Mechanisms of Hemagglutinin Targeted Influenza Virus Neutralization
Publication Date
December 11, 2013
Journal
PLOS ONE
Authors
Boerries Brandenburg, Wouter Koudstaal, Jaap Goudsmit, Vincent Klaren, et al
Volume
8
Issue
12
Pages
e80034
DOI
https://dx.plos.org/10.1371/journal.pone.0080034
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0080034
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/24348996
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862845
Europe PMC
http://europepmc.org/abstract/MED/24348996
Web of Science
000328730300006
Scopus
84892615764
Mendeley
http://www.mendeley.com/research/mechanisms-hemagglutinin-targeted-influenza-virus-neutralization
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{"title"=>"Mechanisms of hemagglutinin targeted influenza virus neutralization", "type"=>"journal", "authors"=>[{"first_name"=>"Boerries", "last_name"=>"Brandenburg", "scopus_author_id"=>"8541161900"}, {"first_name"=>"Wouter", "last_name"=>"Koudstaal", "scopus_author_id"=>"6508125014"}, {"first_name"=>"Jaap", "last_name"=>"Goudsmit", "scopus_author_id"=>"35374719700"}, {"first_name"=>"Vincent", "last_name"=>"Klaren", "scopus_author_id"=>"6602940621"}, {"first_name"=>"Chan", "last_name"=>"Tang", "scopus_author_id"=>"35390023100"}, {"first_name"=>"Miriam V.", "last_name"=>"Bujny", "scopus_author_id"=>"6507945910"}, {"first_name"=>"Hans J.W.M.", "last_name"=>"Korse", "scopus_author_id"=>"49861388800"}, {"first_name"=>"Ted", "last_name"=>"Kwaks", "scopus_author_id"=>"6505918270"}, {"first_name"=>"Jason J.", "last_name"=>"Otterstrom", "scopus_author_id"=>"30567564200"}, {"first_name"=>"Jarek", "last_name"=>"Juraszek", "scopus_author_id"=>"15047903500"}, {"first_name"=>"Antoine M.", "last_name"=>"Van Oijen", "scopus_author_id"=>"6701719704"}, {"first_name"=>"Ronald", "last_name"=>"Vogels", "scopus_author_id"=>"7005841896"}, {"first_name"=>"Robert H.E.", "last_name"=>"Friesen", "scopus_author_id"=>"26648237000"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"372134063", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0080034", "scopus"=>"2-s2.0-84892615764", "pmid"=>"24348996", "sgr"=>"84892615764"}, "id"=>"2fb36133-9bff-3bb1-baf3-98d9137b930c", "abstract"=>"Human monoclonal antibodies have been identified which neutralize broad spectra of influenza A or B viruses. Here, we dissect the mechanisms by which such antibodies interfere with infectivity. We distinguish four mechanisms that link the conserved hemagglutinin (HA) epitopes of broadly neutralizing antibodies to critical processes in the viral life cycle. HA-stem binding antibodies can act intracellularly by blocking fusion between the viral and endosomal membranes and extracellularly by preventing the proteolytic activation of HA. HA-head binding antibodies prevent viral attachment and release. These insights into newly identified ways by which the human immune system can interfere with influenza virus infection may aid the development of novel universal vaccines and antivirals.", "link"=>"http://www.mendeley.com/research/mechanisms-hemagglutinin-targeted-influenza-virus-neutralization", "reader_count"=>97, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Researcher"=>19, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>32, "Student > Postgraduate"=>6, "Student > Master"=>13, "Other"=>1, "Student > Bachelor"=>15, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Researcher"=>19, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>32, "Student > Postgraduate"=>6, "Student > Master"=>13, "Other"=>1, "Student > Bachelor"=>15, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Engineering"=>3, "Biochemistry, Genetics and Molecular Biology"=>18, "Materials Science"=>1, "Agricultural and Biological Sciences"=>38, "Medicine and Dentistry"=>9, "Neuroscience"=>1, "Veterinary Science and Veterinary Medicine"=>3, "Chemical Engineering"=>1, "Chemistry"=>6, "Immunology and Microbiology"=>14}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>3}, "Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>6}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>14}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>38}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>18}, "Unspecified"=>{"Unspecified"=>3}, "Chemical Engineering"=>{"Chemical Engineering"=>1}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>3}}, "reader_count_by_country"=>{"Netherlands"=>1, "United