Broad CTL Response in Early HIV Infection Drives Multiple Concurrent CTL Escapes
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{"title"=>"Broad CTL Response in Early HIV Infection Drives Multiple Concurrent CTL Escapes", "type"=>"journal", "authors"=>[{"first_name"=>"Sivan", "last_name"=>"Leviyang", "scopus_author_id"=>"35604163600"}, {"first_name"=>"Vitaly V.", "last_name"=>"Ganusov", "scopus_author_id"=>"6602157355"}], "year"=>2015, "source"=>"PLoS Computational Biology", "identifiers"=>{"issn"=>"15537358", "scopus"=>"2-s2.0-84946026287", "pui"=>"606741292", "doi"=>"10.1371/journal.pcbi.1004492", "isbn"=>"1553-734x", "sgr"=>"84946026287", "pmid"=>"26506433"}, "id"=>"048e2e44-3765-3bc0-9cbc-298681978d56", "abstract"=>"Recent studies have highlighted the ability of HIV to escape from cytotoxic T lymphocyte (CTL) responses that concurrently target multiple viral epitopes. Yet, the viral dynamics involved in such escape are incompletely understood. Previous analyses have made several strong assumptions regarding HIV escape from CTL responses such as independent or non-concurrent escape from individual CTL responses. Using experimental data from evolution of HIV half genomes in four patients we observe concurrent viral escape from multiple CTL responses during early infection (first 100 days of infection), providing confirmation of a recent result found in a study of one HIV-infected patient. We show that current methods of estimating CTL escape rates, based on the assumption of independent escapes, are biased and perform poorly when CTL escape proceeds concurrently at multiple epitopes. We propose a new method for analyzing longitudinal sequence data to estimate the rate of CTL escape across multiple epitopes; this method involves few parameters and performs well in simulation studies. By applying our novel method to experimental data, we find that concurrent multiple escapes occur at rates between 0.03 and 0.4 day-1, a relatively broad range that reflects uncertainty due to sparse sampling and wide ranges of parameter values. However, we show that concurrent escape at rates 0.1-0.2 day-1 across multiple epitopes is consistent with our patient datasets.", "link"=>"http://www.mendeley.com/research/broad-ctl-response-early-hiv-infection-drives-multiple-concurrent-ctl-escapes", "reader_count"=>13, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Ph. D. Student"=>3, "Other"=>1, "Student > Bachelor"=>1, "Professor"=>1, "Unspecified"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Ph. D. Student"=>3, "Other"=>1, "Student > Bachelor"=>1, "Professor"=>1, "Unspecified"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>4, "Mathematics"=>1, "Agricultural and Biological Sciences"=>3, "Medicine and Dentistry"=>2, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>3}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>2}}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2381974"], "description"=>"<p>Vertices of an escape graph represent viral variants that are part of the escape pathway and edges correspond to epitope mutations needed to change one variant into another. Numbering below each vertex indicates whether a particular putative epitope is wild-type (0) or escape (1). Numbers above each vertex that are separated by a slash represent percent of this particular variant at the two time points <i>t</i><sub>1</sub> and <i>t</i><sub>2</sub>, respectively. For example, in Fig 1A, the vertex numbered below by 111100 corresponds to a viral variant mutated at putative epitopes NEF185, GAG113, GAG395, and VPR74, but not at putative epitopes POL80, VIF57 and comprises 0% and 35% of the sequences sampled at <i>t</i><sub>1</sub> and <i>t</i><sub>2</sub>, respectively. Yellow and red vertices represent initial variants and expansion variants, respectively; in all patients, initial mutations lead to the first escape which is followed by the expansion of viral variants. CTL responses to putative epitopes are supported by ELISpot assays (underlined epitopes), HLA association (non-underlined, black text epitopes), and multiple mutant haplotypes (red text epitopes). See <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.s010\" target=\"_blank\">S3 Table</a> for <i>t</i><sub>1</sub> and <i>t</i><sub>2</sub> values and [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.ref012\" target=\"_blank\">12</a>, <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.ref013\" target=\"_blank\">13</a>] for original descriptions of patient datasets.