Manipulating Adenovirus Hexon Hypervariable Loops Dictates Immune Neutralisation and Coagulation Factor X-dependent Cell Interaction In Vitro and In Vivo
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{"title"=>"Manipulating Adenovirus Hexon Hypervariable Loops Dictates Immune Neutralisation and Coagulation Factor X-dependent Cell Interaction In Vitro and In Vivo", "type"=>"journal", "authors"=>[{"first_name"=>"Jiangtao", "last_name"=>"Ma", "scopus_author_id"=>"56126126900"}, {"first_name"=>"Margaret R.", "last_name"=>"Duffy", "scopus_author_id"=>"37037249600"}, {"first_name"=>"Lin", "last_name"=>"Deng", "scopus_author_id"=>"56542370300"}, {"first_name"=>"Rachel S.", "last_name"=>"Dakin", "scopus_author_id"=>"56702864700"}, {"first_name"=>"Taco", "last_name"=>"Uil", "scopus_author_id"=>"6506202561"}, {"first_name"=>"Jerome", "last_name"=>"Custers", "scopus_author_id"=>"24166327600"}, {"first_name"=>"Sharon M.", "last_name"=>"Kelly", "scopus_author_id"=>"7401618420"}, {"first_name"=>"John H.", "last_name"=>"McVey", "scopus_author_id"=>"7005492040"}, {"first_name"=>"Stuart A.", "last_name"=>"Nicklin", "scopus_author_id"=>"7003912384"}, {"first_name"=>"Andrew H.", "last_name"=>"Baker", "scopus_author_id"=>"7403519922"}], "year"=>2015, "source"=>"PLoS Pathogens", "identifiers"=>{"pmid"=>"25658827", "sgr"=>"84924359777", "doi"=>"10.1371/journal.ppat.1004673", "scopus"=>"2-s2.0-84924359777", "pui"=>"602901783", "issn"=>"15537374"}, "id"=>"bbf40988-135b-39d7-bc9d-ad490ee5b391", "abstract"=>"Adenoviruses are common pathogens, mostly targeting ocular, gastrointestinal and respiratory cells, but in some cases infection disseminates, presenting in severe clinical outcomes. Upon dissemination and contact with blood, coagulation factor X (FX) interacts directly with the adenovirus type 5 (Ad5) hexon. FX can act as a bridge to bind heparan sulphate proteoglycans, leading to substantial Ad5 hepatocyte uptake. FX \"coating\" also protects the virus from host IgM and complement-mediated neutralisation. However, the contribution of FX in determining Ad liver transduction whilst simultaneously shielding the virus from immune attack remains unclear. In this study, we demonstrate that the FX protection mechanism is not conserved amongst Ad types, and identify the hexon hypervariable regions (HVR) of Ad5 as the capsid proteins targeted by this host defense pathway. Using genetic and pharmacological approaches, we manipulate Ad5 HVR interactions to interrogate the interplay between viral cell transduction and immune neutralisation. We show that FX and inhibitory serum components can co-compete and virus neutralisation is influenced by both the location and extent of modifications to the Ad5 HVRs. We engineered Ad5-derived HVRs into the rare, native non FX-binding Ad26 to create Ad26.HVR5C. This enabled the virus to interact with FX at high affinity, as quantified by surface plasmon resonance, FX-mediated cell binding and transduction assays. Concomitantly, Ad26.HVR5C was also sensitised to immune attack in the absence of FX, a direct consequence of the engineered HVRs from Ad5. In both immune competent and deficient animals, Ad26.HVR5C hepatic gene transfer was mediated by FX following intravenous delivery. This study gives mechanistic insight into the pivotal role of the Ad5 HVRs in conferring sensitivity to virus neutralisation by IgM and classical complement-mediated attack. Furthermore, through this gain-of-function approach we demonstrate the dual functionality of FX in protecting Ad26.HVR5C against innate immune factors whilst determining liver