States"=>2, "China"=>1, "South Africa"=>1}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1310888"], "description"=>"<p>(<b>A</b>) Calu-3 cells were infected with A/Puerto Rico/8/1934 (H1N1) and 3 hours later stem-binding antibody CR6261 or head-binding antibody CH65 was added. Twenty hours later, the amounts of HA present in the cell supernatant (S) and lysate (L) were analyzed by Western blot (HA0 band shown). (<b>B</b>) As in (A) except that cells were infected with A/Wisconsin/67/2005 (H3N2) virus and stem- and head-binding antibodies CR8020 and CR8057, respectively, were used. (<b>C</b>) Naïve mice were immunized and boosted twice with DNA encoding the HA of influenza A/Brisbane/59/2007 (H1N1) virus. Serum was collected and added to MDCK cells 3 hours after infection with the same virus. The amount of newly produced particles in culture supernatants and cell lysates were analyzed 20 hours later by Western blot (HA0 band shown). As positive and negative controls 1 µg/mL of CR9020 and CR8057 were included, respectively. (<b>D</b>) Fab fragments of head-binding antibodies CH65 and CR8057 were added 3 hours after infection of MDCK cells with A/Puerto Rico/8/1934 (H1N1) and A/Wisconsin/67/2005 (H3N2) virus, respectively, and 20 hours later the amounts of HA present in the supernatant were analyzed as above. (<b>E</b>) SEM images of the surface of MDCK cells infected with influenza A/New Caledonia/20/1999 (H1N1), A/Wisconsin/67/2005 (H3N2), or influenza B/Florida/04/2006 virus and subsequently incubated (from 3 hours post infection) with CR6261 (50 µg/mL, 333 nM), CH65 (10 µg/mL, 67 nM), CR8057 (0.5 µg/mL, 3 nM) or CR8033 (2.5 µg/mL, 17 nM) respectively. Representative images of three independent experiments are shown. Scale bar 1 µm. (<b>F</b> and <b>G</b>) As in (E) except TEM images of ultrathin sectioned MDCK cell (re-internalized particles indicated with red triangles). Scale bar in (F) 500 nm and in (G) 100 nm.</p>", "links"=>[], "tags"=>["binding", "antibodies", "inhibit", "influenza"], "article_id"=>874482, "categories"=>["Biological Sciences"], "users"=>["Boerries Brandenburg", "Wouter Koudstaal", "Jaap Goudsmit", "Vincent Klaren", "Chan Tang", "Miriam V. Bujny", "Hans J. W. M. Korse", "Ted Kwaks", "Jason J. Otterstrom", "Jarek Juraszek", "Antoine M. van Oijen", "Ronald Vogels", "Robert H. E. Friesen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0080034.g004", "stats"=>{"downloads"=>5, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HA_head_binding_antibodies_inhibit_influenza_virus_egress_/874482", "title"=>"HA head binding antibodies inhibit influenza virus egress.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-11 03:01:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1310919", "https://ndownloader.figshare.com/files/1310920", "https://ndownloader.figshare.com/files/1310921", "https://ndownloader.figshare.com/files/1310922", "https://ndownloader.figshare.com/files/1310923", "https://ndownloader.figshare.com/files/1310924", "https://ndownloader.figshare.com/files/1310925", "https://ndownloader.figshare.com/files/1310926", "https://ndownloader.figshare.com/files/1310927", "https://ndownloader.figshare.com/files/1310928", "https://ndownloader.figshare.com/files/1310929", "https://ndownloader.figshare.com/files/1310930", "https://ndownloader.figshare.com/files/1310931", "https://ndownloader.figshare.com/files/1310932", "https://ndownloader.figshare.com/files/1310933"], "description"=>"<div><p>Human monoclonal antibodies have been identified which neutralize broad spectra of influenza A or B viruses. Here, we dissect the mechanisms by which such antibodies interfere with infectivity. We distinguish four mechanisms that link the conserved hemagglutinin (HA) epitopes of broadly neutralizing antibodies to critical processes in the viral life cycle. HA-stem binding antibodies can act intracellularly by blocking fusion between the viral and endosomal membranes and extracellularly by preventing the proteolytic activation of HA. HA-head binding antibodies prevent viral attachment and release. These insights into newly identified ways by which the human immune system can interfere with influenza virus infection may aid the development of novel universal vaccines and antivirals.