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      Exploitation of glycosylation in enveloped virus pathobiology


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          Glycosylation is a ubiquitous post-translational modification responsible for a multitude of crucial biological roles. As obligate parasites, viruses exploit host-cell machinery to glycosylate their own proteins during replication. Viral envelope proteins from a variety of human pathogens including HIV-1, influenza virus, Lassa virus, SARS, Zika virus, dengue virus, and Ebola virus have evolved to be extensively glycosylated. These host-cell derived glycans facilitate diverse structural and functional roles during the viral life-cycle, ranging from immune evasion by glycan shielding to enhancement of immune cell infection. In this review, we highlight the imperative and auxiliary roles glycans play, and how specific oligosaccharide structures facilitate these functions during viral pathogenesis. We discuss the growing efforts to exploit viral glycobiology in the development of anti-viral vaccines and therapies.


          • Enveloped viruses often hijack host-cell glycosylation pathways.

          • Viral glycans have multifaceted influences on pathobiology.

          • Glycans have intrinsic functionalities but can also be influenced by immune selection.

          • Viral glycobiology is emerging as an important parameter during vaccine design.

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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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            Avian flu: influenza virus receptors in the human airway.

            Although more than 100 people have been infected by H5N1 influenza A viruses, human-to-human transmission is rare. What are the molecular barriers limiting human-to-human transmission? Here we demonstrate an anatomical difference in the distribution in the human airway of the different binding molecules preferred by the avian and human influenza viruses. The respective molecules are sialic acid linked to galactose by an alpha-2,3 linkage (SAalpha2,3Gal) and by an alpha-2,6 linkage (SAalpha2,6Gal). Our findings may provide a rational explanation for why H5N1 viruses at present rarely infect and spread between humans although they can replicate efficiently in the lungs.
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              Assembly of asparagine-linked oligosaccharides.


                Author and article information

                Biochim Biophys Acta Gen Subj
                Biochim Biophys Acta Gen Subj
                Biochimica et Biophysica Acta. General Subjects
                1 October 2019
                October 2019
                : 1863
                : 10
                : 1480-1497
                [a ]School of Biological Sciences and Institute of Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
                [b ]Division of Structural Biology, University of Oxford, Wellcome Centre for Human Genetics, Oxford OX3 7BN, UK
                [c ]Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
                [d ]Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
                [e ]Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
                Author notes
                [* ]Corresponding author. max.crispin@ 123456soton.ac.uk
                © 2019 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                : 27 February 2019
                : 13 May 2019
                : 17 May 2019

                virus-host interactions,glycosylation,virus,glycoprotein,structure,glycan shielding


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