targeting.", "link"=>"http://www.mendeley.com/research/manipulating-adenovirus-hexon-hypervariable-loops-dictates-immune-neutralisation-coagulation-factor", "reader_count"=>24, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>1, "Researcher"=>2, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>1, "Other"=>3, "Student > Master"=>1, "Student > Bachelor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>1, "Researcher"=>2, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>1, "Other"=>3, "Student > Master"=>1, "Student > Bachelor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Biochemistry, Genetics and Molecular Biology"=>7, "Agricultural and Biological Sciences"=>10, "Medicine and Dentistry"=>1, "Chemistry"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>10}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}, "Unspecified"=>{"Unspecified"=>4}}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1883943"], "description"=>"<p>(A) Binding of 1000 or 5000 vp/cell of Ad5, Ad26 or Ad26.HVR5C was quantified after incubation with SKOV3 cells for 1 h at 4°C in the presence or absence of 10 μg/mL hFX. Vector genomes were detected by quantitative PCR. (B) SKOV3 cells were infected with 1000 or 5000 vp/cell of Ad5, Ad26 or Ad26.HVR5C in the absence or presence of 10 μg/mL hFX for 3 h at 37˚C, after which media was replaced by full RPMI-1640 media and cells incubated at 37˚C. Transgene expression was measured 48 h post-infection. *p < 0.001 vs. matched -/+FX controls.</p>", "links"=>[], "tags"=>["FX protection mechanism", "Ad 5 HVRs", "coagulation factor X", "bind heparan sulphate proteoglycans", "Ad liver transduction whilst", "adenovirus type 5", "Ad 26.HVR", "host defense pathway", "Ad 26.HVR hepatic gene transfer", "hexon hypervariable regions", "Ad 5 HVR interactions", "Ad 5 hepatocyte uptake", "surface plasmon resonance", "virus neutralisation", "Manipulating Adenovirus Hexon Hypervariable Loops Dictates Immune Neutralisation"], "article_id"=>1302912, "categories"=>["Biological Sciences"], "users"=>["Jiangtao Ma", "Margaret R. Duffy", "Lin Deng", "Rachel S. Dakin", "Taco Uil", "Jerome Custers", "Sharon M. Kelly", "John H. McVey", "Stuart A. Nicklin", "Andrew H. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004673.g005", "stats"=>{"downloads"=>3, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_FX_mediated_Ad26_HVR5C_cell_surface_binding_and_transduction_/1302912", "title"=>"FX-mediated Ad26.HVR5C cell surface binding and transduction.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-06 04:10:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1883941"], "description"=>"<p>(A) Virus titers and vp/pfu ratios for each of the vectors produced. (B) SPR analysis of Ad5, Ad26 and mutant vector interaction with immobilized hFX (500 RU). Sensorgrams of 10<sup>11</sup> vp/ml of vector injected at a flow rate of 30 μL/min. (C i) SPR analysis of hFX for immobilized Ad26.HVR5C. Samples analysed in triplicate at 4 concentrations of hFX. (C ii) SPR analysis of hFX for immobilized Ad5. Samples analysed in triplicate at 7 concentrations of hFX. The black lines represent the fit to the data. (C iii) Kinetic constants of hFX for immobilized Ad5 or Ad26.HVR5C as determined by SPR.</p>", "links"=>[], "tags"=>["FX protection mechanism", "Ad 5 HVRs", "coagulation factor X", "bind heparan sulphate proteoglycans", "Ad liver transduction whilst", "adenovirus type 5", "Ad 26.HVR", "host defense pathway", "Ad 26.HVR hepatic gene transfer", "hexon hypervariable regions", "Ad 5 HVR interactions", "Ad 5 hepatocyte uptake", "surface plasmon resonance", "virus neutralisation", "Manipulating Adenovirus Hexon Hypervariable Loops Dictates Immune Neutralisation"], "article_id"=>1302910, "categories"=>["Biological Sciences"], "users"=>["Jiangtao Ma", "Margaret R. Duffy", "Lin Deng", "Rachel S. Dakin", "Taco Uil", "Jerome Custers", "Sharon M. Kelly", "John H. McVey", "Stuart A. Nicklin", "Andrew H. