HIV-1 Vaccine-Induced T-Cell Reponses Cluster in Epitope Hotspots that Differ from Those Induced in Natural Infection with HIV-1
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Mendeley | Further Information

{"title"=>"HIV-1 Vaccine-Induced T-Cell Reponses Cluster in Epitope Hotspots that Differ from Those Induced in Natural Infection with HIV-1", "type"=>"journal", "authors"=>[{"first_name"=>"Tomer", "last_name"=>"Hertz", "scopus_author_id"=>"6701622592"}, {"first_name"=>"Hasan", "last_name"=>"Ahmed", "scopus_author_id"=>"55315921500"}, {"first_name"=>"David P.", "last_name"=>"Friedrich", "scopus_author_id"=>"7007011407"}, {"first_name"=>"Danilo R.", "last_name"=>"Casimiro", "scopus_author_id"=>"6701824527"}, {"first_name"=>"Steven G.", "last_name"=>"Self", "scopus_author_id"=>"34572681000"}, {"first_name"=>"Lawrence", "last_name"=>"Corey", "scopus_author_id"=>"36068227600"}, {"first_name"=>"M. Juliana", "last_name"=>"McElrath", "scopus_author_id"=>"7005723330"}, {"first_name"=>"Susan", "last_name"=>"Buchbinder", "scopus_author_id"=>"35391587900"}, {"first_name"=>"Helen", "last_name"=>"Horton", "scopus_author_id"=>"7006928293"}, {"first_name"=>"Nicole", "last_name"=>"Frahm", "scopus_author_id"=>"6507123982"}, {"first_name"=>"Michael N.", "last_name"=>"Robertson", "scopus_author_id"=>"7401592196"}, {"first_name"=>"Barney S.", "last_name"=>"Graham", "scopus_author_id"=>"7201610365"}, {"first_name"=>"Peter", "last_name"=>"Gilbert", "scopus_author_id"=>"35236733500"}], "year"=>2013, "source"=>"PLoS Pathogens", "identifiers"=>{"pui"=>"369208254", "sgr"=>"84879515547", "issn"=>"15537366", "pmid"=>"23818843", "scopus"=>"2-s2.0-84879515547", "doi"=>"10.1371/journal.ppat.1003404", "isbn"=>"1553-7366"}, "id"=>"1782db00-7872-3450-8a1b-2173606d9bb7", "abstract"=>"Several recent large clinical trials evaluated HIV vaccine candidates that were based on recombinant adenovirus serotype 5 (rAd-5) vectors expressing HIV-derived antigens. These vaccines primarily elicited T-cell responses, which are known to be critical for controlling HIV infection. In the current study, we present a meta-analysis of epitope mapping data from 177 participants in three clinical trials that tested two different HIV vaccines: MRKAd-5 HIV and VRC-HIVAD014-00VP. We characterized the population-level epitope responses in these trials by generating population-based epitope maps, and also designed such maps using a large cohort of 372 naturally infected individuals. We used these maps to address several questions: (1) Are vaccine-induced responses randomly distributed across vaccine inserts, or do they cluster into immunodominant epitope hotspots? (2) Are the immunodominance patterns observed for these two vaccines in three vaccine trials different from one another? (3) Do vaccine-induced hotspots overlap with epitope hotspots induced by chronic natural infection with HIV-1? (4) Do immunodominant hotspots target evolutionarily conserved regions of the HIV genome? (5) Can epitope prediction methods be used to identify these hotspots? We found that vaccine responses clustered into epitope hotspots in all three vaccine trials and some of these hotspots were not observed in chronic natural infection. We also found significant differences between the immunodominance patterns generated in each trial, even comparing two trials that tested the same vaccine in different populations. Some of the vaccine-induced immunodominant hotspots were located in highly variable regions of the HIV genome, and this was more evident for the MRKAd-5 HIV vaccine. Finally, we found that epitope prediction methods can partially predict the location of vaccine-induced epitope hotspots. Our findings have implications for vaccine design and suggest a framework by which different vaccine candidates can be compared in early phases of evaluation.", "link"=>"http://www.mendeley.com/research/hiv1-vaccineinduced-tcell-reponses-cluster-epitope-hotspots-differ-those-induced-natural-infection-h", "reader_count"=>36, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>1, "Librarian"=>1, "Researcher"=>16, "Student > Ph. D. Student"=>3, "Student > Master"=>4, "Other"=>1, "Student > Bachelor"=>2, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>1, "Librarian"=>1, "Researcher"=>16, "Student > Ph. D. Student"=>3, "Student > Master"=>4, "Other"=>1, "Student > Bachelor"=>2, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>15, "Medicine and Dentistry"=>9, "Chemistry"=>1, "Social