</p>", "links"=>[], "tags"=>["HIV half genomes", "Broad CTL Response", "HIV Infection Drives Multiple", "cytotoxic T lymphocyte", "method", "epitope", "CTL responses"], "article_id"=>1586673, "categories"=>["Uncategorised"], "users"=>["Sivan Leviyang", "Vitaly V. Ganusov"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004492.g001", "stats"=>{"downloads"=>2, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HIV_follows_a_similar_escape_pattern_in_multiple_patients_panel_A_CH40_panel_B_CH58_panel_C_CH77_panel_D_CH256_/1586673", "title"=>"HIV follows a similar escape pattern in multiple patients (panel A: CH40, panel B: CH58, panel C: CH77, panel D: CH256).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-27 03:59:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/2381975"], "description"=>"<p>We simulate dynamics of viral escape from constant CTL response with killing rates of 0.4, 0.3, and 0.5 day<sup>−1</sup> against epitopes a, b, and c, respectively. All variants have equal replicative fitness, mutation is ignored, and dynamics are generated deterministically according to <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.e001\" target=\"_blank\">Eq (1)</a>. Simulation is started at day <i>t</i><sub>1</sub> = 0 with the initial frequencies shown to the left of the slashes and run to <i>t</i><sub>2</sub> = 10. In this case <i>t</i><sub>1</sub> = 0 does not model initial infection; instead it simply serves as the initial time point. The escape graph obtained by sampling the virus population at times <i>t</i><sub>1</sub> = 0 and <i>t</i><sub>2</sub> = 10 days with <i>N</i> = 15 sequences is shown in panel A and the dynamics of different viral variants are shown in panel B.</p>", "links"=>[], "tags"=>["HIV half genomes", "Broad CTL Response", "HIV Infection Drives Multiple", "cytotoxic T lymphocyte", "method", "epitope", "CTL responses"], "article_id"=>1586674, "categories"=>["Uncategorised"], "users"=>["Sivan Leviyang", "Vitaly V. Ganusov"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004492.g002", "stats"=>{"downloads"=>3, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Example_of_an_escape_graph_generated_by_sampling_the_virus_population_at_two_time_points_/1586674", "title"=>"Example of an escape graph generated by sampling the virus population at two time points.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-27 03:59:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/2381976"], "description"=>"<p>See text for details of simulations and <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.g001\" target=\"_blank\">Fig 1</a> for details of escape graph notation.</p>", "links"=>[], "tags"=>["HIV half genomes", "Broad CTL Response", "HIV Infection Drives Multiple", "cytotoxic T lymphocyte", "method", "epitope", "CTL responses"], "article_id"=>1586675, "categories"=>["Uncategorised"], "users"=>["Sivan Leviyang", "Vitaly V. Ganusov"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004492.g003", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Two_escape_graphs_generated_using_our_stochastic_simulation_model_/1586675", "title"=>"Two escape graphs generated using our stochastic simulation model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-27 03:59:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/2381977"], "description"=>"<p>We ran stochastic simulations of viral escape assuming CTL response at 6 epitopes with an early CTL response at a single epitope followed roughly a week later by CTL response at five additional epitopes. For each simulation, we estimate the escape rate at the 5 additional epitopes using <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.e001\" target=\"_blank\">Eq (1)</a> assuming sampling at <i>t</i><sub>1</sub> = 30 and <i>t</i><sub>2</sub> = 60 and then calculate the relative error of the estimated escape rate, (estimate-true rate)/true rate, based on sampling <i>N</i> = 15 sequences at <i>t</i><sub>1</sub> and <i>t</i><sub>2</sub> (column “sampled freq”), based on the exact frequencies of wild type and mutant variants at <i>t</i><sub>1</sub> and <i>t</i><sub>2</sub> (column “exact freq”), and based on exact frequencies as well as a model in which no mutations occur after <i>t</i><sub>1</sub> (column “exact freq/no mutation”). Due to the later CTL response, the 5 additional epitopes correspond to expansion variants. We show relative errors of escape rate estimates under linear and full escape graphs. The linear escape graphs can include only the variants 000000, 100000, 110000, …, 111111. The full escape graphs can include all 2<sup>6</sup> possible haplotypes formed by wild type and mutants at the 6 epitopes. Strong and weak CTL response reflect simulations in which the killing rate at the 5 additional epitopes had a maximum value of <i>k</i> = 0.3 day<sup>−1</sup> and <i>k</i> = 0.12 day<sup>−1</sup>, respectively, with the exact kill rate varying across simulations (see <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#sec009\" target=\"_blank\">Methods</a> for details). We assume equal replicative fitness across all variants. Confidence intervals (CIs) presented are based on 1,000 simulations for each case of CTL response and escape graph type.