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004673.g003", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Generation_of_Ad26_hexon_modified_vectors_and_effects_on_FX_binding_by_SPR_/1302910", "title"=>"Generation of Ad26 hexon modified vectors and effects on FX binding by SPR.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-06 04:10:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1883946", "https://ndownloader.figshare.com/files/1883947", "https://ndownloader.figshare.com/files/1883948", "https://ndownloader.figshare.com/files/1883949", "https://ndownloader.figshare.com/files/1883950", "https://ndownloader.figshare.com/files/1883951", "https://ndownloader.figshare.com/files/1883952", "https://ndownloader.figshare.com/files/1883953"], "description"=>"<div><p>Adenoviruses are common pathogens, mostly targeting ocular, gastrointestinal and respiratory cells, but in some cases infection disseminates, presenting in severe clinical outcomes. Upon dissemination and contact with blood, coagulation factor X (FX) interacts directly with the adenovirus type 5 (Ad5) hexon. FX can act as a bridge to bind heparan sulphate proteoglycans, leading to substantial Ad5 hepatocyte uptake. FX “coating” also protects the virus from host IgM and complement-mediated neutralisation. However, the contribution of FX in determining Ad liver transduction whilst simultaneously shielding the virus from immune attack remains unclear. In this study, we demonstrate that the FX protection mechanism is not conserved amongst Ad types, and identify the hexon hypervariable regions (HVR) of Ad5 as the capsid proteins targeted by this host defense pathway. Using genetic and pharmacological approaches, we manipulate Ad5 HVR interactions to interrogate the interplay between viral cell transduction and immune neutralisation. We show that FX and inhibitory serum components can co-compete and virus neutralisation is influenced by both the location and extent of modifications to the Ad5 HVRs. We engineered Ad5-derived HVRs into the rare, native non FX-binding Ad26 to create Ad26.HVR5C. This enabled the virus to interact with FX at high affinity, as quantified by surface plasmon resonance, FX-mediated cell binding and transduction assays. Concomitantly, Ad26.HVR5C was also sensitised to immune attack in the absence of FX, a direct consequence of the engineered HVRs from Ad5. In both immune competent and deficient animals, Ad26.HVR5C hepatic gene transfer was mediated by FX following intravenous delivery. This study gives mechanistic insight into the pivotal role of the Ad5 HVRs in conferring sensitivity to virus neutralisation by IgM and classical complement-mediated attack. Furthermore, through this gain-of-function approach we demonstrate the dual functionality of FX in protecting Ad26.HVR5C against innate immune factors whilst determining liver targeting.</p></div>", "links"=>[], "tags"=>["FX protection mechanism", "Ad 5 HVRs", "coagulation factor X", "bind heparan sulphate proteoglycans", "Ad liver transduction whilst", "adenovirus type 5", "Ad 26.HVR", "host defense pathway", "Ad 26.HVR hepatic gene transfer", "hexon hypervariable regions", "Ad 5 HVR interactions", "Ad 5 hepatocyte uptake", "surface plasmon resonance", "virus neutralisation", "Manipulating Adenovirus Hexon Hypervariable Loops Dictates Immune Neutralisation"], "article_id"=>1302915, "categories"=>["Biological Sciences"], "users"=>["Jiangtao Ma", "Margaret R. Duffy", "Lin Deng", "Rachel S. Dakin", "Taco Uil", "Jerome Custers", "Sharon M. Kelly", "John H. McVey", "Stuart A. Nicklin", "Andrew