Sciences"=>1, "Immunology and Microbiology"=>3}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Chemistry"=>{"Chemistry"=>1}, "Social Sciences"=>{"Social Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>15}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"United States"=>1, "Ireland"=>1, "South Africa"=>1, "India"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1096114"], "description"=>"<p>Epitope mapping data from 72 individuals from the HVTN 502/Step trial were obtained using and IFN-γ ELISPOT assay with sets of overlapping 15-mer peptides that span the HIV-1 Gag Step vaccine insert. Responses of the 29 individuals that had at least a single epitope response to the gag insert are plotted on the bottom part of the figure. Each row represents a single participant. Each box represents a single response. Responses to overlapping positions are marked by overlapping boxes. These responses are then summed up to create the population-based map shown on the top part of the figure, in which frequencies of detection for each site along Gag are shown for this cohort. Consecutive responses made by a single individual were consolidated into a single response at the intersection of the two adjacent peptides.</p>", "links"=>[], "tags"=>["Clinical immunology", "Immune response", "Clinical research design", "clinical trials", "meta-analyses", "population-based", "epitope"], "article_id"=>727492, "categories"=>["Medicine"], "users"=>["Tomer Hertz", "Hasan Ahmed", "David P. Friedrich", "Danilo R. Casimiro", "Steven G. Self", "Lawrence Corey", "M. Juliana McElrath", "Susan Buchbinder", "Helen Horton", "Nicole Frahm", "Michael N. Robertson", "Barney S. Graham", "Peter Gilbert"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003404.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Generating_population_based_epitope_maps_/727492", "title"=>"Generating population-based epitope maps.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-20 02:04:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1096115"], "description"=>"<p>Population-based epitope maps for each protein are presented for HVTN/Step 502, Merck16, HVTN 054 and the Natural infection cohort. Shaded regions mark the four most frequent immunodominant hotspots in the HVTN 502/Step maps. (a–d) Population-based epitope map of Gag. (e–g) Population-based epitope maps of Nef. (h–k) Population-based epitope maps of Pol.</p>", "links"=>[], "tags"=>["Clinical immunology", "Immune response", "Clinical research design", "clinical trials", "meta-analyses", "vaccines", "induce", "immunodominant"], "article_id"=>727493, "categories"=>["Medicine"], "users"=>["Tomer Hertz", "Hasan Ahmed", "David P. Friedrich", "Danilo R. Casimiro", "Steven G. Self", "Lawrence Corey", "M. Juliana McElrath", "Susan Buchbinder", "Helen Horton", "Nicole Frahm", "Michael N. Robertson", "Barney S. Graham", "Peter Gilbert"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003404.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Different_vaccines_induce_different_immunodominant_hotspots_/727493", "title"=>"Different vaccines induce different immunodominant hotspots.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-20 02:04:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/1096116"], "description"=>"<p>Differences between tests were not significant (p = 0.1825, Fisher's exact test).</p>", "links"=>[], "tags"=>["Clinical immunology", "Immune response", "Clinical research design", "clinical trials", "meta-analyses", "distributions"], "article_id"=>727494, "categories"=>["Medicine"], "users"=>["Tomer Hertz", "Hasan Ahmed", "David P. Friedrich", "Danilo R. Casimiro", "Steven G. Self", "Lawrence Corey", "M. Juliana McElrath", "Susan Buchbinder", "Helen Horton", "Nicole Frahm", "Michael N. Robertson", "Barney S. Graham", "Peter Gilbert"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003404.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HLA_distributions_of_participants_in_the_three_clinical_trials_/727494", "title"=>"HLA distributions of participants in the three clinical trials.