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  • 1
    Publication Date: 2012-08-31
    Description: Influenza viruses take a yearly toll on human life despite efforts to contain them with seasonal vaccines. These viruses evade human immunity through the evolution of variants that resist neutralization. The identification of antibodies that recognize invariant structures on the influenza haemagglutinin (HA) protein have invigorated efforts to develop universal influenza vaccines. Specifically, antibodies to the highly conserved stem region of HA neutralize diverse viral subtypes. These antibodies largely derive from a specific antibody gene, heavy-chain variable region IGHV1-69, after limited affinity maturation from their germline ancestors, but how HA stimulates naive B cells to mature and induce protective immunity is unknown. To address this question, we analysed the structural and genetic basis for their engagement and maturation into broadly neutralizing antibodies. Here we show that the germline-encoded precursors of these antibodies act as functional B-cell antigen receptors (BCRs) that initiate subsequent affinity maturation. Neither the germline precursor of a prototypic antibody, CR6261 (ref. 3), nor those of two other natural human IGHV1-69 antibodies, bound HA as soluble immunoglobulin-G (IgG). However, all three IGHV1-69 precursors engaged HA when the antibody was expressed as cell surface IgM. HA triggered BCR-associated tyrosine kinase signalling by germline transmembrane IgM. Recognition and virus neutralization was dependent solely on the heavy chain, and affinity maturation of CR6261 required only seven amino acids in the complementarity-determining region (CDR) H1 and framework region 3 (FR3) to restore full activity. These findings provide insight into the initial events that lead to the generation of broadly neutralizing antibodies to influenza, informing the rational design of vaccines to elicit such antibodies and providing a model relevant to other infectious diseases, including human immunodeficiency virus/AIDS. The data further suggest that selected immunoglobulin genes recognize specific protein structural 'patterns' that provide a substrate for further affinity maturation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lingwood, Daniel -- McTamney, Patrick M -- Yassine, Hadi M -- Whittle, James R R -- Guo, Xiaoti -- Boyington, Jeffrey C -- Wei, Chih-Jen -- Nabel, Gary J -- Intramural NIH HHS/ -- England -- Nature. 2012 Sep 27;489(7417):566-70. doi: 10.1038/nature11371. Epub 2012 Aug 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-3005, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22932267" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Antibodies, Neutralizing/*chemistry/genetics/*immunology ; Antibodies, Viral/chemistry/*genetics/*immunology ; Antibody Affinity/immunology ; Binding Sites, Antibody/immunology ; Complementarity Determining Regions/chemistry/immunology ; Cross Reactions/immunology ; Humans ; Immunoglobulin G/chemistry/immunology ; Immunoglobulin Heavy Chains/chemistry/immunology ; Immunoglobulin M/chemistry/immunology ; Influenza Vaccines/immunology ; Models, Molecular ; Molecular Sequence Data ; Orthomyxoviridae/chemistry/*classification/*immunology ; Protein Conformation ; Receptors, Antigen, B-Cell/chemistry/immunology ; Sequence Alignment
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-05-24
    Description: Influenza viruses pose a significant threat to the public and are a burden on global health systems. Each year, influenza vaccines must be rapidly produced to match circulating viruses, a process constrained by dated technology and vulnerable to unexpected strains emerging from humans and animal reservoirs. Here we use knowledge of protein structure to design self-assembling nanoparticles that elicit broader and more potent immunity than traditional influenza vaccines. The viral haemagglutinin was genetically fused to ferritin, a protein that naturally forms nanoparticles composed of 24 identical polypeptides. Haemagglutinin was inserted at the interface of adjacent subunits so that it spontaneously assembled and generated eight trimeric viral spikes on its surface. Immunization with this influenza nanoparticle vaccine elicited haemagglutination inhibition antibody titres more than tenfold higher than those from the licensed inactivated vaccine. Furthermore, it elicited neutralizing antibodies to two highly conserved vulnerable haemagglutinin structures that are targets of universal vaccines: the stem and the receptor binding site on the head. Antibodies elicited by a 1999 haemagglutinin-nanoparticle vaccine neutralized H1N1 viruses from 1934 to 2007 and protected ferrets from an unmatched 2007 H1N1 virus challenge. This structure-based, self-assembling synthetic nanoparticle vaccine improves the potency and breadth of influenza virus immunity, and it provides a foundation for building broader vaccine protection against emerging influenza viruses and other pathogens.