H. Baker"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1004673.s001", "https://dx.doi.org/10.1371/journal.ppat.1004673.s002", "https://dx.doi.org/10.1371/journal.ppat.1004673.s003", "https://dx.doi.org/10.1371/journal.ppat.1004673.s004", "https://dx.doi.org/10.1371/journal.ppat.1004673.s005", "https://dx.doi.org/10.1371/journal.ppat.1004673.s006", "https://dx.doi.org/10.1371/journal.ppat.1004673.s007", "https://dx.doi.org/10.1371/journal.ppat.1004673.s008"], "stats"=>{"downloads"=>8, "page_views"=>41, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Manipulating_Adenovirus_Hexon_Hypervariable_Loops_Dictates_Immune_Neutralisation_and_Coagulation_Factor_X_dependent_Cell_Interaction_In_Vitro_and_In_Vivo_/1302915", "title"=>"Manipulating Adenovirus Hexon Hypervariable Loops Dictates Immune Neutralisation and Coagulation Factor X-dependent Cell Interaction <i>In Vitro</i> and <i>In Vivo</i>", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-02-06 04:10:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1883945"], "description"=>"<p>(A + B) Luciferase expression was visualised (A) and quantitatively assessed (B) by whole-body bioluminescence (IVIS) imaging 72 h after intravascular administration of 1x10<sup>11</sup> vp/mouse Ad5, Ad26 or Ad26.HVR5C in the absence or presence of 133 μg/mouse warfarin (n = 4 animals/group) or PBS (n = 3 animals/group) in RAG<sup>2-/-</sup> mice. (C) Livers were harvested 72 h post-injection and processed for quantification of luciferase transgene expression and (D) quantification of viral genomes, using 200 ng of DNA for analysis. *p<0.05 and NS (not significant) vs the matched non-warfarin treated control.</p>", "links"=>[], "tags"=>["FX protection mechanism", "Ad 5 HVRs", "coagulation factor X", "bind heparan sulphate proteoglycans", "Ad liver transduction whilst", "adenovirus type 5", "Ad 26.HVR", "host defense pathway", "Ad 26.HVR hepatic gene transfer", "hexon hypervariable regions", "Ad 5 HVR interactions", "Ad 5 hepatocyte uptake", "surface plasmon resonance", "virus neutralisation", "Manipulating Adenovirus Hexon Hypervariable Loops Dictates Immune Neutralisation"], "article_id"=>1302914, "categories"=>["Biological Sciences"], "users"=>["Jiangtao Ma", "Margaret R. Duffy", "Lin Deng", "Rachel S. Dakin", "Taco Uil", "Jerome Custers", "Sharon M. Kelly", "John H. McVey", "Stuart A. Nicklin", "Andrew H. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004673.g007", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vivo_analysis_of_Ad26_HVR5C_biodistribution_in_immune_deficient_mice_/1302914", "title"=>"<i>In vivo</i> analysis of Ad26.HVR5C biodistribution in immune deficient mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-06 04:10:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1883940"], "description"=>"<p>(A) A549 and (B) SKOV3 cells: Ad5 and its derivatives (2x10<sup>10</sup> vp/mL) were incubated with RPMI-1640 media, 90% C57BL/6 mouse serum or 1–90% C57BL/6 mouse serum in RPMI-1640 media for 30 min at 37°C and (C) A549 cells: Ad5T* or Ad5.HVR5* (2x10<sup>10</sup> vp/mL) were incubated with RPMI-1640 media, 1–90% C57BL/6 mouse serum in RPMI-1640 media in the absence or presence of 10 μg/mL hFX for 30 min at 37°C. Virus suspensions were diluted 200-fold in serum-free media and 100 μL added to cells for 2 h at 37°C before being replaced with RPMI-1640 media with 2% FCS. Transgene expression was quantified ∼16 h post-transduction and relative light units (RLU) normalized to mg total protein. Results for each vector are shown as percentage of the matched media control. Groups that do not share the same letter (a, b, c, d) are significantly different to samples within that group. *p < 0.05 vs. matched controls.