                Author and article information

                Journal
                Virology
                Virology
                Virology
                Academic Press
                0042-6822
                1096-0341
                1 December 2013
                December 2013
                : 447
                : 1-2
                : 326-337
                Affiliations
                [a ]Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
                [b ]Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
                [c ]MRC National Institute for Medical Research, London, United Kingdom
                [d ]The Glycosciences Laboratory, Department of Medicine, Imperial College London, United Kingdom
                [e ]REQUIMTE/CQFB, Faculty of Science and Technology, New University of Lisbon, Caparica, Portugal
                [f ]Institute of Virology, Philipps University, Marburg, Germany
                [g ]Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
                [h ]GlycoThera GmbH, Hannover, Germany
                [i ]Department of Applied Bio-organic Chemistry, Gifu University, Japan
                [j ]National University of Singapore, Singapore
                Author notes
                [* ]Corresponding author at: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands dejongmd@ 123456gmail.com
                [** ]Corresponding author. Tel.: +44 (0)20-7594 7207. t.feizi@ 123456imperial.ac.uk
                [1]

                Present address: Research Unit in Pediatric Vaccines, Galician Genetics Group, Hospital Clínico Universitario de Santiago de Compostela, Spain.

                [2]

                These authors contributed equally.

                [3]

                Present address: MOA Key Laboratory of Plant Pathology, China Agricultural University, No. 2 Yuanmingyuan Xilu, Beijing, PR China.

                [4]

                Present address: MRC Technology, 1–3 Burtonhole Lane, London NW7 1AD, United Kingdom.

                [5]

                Present address: Xiang Ya Second Affiliated Hospital, Central South University, PR China.

                Article
                S0042-6822(13)00481-9
                10.1016/j.virol.2013.08.010
                3820038
                24050651
                d76bf5c0-aa73-4d65-ad66-6f27ea7aaef1
                © 2013 The Authros

                This document may be redistributed and reused, subject to certain conditions.

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