</p></div>", "links"=>[], "tags"=>["hemagglutinin", "targeted", "influenza"], "article_id"=>874507, "categories"=>["Biological Sciences"], "users"=>["Boerries Brandenburg", "Wouter Koudstaal", "Jaap Goudsmit", "Vincent Klaren", "Chan Tang", "Miriam V. Bujny", "Hans J. W. M. Korse", "Ted Kwaks", "Jason J. Otterstrom", "Jarek Juraszek", "Antoine M. van Oijen", "Ronald Vogels", "Robert H. E. Friesen"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0080034.s001", "https://dx.doi.org/10.1371/journal.pone.0080034.s002", "https://dx.doi.org/10.1371/journal.pone.0080034.s003", "https://dx.doi.org/10.1371/journal.pone.0080034.s004", "https://dx.doi.org/10.1371/journal.pone.0080034.s005", "https://dx.doi.org/10.1371/journal.pone.0080034.s006", "https://dx.doi.org/10.1371/journal.pone.0080034.s007", "https://dx.doi.org/10.1371/journal.pone.0080034.s008", "https://dx.doi.org/10.1371/journal.pone.0080034.s009", "https://dx.doi.org/10.1371/journal.pone.0080034.s010", "https://dx.doi.org/10.1371/journal.pone.0080034.s011", "https://dx.doi.org/10.1371/journal.pone.0080034.s012", "https://dx.doi.org/10.1371/journal.pone.0080034.s013", "https://dx.doi.org/10.1371/journal.pone.0080034.s014", "https://dx.doi.org/10.1371/journal.pone.0080034.s015"], "stats"=>{"downloads"=>16, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mechanisms_of_Hemagglutinin_Targeted_Influenza_Virus_Neutralization_/874507", "title"=>"Mechanisms of Hemagglutinin Targeted Influenza Virus Neutralization", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-12-11 03:01:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1310875"], "description"=>"<p>(<b>A</b>) Experimental layout. Fluorescently labeled viruses and antibodies were pre-incubated and subsequently added to live cells and tracked. Whether or not cells were eventually infected was determined by staining for influenza NP after tracking individual cells for 15 hours. (<b>B</b> and <b>C</b>) Stills of movies (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080034#pone.0080034.s007\" target=\"_blank\">Movies S1</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080034#pone.0080034.s008\" target=\"_blank\">S2</a>) showing the joint and directed motion of R18-labeled A/Aichi/2/1968-X31 (H3N2) (red) and AF647-labeled CR8020 (green) (<b>B</b>), and R18-labeled A/Puerto Rico/8/1934 (H1N1) virus (red) and AF647-labeled CR6261 (green) (<b>C</b>), along <i>TubulinTracker</i>-stained microtubules (white) of live MDCK cells (nucleus, blue) approximately 30 minutes after addition of the pre-incubated virus-antibody mixtures. Dashed lines outline the trajectories of the virus-antibody complexes (red triangles) as seen in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080034#pone.0080034.s007\" target=\"_blank\">movies S1</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080034#pone.0080034.s008\" target=\"_blank\">S2</a>. (<b>D</b>) A/Aichi/2/1968-X31 (H3N2) virus was pre-incubated with AF647-labeled CR8020 (green) before addition to live MDCK cells labeled with <i>LysoTracker</i> (magenta) and imaged when virus-antibody complexes reached the perinuclear region. Arrows indicate co-localization of virus-antibody complexes with low-pH vesicles (white). (<b>E</b>) As in (<b>D</b>), except that here A/Puerto Rico/8/1934 (H1N1) virus and AF647-labeled CR6261 were used. (<b>F</b>) R18-labeled A/Aichi/2/1968-X31 (H3N2) virus (red) was incubated with AF647-labeled CR8020 (green) before addition to live MDCK cells expressing a GFP-cell tracer (grey cell outline). Virus-antibody complexes (co-localization shown in yellow, compare also split channels in the inset) were detected in live cells 30 minutes after inoculation. (<b>G</b>) To determine whether internalized virus-antibody complexes prevent infection, the fate of individual cells was assessed by tracking them over night (imaged in 30 min intervals). 15 hours post-incubation (hpi) the same cells (including their progeny) were fixed and stained for expression of influenza nuclear protein (NP, blue). (<b>H</b>) Incubation of R18-labeled A/Aichi/2/1968-X31 (H3N2) virus (red) with non-binding AF647-labeled CR6261 did not result in internalization of antibody. Only viral particles were detected in live cells 30 minutes after addition of the virus-antibody mixture and infection was not prevented, as demonstrated by the expression of NP (blue) in these same cells 15 hours later (<b>I</b>). Examples of progeny cells are indicated with numbers. Scale bars B–E equal 10 µm, F–I equal 25 µm.