</p>", "links"=>[], "tags"=>["HIV half genomes", "Broad CTL Response", "HIV Infection Drives Multiple", "cytotoxic T lymphocyte", "method", "epitope", "CTL responses"], "article_id"=>1586676, "categories"=>["Uncategorised"], "users"=>["Sivan Leviyang", "Vitaly V. Ganusov"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004492.t001", "stats"=>{"downloads"=>3, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Conventional_methods_dramatically_underestimate_the_rate_of_of_viral_escape_from_CTL_responses_/1586676", "title"=>"Conventional methods dramatically underestimate the rate of of viral escape from CTL responses.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-10-27 03:59:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/2381979"], "description"=>"<p>We use the same simulations as described in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.t001\" target=\"_blank\">Table 1</a>, but estimate escape rates using <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.e002\" target=\"_blank\">Eq (2)</a>. As in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.t001\" target=\"_blank\">Table 1</a>, we show relative error in estimated escape rates. Note that in this analysis we track escape variant haplotypes using linkage information available from simulations. Notations are identical to those shown in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.t001\" target=\"_blank\">Table 1</a>. Of note, negative bias less than negative one implies that the method estimates negative escape rate (decline in frequency of the escape variant).</p>", "links"=>[], "tags"=>["HIV half genomes", "Broad CTL Response", "HIV Infection Drives Multiple", "cytotoxic T lymphocyte", "method", "epitope", "CTL responses"], "article_id"=>1586678, "categories"=>["Uncategorised"], "users"=>["Sivan Leviyang", "Vitaly V. Ganusov"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004492.t002", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Estimating_escape_rates_using_parent_child_variants_removes_the_bias_associated_with_concurrent_escapes_/1586678", "title"=>"Estimating escape rates using parent-child variants removes the bias associated with concurrent escapes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-10-27 03:59:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/2381980"], "description"=>"<p>We use the same simulations as described in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.t001\" target=\"_blank\">Table 1</a> to investigate the impact of <i>A</i>, <i>μ</i>, <i>t</i><sub><i>I</i></sub> on escape rate estimates using <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.e003\" target=\"_blank\">Eq (3)</a>. We set one of <i>A</i>, <i>μ</i>, <i>t</i><sub><i>I</i></sub> to a value, as shown in the column labels, and set the other two values to the true value of the escape, which we record during the simulations, and then compute the relative error of the escape rate estimate. Changing the value of each of the three parameters within a reasonable range can lead to under or over estimates.</p>", "links"=>[], "tags"=>["HIV half genomes", "Broad CTL Response", "HIV Infection Drives Multiple", "cytotoxic T lymphocyte", "method", "epitope", "CTL responses"], "article_id"=>1586679, "categories"=>["Uncategorised"], "users"=>["Sivan Leviyang", "Vitaly V. Ganusov"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004492.t003", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Impact_of_the_model_parameters_A_956_t_I_on_the_estimates_of_the_escape_rates_/1586679", "title"=>"Impact of the model parameters <i>A</i>, <i>μ</i>, <i>t</i><sub><i>I</i></sub> on the estimates of the escape rates.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-10-27 03:59:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/2381981"], "description"=>"<p>We use the same simulations as described in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.t001\" target=\"_blank\">Table 1</a> and estimate escape rates using <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.e003\" target=\"_blank\">Eq (3)</a>. Shown are the relative errors of the escape rate estimates. The lower and upper bounds lead to under and over estimates of the escape rate and are calculated using <i>A</i> = 10, <i>t</i><sub><i>I</i></sub> = −5 days (5 days before peak viral load), <i>μ</i> = 3 × 10<sup>−4</sup> and <i>A</i> = 1, <i>t</i><sub><i>I</i></sub> = 14 days post peak viral load, <i>μ</i> = 3 × 10<sup>−5</sup>, respectively. The intermediate values are calculate using <i>A</i> = 1.25, <i>t</i><sub><i>I</i></sub> = 4 days post peak viral load, and <i>μ</i> = 10<sup>−4</sup>. Lower and upper bounds provide an estimated range for the escape rate, while the intermediate estimate reflects escape rates assuming less extreme parameter choices.