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-20 02:04:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/1096117"], "description"=>"<p>Population epitope maps of HVTN 502/Step for Gag (a) and Nef (b) overlaid with conservation scores (red line). Conservation scores were scaled to the range of 0–1, where lower scores correspond to more variable sites. The four immunodominant hotspots are shaded in blue. (c) Boxplots comparing the conservation patterns of hotspots vs. non-targeted sites along each protein are presented. Targeted hotspots were defined as areas targeted by more than 15% of individuals in a trial vs. all other sites along the protein. P-values reported are based on the Wilcoxon rank sum test. Medians are represented by black lines, and the bottom and top of the box denotes the 25<sup>th</sup> and 75<sup>th</sup> percentiles, respectively. The whiskers extend to the most extreme data point, which is no more than 1.5 times the interquartile range from the box and outliers are marked by circles.</p>", "links"=>[], "tags"=>["Clinical immunology", "Immune response", "Clinical research design", "clinical trials", "meta-analyses", "vaccine-induced", "hotspots", "regions"], "article_id"=>727495, "categories"=>["Medicine"], "users"=>["Tomer Hertz", "Hasan Ahmed", "David P. Friedrich", "Danilo R. Casimiro", "Steven G. Self", "Lawrence Corey", "M. Juliana McElrath", "Susan Buchbinder", "Helen Horton", "Nicole Frahm", "Michael N. Robertson", "Barney S. Graham", "Peter Gilbert"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003404.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Some_vaccine_induced_hotspots_target_highly_variable_regions_of_HIV_/727495", "title"=>"Some vaccine-induced hotspots target highly variable regions of HIV.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-20 02:04:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1096118"], "description"=>"<p>A comparison of the measured (black) vs. predicted (dashed) population-based epitope maps in HVTN 502/Step. Predictions were computed using the HLA alleles of trial participants and were weighted by HLA frequencies in this cohort. (a) Predicted vs. measured map for Gag. (b) Predicted vs. measured map for Nef. (c) Spearman correlation coefficients between measured and predicted epitope maps. Predicted maps were generated using three different IC50 thresholds on predicted binders: low (50 nM), intermediate (150 nM) and high (500 nM). Different thresholds yield higher correlations for different proteins: for all proteins but Pol, lower thresholds yield higher correlations, suggesting that the responses detected by the experimental assay are focused on the most immunogenic, high-affinity HLA binders. Since predicted population-based maps were obtained using predicted 9-mers, peaks in these maps are by definition more narrow than the experimentally measured maps in which 15 mers were used for epitope mapping.</p>", "links"=>[], "tags"=>["Clinical immunology", "Immune response", "Clinical research design", "clinical trials", "meta-analyses", "binding", "algorithms", "vaccine-induced", "immunodominant"], "article_id"=>727496, "categories"=>["Medicine"], "users"=>["Tomer Hertz", "Hasan Ahmed", "David P. Friedrich", "Danilo R. Casimiro", "Steven G. Self", "Lawrence Corey", "M. Juliana McElrath", "Susan Buchbinder", "Helen Horton", "Nicole Frahm", "Michael N. Robertson", "Barney S. Graham", "Peter Gilbert"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003404.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HLA_binding_prediction_algorithms_can_be_used_to_identify_vaccine_induced_immunodominant_hotspots_/727496", "title"=>"HLA binding prediction algorithms can be used to identify vaccine-induced immunodominant hotspots.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-20 02:04:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/1096119"], "description"=>"<p>Clinical datasets used in this study.</p>", "links"=>[], "tags"=>["Clinical immunology", "Immune response", "Clinical research design", "clinical trials", "meta-analyses", "datasets"], "article_id"=>727497, "categories"=>["Medicine"], "users"=>["Tomer Hertz", "Hasan Ahmed", "David P. Friedrich", "Danilo R. Casimiro", "Steven G. Self", "Lawrence Corey", "M. Juliana McElrath", "Susan Buchbinder", "Helen Horton", "Nicole Frahm", "Michael N. Robertson", "Barney S. Graham", "Peter Gilbert"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003404.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Clinical_datasets_used_in_this_study_/727497", "title"=>"Clinical datasets used in this study.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-06-20 02:04:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1096120"], "description"=>"<p>Distributions were compared using Fisher's exact test.