</p>", "links"=>[], "tags"=>["bnabs", "internalized", "cells", "viral"], "article_id"=>874469, "categories"=>["Biological Sciences"], "users"=>["Boerries Brandenburg", "Wouter Koudstaal", "Jaap Goudsmit", "Vincent Klaren", "Chan Tang", "Miriam V. Bujny", "Hans J. W. M. Korse", "Ted Kwaks", "Jason J. Otterstrom", "Jarek Juraszek", "Antoine M. van Oijen", "Ronald Vogels", "Robert H. E. Friesen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0080034.g001", "stats"=>{"downloads"=>2, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Stem_binding_bnAbs_are_internalized_into_live_cells_in_complex_with_viral_particles_reach_late_endosomes_and_prevent_infection_/874469", "title"=>"Stem-binding bnAbs are internalized into live cells in complex with viral particles, reach late endosomes, and prevent infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-11 03:01:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1310895"], "description"=>"<p>(<b>A</b>) Influenza virus life cycle highlighting the four distinct mechanism of actions of HA head-binding (green) and stem-binding (blue) bnAb. (Panel <b>B</b>, left) X-ray structure of an uncleaved H3 trimer (A/Hong Kong/1/68 PDB 1HA0) in a space filling representation. For clarity, only one monomer of the trimer is colored (HA1 green, HA2, yellow). The head region, comprising lectin and vestigial esterase domains, and the stem region, containing the fusion machinery, are indicated with dotted black lines. The receptor binding site is plotted in blue and the cleavage site in pink. The regions around these sites (solid orange lines) are the footprints of sialic acid and trypsin, respectively. To roughly estimate the trypsin footprint, a trypsin structure (PDB 1YF4) was docked on the HA cleavage site such that the cleaved HA arginine overlapped with the bound arginine from 1YF4. HA amino-acids within 5A from trypsin were then taken as an approximation of the footprint. (Panel <b>B</b>, right) Footprints, indicated by solid cyan lines, of the bnAbs studied here superimposed on HA: CH65 and CR6261 footprints are plotted on HA from A/South Carolina/1/1918 (PDB ID 3GBN), and the CR8020 footprint on A/Hong Kong/1/1968 HA (PDB ID 3SDY). For the flu B antibodies, the B/Brisbane/60/2008 structure (PDB ID 4FQM) is used. Each of the HA structures has been colored with amino-acid conservation index, corresponding to their respective virus groups: H1 – group1, H3 – group 2 and B – entire influenza B. Conservation was calculated based on the NCBI flu database set as of December 2011, assuming a number of conservative substitutions <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080034#pone.0080034-Ekiert2\" target=\"_blank\">[8]</a>. Red color corresponds to more than 99% conservation, white to less than 60% conservation. Additional human antibodies of which the epitopes and/or mechanism(s) of action are known are indicated on the far right.</p>", "links"=>[], "tags"=>["bnabs", "conserved", "regions", "vulnerabilities", "influenza"], "article_id"=>874489, "categories"=>["Biological Sciences"], "users"=>["Boerries Brandenburg", "Wouter Koudstaal", "Jaap Goudsmit", "Vincent Klaren", "Chan Tang", "Miriam V. Bujny", "Hans J. W. M. Korse", "Ted Kwaks", "Jason J. Otterstrom", "Jarek Juraszek", "Antoine M. van Oijen", "Ronald Vogels", "Robert H. E. Friesen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0080034.g005", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mechanisms_of_action_of_bnAbs_map_to_conserved_regions_on_HA_and_thereby_reveal_conserved_vulnerabilities_of_influenza_virus_/874489", "title"=>"Mechanisms of action of bnAbs map to conserved regions on HA and thereby reveal conserved vulnerabilities of influenza virus.