</p>", "links"=>[], "tags"=>["HIV half genomes", "Broad CTL Response", "HIV Infection Drives Multiple", "cytotoxic T lymphocyte", "method", "epitope", "CTL responses"], "article_id"=>1586680, "categories"=>["Uncategorised"], "users"=>["Sivan Leviyang", "Vitaly V. Ganusov"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004492.t004", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Novel_method_allows_for_estimates_of_the_escape_rate_by_considering_a_range_of_values_for_A_956_t_I_/1586680", "title"=>"Novel method allows for estimates of the escape rate by considering a range of values for <i>A</i>, <i>μ</i>, <i>t</i><sub><i>I</i></sub>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-10-27 03:59:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/2381982"], "description"=>"<p>We use experimental data on kinetics of HIV escape from multiple CTL responses (see <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.g001\" target=\"_blank\">Fig 1</a>) and estimate escape rates using <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.e003\" target=\"_blank\">Eq (3)</a> with parameters given in the ranges in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.t004\" target=\"_blank\">Table 4</a>. Column “single epitope” denotes estimate of the escape rate assuming independent escape using <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.e001\" target=\"_blank\">Eq (1)</a>. Column “previous” denotes values of escape rates as estimated in previous publications [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.ref013\" target=\"_blank\">13</a>, <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.ref020\" target=\"_blank\">20</a>]. All putative epitopes are supported by ELISpot assays or HLA association except for ENV830 in CH58. All estimates of the escape rates are given in day<sup>−1</sup> units.</p>", "links"=>[], "tags"=>["HIV half genomes", "Broad CTL Response", "HIV Infection Drives Multiple", "cytotoxic T lymphocyte", "method", "epitope", "CTL responses"], "article_id"=>1586681, "categories"=>["Uncategorised"], "users"=>["Sivan Leviyang", "Vitaly V. Ganusov"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004492.t005", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Novel_method_provides_higher_estimates_of_the_escape_rates_for_most_of_early_escapes_in_4_HIV_infected_patients_/1586681", "title"=>"Novel method provides higher estimates of the escape rates for most of early escapes in 4 HIV-infected patients.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-10-27 03:59:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/2381983"], "description"=>"<p><i>L</i>, <i>T</i><sub>on</sub>, <i>k</i><sub>max,<i>i</i></sub>, <i>S</i><sub><i>i</i></sub>, <i>α</i>, and <i>β</i> are parameters associated with CTL response. Values shown in the Dominant (Subdominant) column apply to response at the first (second-sixth) epitopes. <i>U</i> is a uniform random number on [0, 1], meaning that the timing and strength of the subdominant responses is different for each simulation. Values of <i>k</i><sub>max,<i>i</i></sub> shown are for the strong CTL response simulation. Weak CTL response simulation differ only in <i>k</i><sub>max,<i>i</i></sub> = .12<i>U</i> for the subdominant responses. <i>ρ</i>, <i>n</i><sub>rec</sub>, and <i>μ</i> are parameters associated with recombination and mutation. CTL response parameters are chosen to qualitatively match responses seen in CTL datasets [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.ref011\" target=\"_blank\">11</a>, <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.ref013\" target=\"_blank\">13</a>] and match estimates given in [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004492#pcbi.1004492.ref044\" target=\"_blank\">44</a>].</p>", "links"=>[], "tags"=>["HIV half genomes", "Broad CTL Response", "HIV Infection Drives Multiple", "cytotoxic T lymphocyte", "method", "epitope", "CTL responses"], "article_id"=>1586682, "categories"=>["Uncategorised"], "users"=>["Sivan Leviyang", "Vitaly V. Ganusov"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004492.t006", "stats"=>{"downloads"=>3, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Stochastic_simulation_parameters_/1586682", "title"=>"Stochastic simulation parameters.