</p>", "links"=>[], "tags"=>["FX protection mechanism", "Ad 5 HVRs", "coagulation factor X", "bind heparan sulphate proteoglycans", "Ad liver transduction whilst", "adenovirus type 5", "Ad 26.HVR", "host defense pathway", "Ad 26.HVR hepatic gene transfer", "hexon hypervariable regions", "Ad 5 HVR interactions", "Ad 5 hepatocyte uptake", "surface plasmon resonance", "virus neutralisation", "Manipulating Adenovirus Hexon Hypervariable Loops Dictates Immune Neutralisation"], "article_id"=>1302909, "categories"=>["Biological Sciences"], "users"=>["Jiangtao Ma", "Margaret R. Duffy", "Lin Deng", "Rachel S. Dakin", "Taco Uil", "Jerome Custers", "Sharon M. Kelly", "John H. McVey", "Stuart A. Nicklin", "Andrew H. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004673.g002", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Neutralisation_of_FX_binding_deficient_Ad5_vectors_by_na_239_ve_murine_serum_/1302909", "title"=>"Neutralisation of FX-binding deficient Ad5 vectors by naïve murine serum.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-06 04:10:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1883939"], "description"=>"<p>SKOV3 (A) or A549 cells (B-C): Vectors (2x10<sup>10</sup> vp/mL) were incubated with RPMI-1640 media, 90% C57BL/6 mouse serum in RPMI-1640 media in the absence or presence of 40 μg/mL Xbp for 30 min at 37°C. Virus suspensions were diluted 200-fold in serum-free media and 100 μL added to cells for 2 h at 37°C before being replaced with RPMI-1640 media with 2% FCS. Transgene expression was quantified ∼16 h post-transduction and relative light units (RLU) normalized to mg total protein. Results for each vector are shown as percentage of the matched media control. White bars = media alone, grey bars = serum and black bars = serum + Xbp. (D) C57BL/6 mouse serum was incubated with Ad (5x10<sup>10</sup> vp/mL) in the presence or absence of 40 μg/mL Xbp for 90 min at 37°C. C3a levels were quantified by ELISA. *p < 0.005 vs. matched controls.</p>", "links"=>[], "tags"=>["FX protection mechanism", "Ad 5 HVRs", "coagulation factor X", "bind heparan sulphate proteoglycans", "Ad liver transduction whilst", "adenovirus type 5", "Ad 26.HVR", "host defense pathway", "Ad 26.HVR hepatic gene transfer", "hexon hypervariable regions", "Ad 5 HVR interactions", "Ad 5 hepatocyte uptake", "surface plasmon resonance", "virus neutralisation", "Manipulating Adenovirus Hexon Hypervariable Loops Dictates Immune Neutralisation"], "article_id"=>1302908, "categories"=>["Biological Sciences"], "users"=>["Jiangtao Ma", "Margaret R. Duffy", "Lin Deng", "Rachel S. Dakin", "Taco Uil", "Jerome Custers", "Sharon M. Kelly", "John H. McVey", "Stuart A. Nicklin", "Andrew H. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004673.g001", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ad5_HVRs_mediate_neutralisation_by_na_239_ve_murine_serum_/1302908", "title"=>"Ad5 HVRs mediate neutralisation by naïve murine serum.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-06 04:10:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1883944"], "description"=>"<p>(A + B) Luciferase expression was visualised (A) and quantitatively assessed (B) by whole-body bioluminescence imaging 72 h after intravascular administration of 1x10<sup>11</sup> vp/mouse Ad5, Ad26 or Ad26.HVR5C in the absence or presence of 133 μg/mouse warfarin (n = 6 animals/group) or PBS (n = 3 animals/group) in MF1 mice. (C) Livers were harvested 72 h post vector injection and processed for quantification of luciferase transgene expression and (D) quantification of viral genomes, using 200 ng of DNA for analysis. *p<0.05, ***p<0.001 and NS (not significant) vs the matched non-warfarin treated control.