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kanekiyo, Masaru -- Wei, Chih-Jen -- Yassine, Hadi M -- McTamney, Patrick M -- Boyington, Jeffrey C -- Whittle, James R R -- Rao, Srinivas S -- Kong, Wing-Pui -- Wang, Lingshu -- Nabel, Gary J -- Intramural NIH HHS/ -- England -- Nature. 2013 Jul 4;499(7456):102-6. doi: 10.1038/nature12202. Epub 2013 May 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23698367" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Neutralizing/*immunology ; Antibodies, Viral/*immunology ; Binding Sites ; Cross Reactions/immunology ; Female ; Ferrets/immunology/virology ; Ferritins/chemistry ; Hemagglutination Inhibition Tests ; Hemagglutinin Glycoproteins, Influenza Virus/immunology ; Influenza A Virus, H1N1 Subtype/classification/*immunology ; Influenza Vaccines/*chemistry/*immunology ; Male ; Mice ; Mice, Inbred BALB C ; Nanoparticles/*chemistry ; Orthomyxoviridae Infections/immunology/prevention & control/virology ; Vaccines, Inactivated/immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2016-03-05
    Description: HKU1 is a human betacoronavirus that causes mild yet prevalent respiratory disease, and is related to the zoonotic SARS and MERS betacoronaviruses, which have high fatality rates and pandemic potential. Cell tropism and host range is determined in part by the coronavirus spike (S) protein, which binds cellular receptors and mediates membrane fusion. As the largest known class I fusion protein, its size and extensive glycosylation have hindered structural studies of the full ectodomain, thus preventing a molecular understanding of its function and limiting development of effective interventions. Here we present the 4.0 A resolution structure of the trimeric HKU1 S protein determined using single-particle cryo-electron microscopy. In the pre-fusion conformation, the receptor-binding subunits, S1, rest above the fusion-mediating subunits, S2, preventing their conformational rearrangement. Surprisingly, the S1 C-terminal domains are interdigitated and form extensive quaternary interactions that occlude surfaces known in other coronaviruses to bind protein receptors. These features, along with the location of the two protease sites known to be important for coronavirus entry, provide a structural basis to support a model of membrane fusion mediated by progressive S protein destabilization through receptor binding and proteolytic cleavage. These studies should also serve as a foundation for the structure-based design of betacoronavirus vaccine immunogens.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860016/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860016/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kirchdoerfer, Robert N -- Cottrell, Christopher A -- Wang, Nianshuang -- Pallesen, Jesper -- Yassine, Hadi M -- Turner, Hannah L -- Corbett, Kizzmekia S -- Graham, Barney S -- McLellan, Jason S -- Ward, Andrew B -- R56 AI118016/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2016 Mar 3;531(7592):118-21. doi: 10.1038/nature17200.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. ; Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA. ; Viral Pathogenesis Laboratory, National Institute of Allergy and Infectious Diseases, Building 40, Room 2502, 40 Convent Drive, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26935699" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Coronavirus/*chemistry/*ultrastructure ; Cryoelectron Microscopy ; Humans ; Membrane Fusion ; Models, Molecular ; Protein Binding ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Proteolysis ; Receptors, Virus/metabolism ; Spike Glycoprotein, Coronavirus/*chemistry/metabolism/*ultrastructure ; Viral Vaccines/chemistry/immunology ; Virus Internalization
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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