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-11 03:01:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1310881"], "description"=>"<p>(<b>A</b>) Assay setup in microfluidic chamber mounted on an inverted fluorescent microscope. (<b>B</b> and <b>D</b>) Stills of movies of individual R18-labeled A/Aichi/2/1968-X31 (H3N2) or (<b>C</b> and <b>E</b>) A/Puerto Rico/8/1934 (H1N1, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080034#pone.0080034.s011\" target=\"_blank\">Movie S5</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080034#pone.0080034.s012\" target=\"_blank\">S6</a>) virus particles (magenta) incubated with AF488-labeled bnAbs (green) and bound to sialic acid decorated proteins embedded in a supported lipid bilayer where they co-localize (white, merge). Upon lowering the pH from 7.4 to 5.0 (t = 0 seconds), viruses incubated with only 15 nM CR8020 or CR6261 undergo HA-mediated fusion with the target membrane, visualized as a rapid increase in signal due to fluorescence dequenching followed by diffusion of R18 molecules away from the fusion site (<b>B</b> and <b>C</b>, yellow triangles), whereas no fusion events occur when viruses are incubated with 1500 nM bnAbs (<b>D</b> and <b>E</b>). Scale bars equal 3 µm; illumination conditions and image contrast settings are identical in B–E. (<b>F</b> and <b>G</b>) The percentage of H3N2 and H1N1 particles undergoing fusion after the pH drop decreases with increasing concentrations of CR8020 and CR6261, respectively (black symbols). In contrast, high concentrations of bnAbs used as non-binding control antibody have no effect on the percentage of fusion (open symbols).</p>", "links"=>[], "tags"=>["bnabs", "membrane", "fusion"], "article_id"=>874475, "categories"=>["Biological Sciences"], "users"=>["Boerries Brandenburg", "Wouter Koudstaal", "Jaap Goudsmit", "Vincent Klaren", "Chan Tang", "Miriam V. Bujny", "Hans J. W. M. Korse", "Ted Kwaks", "Jason J. Otterstrom", "Jarek Juraszek", "Antoine M. van Oijen", "Ronald Vogels", "Robert H. E. Friesen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0080034.g002", "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Stem_binding_bnAbs_prevent_membrane_fusion_in_an_in_vitro_single_particle_fusion_assay_/874475", "title"=>"Stem-binding bnAbs prevent membrane fusion in an <i>in vitro</i> single particle fusion assay.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-11 03:01:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1310885"], "description"=>"<p>(<b>A</b>) Expression of influenza NP (green) in MDCK cells (nuclei labeled with DAPI in blue) 16 hours after inoculation with A/Wisconsin/67/2005 (H3N2) virus of which the HA was uncleaved (top) or cleaved by prior incubation with trypsin (bottom). (<b>B</b>) Experimental layout to study the additive effect of cleavage inhibition on the potency of CR8020 <i>in vitro</i>. (<b>C</b>) A/Wisconsin/67/2005 (H3N2) virus was either first incubated with trypsin and then with a serial dilution of neutralizing antibody (i.e. CR8020 after trypsin), or the virus was first incubated with serial dilutions of antibody and then treated with trypsin (i.e. CR8020 before trypsin). After 18 hours of infection, cells (nuclei stained with DAPI, blue) were stained for infection (NP expression, green). (<b>D</b>) Graph shows numerical analysis of results; normalized percentage of infection versus antibody concentration was used to compare the IC<sub>50</sub> values for each condition. Change in IC<sub>50</sub> is 9.2-fold (95% C.I. 6.8–12.3). (<b>E</b>) Calu-3 cells (polarized human lung epithelia) were infected with cleaved A/Wisconsin/67/2005 (H3N2). Virus was washed away after 2 hours, and cells were incubated with test and control antibody for 18 hours in the absence of trypsin. Newly produced viral particles released into the culture supernatant were harvested and the HA cleavage status was analyzed by Western blot (using rabbit polyclonal anti-HA serum). The presence of the HA2 band is indicative for cleavage (the HA1 band is not efficiently stained by the polyclonal serum).</p>", "links"=>[], "tags"=>["cleavage", "cr8020", "additive", "neutralization"], "article_id"=>874479, "categories"=>["Biological Sciences"], "users"=>["Boerries Brandenburg", "Wouter Koudstaal", "Jaap Goudsmit", "Vincent Klaren", "Chan Tang", "Miriam V. Bujny", "Hans J. W. M. Korse", "Ted Kwaks", "Jason J. Otterstrom", "Jarek Juraszek", "Antoine M. van Oijen", "Ronald Vogels", "Robert H. E. Friesen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0080034.g003", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Blocking_HA_cleavage_by_CR8020_has_an_additive_effect_on_virus_neutralization_in_vitro_/874479", "title"=>"Blocking HA cleavage by CR8020 has an additive effect on virus neutralization <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-11 03:01:41"}

PMC Usage Stats | Further Information

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Relative Metric

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