</p>", "links"=>[], "tags"=>["FX protection mechanism", "Ad 5 HVRs", "coagulation factor X", "bind heparan sulphate proteoglycans", "Ad liver transduction whilst", "adenovirus type 5", "Ad 26.HVR", "host defense pathway", "Ad 26.HVR hepatic gene transfer", "hexon hypervariable regions", "Ad 5 HVR interactions", "Ad 5 hepatocyte uptake", "surface plasmon resonance", "virus neutralisation", "Manipulating Adenovirus Hexon Hypervariable Loops Dictates Immune Neutralisation"], "article_id"=>1302913, "categories"=>["Biological Sciences"], "users"=>["Jiangtao Ma", "Margaret R. Duffy", "Lin Deng", "Rachel S. Dakin", "Taco Uil", "Jerome Custers", "Sharon M. Kelly", "John H. McVey", "Stuart A. Nicklin", "Andrew H. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004673.g006", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vivo_analysis_of_Ad26_HVR5C_mediated_liver_transduction_in_MF1_mice_/1302913", "title"=>"<i>In vivo</i> analysis of Ad26.HVR5C mediated liver transduction in MF1 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-06 04:10:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1883942"], "description"=>"<p>(A) 2x10<sup>10</sup> vp/mL of Ad5, Ad26 or Ad26 hexon modified vectors were incubated with RPMI-1640 media, 90% C57BL/6 mouse serum, 90% C57BL/6 mouse serum with 40 μg/mL X-bp, 90% RAG<sup>2-/-</sup> mouse serum or 90% RAG<sup>2-/-</sup> mouse serum with X-bp, for 30 min at 37°C. Virus suspensions were diluted 200-fold in serum-free media and 100 μL added to SKOV3 cells for 2 h at 37°C before being replaced with RPMI-1640 media with 2% FCS. Transgene expression was quantified ∼16 h post-transduction and relative light units (RLU) normalized to mg total protein. Results for each vector are shown as percentage of the matched media control. *p < 0.001 vs. matched media controls. (B) C57BL/6 mouse serum was incubated with Ad (5x10<sup>10</sup> vp/mL) in the presence or absence of 40 μg/mL Xbp for 90 min at 37°C. C3a levels were quantified by ELISA. (C) C57BL/6 mouse serum was incubated with Ad5 or Ad5T* (5x10<sup>10</sup> vp/mL) in the presence or absence of 20 μg/mL NapC2 for 90 min at 37°C. C3a levels were quantified by ELISA. *p < 0.005 vs. matched controls.</p>", "links"=>[], "tags"=>["FX protection mechanism", "Ad 5 HVRs", "coagulation factor X", "bind heparan sulphate proteoglycans", "Ad liver transduction whilst", "adenovirus type 5", "Ad 26.HVR", "host defense pathway", "Ad 26.HVR hepatic gene transfer", "hexon hypervariable regions", "Ad 5 HVR interactions", "Ad 5 hepatocyte uptake", "surface plasmon resonance", "virus neutralisation", "Manipulating Adenovirus Hexon Hypervariable Loops Dictates Immune Neutralisation"], "article_id"=>1302911, "categories"=>["Biological Sciences"], "users"=>["Jiangtao Ma", "Margaret R. Duffy", "Lin Deng", "Rachel S. Dakin", "Taco Uil", "Jerome Custers", "Sharon M. Kelly", "John H. McVey", "Stuart A. Nicklin", "Andrew H. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004673.g004", "stats"=>{"downloads"=>2, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_FX_protects_Ad26_HVR5C_against_immune_attack_/1302911", "title"=>"FX protects Ad26.HVR5C against immune attack.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-06 04:10:48"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"11", "full-text"=>"7", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"9", "full-text"=>"3", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"15", "cited-by"=>"0", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"11", "full-text"=>"4", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"9", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}
  • {"unique-ip"=>"15", "full-text"=>"9", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"9"}

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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