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-10-27 03:59:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/2381986", "https://ndownloader.figshare.com/files/2381987", "https://ndownloader.figshare.com/files/2381988", "https://ndownloader.figshare.com/files/2381989", "https://ndownloader.figshare.com/files/2381990", "https://ndownloader.figshare.com/files/2381991", "https://ndownloader.figshare.com/files/2381992", "https://ndownloader.figshare.com/files/2381993", "https://ndownloader.figshare.com/files/2381994", "https://ndownloader.figshare.com/files/2381995"], "description"=>"<div><p>Recent studies have highlighted the ability of HIV to escape from cytotoxic T lymphocyte (CTL) responses that concurrently target multiple viral epitopes. Yet, the viral dynamics involved in such escape are incompletely understood. Previous analyses have made several strong assumptions regarding HIV escape from CTL responses such as independent or non-concurrent escape from individual CTL responses. Using experimental data from evolution of HIV half genomes in four patients we observe concurrent viral escape from multiple CTL responses during early infection (first 100 days of infection), providing confirmation of a recent result found in a study of one HIV-infected patient. We show that current methods of estimating CTL escape rates, based on the assumption of independent escapes, are biased and perform poorly when CTL escape proceeds concurrently at multiple epitopes. We propose a new method for analyzing longitudinal sequence data to estimate the rate of CTL escape across multiple epitopes; this method involves few parameters and performs well in simulation studies. By applying our novel method to experimental data, we find that concurrent multiple escapes occur at rates between 0.03 and 0.4 day<sup>−1</sup>, a relatively broad range that reflects uncertainty due to sparse sampling and wide ranges of parameter values. However, we show that concurrent escape at rates 0.1–0.2 day<sup>−1</sup> across multiple epitopes is consistent with our patient datasets.</p></div>", "links"=>[], "tags"=>["HIV half genomes", "Broad CTL Response", "HIV Infection Drives Multiple", "cytotoxic T lymphocyte", "method", "epitope", "CTL responses"], "article_id"=>1586684, "categories"=>["Uncategorised"], "users"=>["Sivan Leviyang", "Vitaly V. Ganusov"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1004492.s001", "https://dx.doi.org/10.1371/journal.pcbi.1004492.s002", "https://dx.doi.org/10.1371/journal.pcbi.1004492.s003", "https://dx.doi.org/10.1371/journal.pcbi.1004492.s004", "https://dx.doi.org/10.1371/journal.pcbi.1004492.s005", "https://dx.doi.org/10.1371/journal.pcbi.1004492.s006", "https://dx.doi.org/10.1371/journal.pcbi.1004492.s007", "https://dx.doi.org/10.1371/journal.pcbi.1004492.s008", "https://dx.doi.org/10.1371/journal.pcbi.1004492.s009", "https://dx.doi.org/10.1371/journal.pcbi.1004492.s010"], "stats"=>{"downloads"=>8, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Broad_CTL_Response_in_Early_HIV_Infection_Drives_Multiple_Concurrent_CTL_Escapes_/1586684", "title"=>"Broad CTL Response in Early HIV Infection Drives Multiple Concurrent CTL Escapes", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-10-27 03:59:02"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"2", "full-text"=>"2", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"3", "full-text"=>"3", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"9", "full-text"=>"10", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"11", "full-text"=>"11", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"6", "full-text"=>"2", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
  • {"unique-ip"=>"4", "full-text"=>"2", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"2", "year"=>"2020", "month"=>"2"}
  • {"unique-ip"=>"2", "full-text"=>"3", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"3"}
  • {"unique-ip"=>"6", "full-text"=>"5", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"4"}
  • {"unique-ip"=>"2", "full-text"=>"2", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"4", "full-text"=>"3", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"4", "full-text"=>"2", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"3", "full-text"=>"3", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}

Relative Metric

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

Net::HTTPInternalServerError

Source
Counter
Time
2019-04-06 02:41:28 UTC
Target URL
http://counter-101.soma.plos.org/api/v1.0/stats/doi/10.1371%2Fjournal.pcbi.1004492
Trace

/app/models/concerns/networkable.rb:21:in `get_result'
/app/models/source.rb:165:in `get_data'
/app/models/retrieval_status.rb:47:in `perform_get_data'
/app/jobs/source_job.rb:52:in `block (2 levels) in perform'
/app/jobs/source_job.rb:51:in `block in perform'
/app/jobs/source_job.rb:35:in `each'
/app/jobs/source_job.rb:35:in `perform'