</p>", "links"=>[], "tags"=>["Clinical immunology", "Immune response", "Clinical research design", "clinical trials", "meta-analyses", "hla", "distributions"], "article_id"=>727498, "categories"=>["Medicine"], "users"=>["Tomer Hertz", "Hasan Ahmed", "David P. Friedrich", "Danilo R. Casimiro", "Steven G. Self", "Lawrence Corey", "M. Juliana McElrath", "Susan Buchbinder", "Helen Horton", "Nicole Frahm", "Michael N. Robertson", "Barney S. Graham", "Peter Gilbert"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003404.t003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparisons_of_HLA_distributions_of_the_different_vaccine_trials_/727498", "title"=>"Comparisons of HLA distributions of the different vaccine trials.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-06-20 02:04:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/1096121"], "description"=>"<p>The four dominant hotspots for each protein are presented. Restricting HLAs were imputed using HLA binding predictors.</p>", "links"=>[], "tags"=>["Clinical immunology", "Immune response", "Clinical research design", "clinical trials", "meta-analyses", "hotspots", "observed"], "article_id"=>727499, "categories"=>["Medicine"], "users"=>["Tomer Hertz", "Hasan Ahmed", "David P. Friedrich", "Danilo R. Casimiro", "Steven G. Self", "Lawrence Corey", "M. Juliana McElrath", "Susan Buchbinder", "Helen Horton", "Nicole Frahm", "Michael N. Robertson", "Barney S. Graham", "Peter Gilbert"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003404.t002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Epitope_hotspots_observed_in_each_vaccine_trial_/727499", "title"=>"Epitope hotspots observed in each vaccine trial.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-06-20 02:04:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/1096122"], "description"=>"<p>Scores can range from −1 to 1. Positive scores indicate that epitopes tend to be in the more conserved regions of the targeted protein, while negative scores indicate targeting of the more variable sites along the insert. P-values were computed using the bootstrap procedure, and denote the significance of the correlation between epitope hotspot location and evolutionary conservation.</p>", "links"=>[], "tags"=>["Clinical immunology", "Immune response", "Clinical research design", "clinical trials", "meta-analyses", "hotspots", "evolutionary", "hla", "targeting"], "article_id"=>727500, "categories"=>["Medicine"], "users"=>["Tomer Hertz", "Hasan Ahmed", "David P. Friedrich", "Danilo R. Casimiro", "Steven G. Self", "Lawrence Corey", "M. Juliana McElrath", "Susan Buchbinder", "Helen Horton", "Nicole Frahm", "Michael N. Robertson", "Barney S. Graham", "Peter Gilbert"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003404.t005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Epitope_hotspots_and_their_relationship_to_evolutionary_conservation_as_measured_by_the_HLA_targeting_efficiency_scores_/727500", "title"=>"Epitope hotspots and their relationship to evolutionary conservation as measured by the HLA targeting efficiency scores.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-06-20 02:05:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1096123"], "description"=>"<p>P-values for the max and sum tests of differences between population hotspots maps of HVTN Step and Merck16 with and without HLA stratification.</p>", "links"=>[], "tags"=>["Clinical immunology", "Immune response", "Clinical research design", "clinical trials", "meta-analyses", "max", "differences", "hotspots", "maps", "hvtn", "merck16", "hla"], "article_id"=>727501, "categories"=>["Medicine"], "users"=>["Tomer Hertz", "Hasan Ahmed", "David P. Friedrich", "Danilo R. Casimiro", "Steven G. Self", "Lawrence Corey", "M. Juliana McElrath", "Susan Buchbinder", "Helen Horton", "Nicole Frahm", "Michael N. Robertson", "Barney S. Graham", "Peter Gilbert"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003404.t004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P_values_for_the_max_and_sum_tests_of_differences_between_population_hotspots_maps_of_HVTN_Step_and_Merck16_with_and_without_HLA_stratification_/727501", "title"=>"P-values for the max and sum tests of differences between population hotspots maps of HVTN Step and Merck16 with and without HLA stratification.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-06-20 02:05:01"}

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Relative Metric

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