Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing
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{"title"=>"Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing", "type"=>"journal", "authors"=>[{"first_name"=>"Datsen George", "last_name"=>"Wei", "scopus_author_id"=>"56652475100"}, {"first_name"=>"Vicki", "last_name"=>"Chiang", "scopus_author_id"=>"50960935900"}, {"first_name"=>"Elizabeth", "last_name"=>"Fyne", "scopus_author_id"=>"40761247700"}, {"first_name"=>"Mini", "last_name"=>"Balakrishnan", "scopus_author_id"=>"7006558381"}, {"first_name"=>"Tiffany", "last_name"=>"Barnes", "scopus_author_id"=>"35195180700"}, {"first_name"=>"Michael", "last_name"=>"Graupe", "scopus_author_id"=>"36905515800"}, {"first_name"=>"Joseph", "last_name"=>"Hesselgesser", "scopus_author_id"=>"6603912024"}, {"first_name"=>"Alivelu", "last_name"=>"Irrinki", "scopus_author_id"=>"6506183184"}, {"first_name"=>"Jeffrey P.", "last_name"=>"Murry", "scopus_author_id"=>"56435989500"}, {"first_name"=>"George", "last_name"=>"Stepan", "scopus_author_id"=>"7004247596"}, {"first_name"=>"Kirsten M.", "last_name"=>"Stray", "scopus_author_id"=>"6508142086"}, {"first_name"=>"Angela", "last_name"=>"Tsai", "scopus_author_id"=>"55847486900"}, {"first_name"=>"Helen", "last_name"=>"Yu", "scopus_author_id"=>"56094892800"}, {"first_name"=>"Jonathan", "last_name"=>"Spindler", "scopus_author_id"=>"24475560300"}, {"first_name"=>"Mary", "last_name"=>"Kearney", "scopus_author_id"=>"7102876601"}, {"first_name"=>"Celsa A.", "last_name"=>"Spina", "scopus_author_id"=>"7005595778"}, {"first_name"=>"Deborah", "last_name"=>"McMahon", "scopus_author_id"=>"16750541200"}, {"first_name"=>"Jacob", "last_name"=>"Lalezari", "scopus_author_id"=>"56959536100"}, {"first_name"=>"Derek", "last_name"=>"Sloan", "scopus_author_id"=>"8148431900"}, {"first_name"=>"John", "last_name"=>"Mellors", "scopus_author_id"=>"7007008426"}, {"first_name"=>"Romas", "last_name"=>"Geleziunas", "scopus_author_id"=>"57192120271"}, {"first_name"=>"Tomas", "last_name"=>"Cihlar", "scopus_author_id"=>"6701481609"}], "year"=>2014, "source"=>"PLoS Pathogens", "identifiers"=>{"pmid"=>"24722454", "issn"=>"15537374", "doi"=>"10.1371/journal.ppat.1004071", "pui"=>"373162942", "isbn"=>"1553-7374 (Electronic)\\r1553-7366 (Linking)", "scopus"=>"2-s2.0-84901309171", "sgr"=>"84901309171"}, "id"=>"86d242e8-4975-3ef0-b416-cc4ac942ec59", "abstract"=>"Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART.", "link"=>"http://www.mendeley.com/research/histone-deacetylase-inhibitor-romidepsin-induces-hiv-expression-cd4-t-cells-patients-suppressive-ant", "reader_count"=>102, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>9, "Researcher"=>27, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>30, "Student > Postgraduate"=>2, "Other"=>6, "Student > Master"=>11, "Student > Bachelor"=>10, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>9, "Researcher"=>27, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>30, "Student > Postgraduate"=>2, "Other"=>6, "Student > Master"=>11, "Student > Bachelor"=>10, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Engineering"=>2, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>12, "Mathematics"=>1, "Agricultural and Biological Sciences"=>39, "Medicine and Dentistry"=>25, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Chemistry"=>7, "Social Sciences"=>2, "Immunology and Microbiology"=>8}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>25}, "Chemistry"=>{"Chemistry"=>7}, "Social Sciences"=>{"Social Sciences"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>8}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>39}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>12}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>3}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>2, "Denmark"=>1, "South Africa"=>1, "United Kingdom"=>1, "Spain"=>1, "Indonesia"=>1}, "group_count"=>4}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1458579"], "description"=>"<p>Latently infected primary CD4 T cells prepared from three independent healthy donors were treated with the indicated compounds continuously for 48 hours. EC<sub>50</sub> and CC<sub>50</sub> values were determined from each dose-dependent response using a multi-parameter algorithm. Data are mean ± SD from three independent experiments performed in quadruplicate.</p>", "links"=>[], "tags"=>["microbiology", "Medical microbiology", "Microbial pathogens", "Viral pathogens", "Immunodeficiency viruses", "hiv", "Infectious diseases", "Viral diseases", "cytotoxicity", "hdac", "inhibitors", "vitro", "latency"], "article_id"=>994317, "categories"=>["Biological Sciences"], "users"=>["Datsen George Wei", "Vicki Chiang", "Elizabeth Fyne", "Mini Balakrishnan", "Tiffany Barnes", "Michael Graupe", "Joseph Hesselgesser", "Alivelu Irrinki", "Jeffrey P. Murry", "George Stepan", "Kirsten M. Stray", "Angela Tsai", "Helen Yu", "Jonathan Spindler", "Mary Kearney", "Celsa A. Spina", "Deborah McMahon", "Jacob Lalezari", "Derek Sloan", "John Mellors", "Romas Geleziunas", "Tomas Cihlar"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004071.t001", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Activity_and_cytotoxicity_of_HDAC_inhibitors_in_the_in_vitro_HIV_latency_model_/994317", "title"=>"Activity and cytotoxicity of HDAC inhibitors in the in vitro HIV latency model.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-04-10 02:46:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/1458578"], "description"=>"<p>Recombinant human HDAC isoenzymes were incubated with the indicated HDACi and fluorogenic peptide substrates as described in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#s4\" target=\"_blank\">Materials and Methods</a>. IC<sub>50</sub> values were calculated from 10-point dose-response curves using a multi-parameter curve fit. Data represent mean values from two independent experiments.</p>", "links"=>[], "tags"=>["microbiology", "Medical microbiology", "Microbial pathogens", "Viral pathogens", "Immunodeficiency viruses", "hiv", "Infectious diseases", "Viral diseases", "pnb", "hdac"], "article_id"=>994316, "categories"=>["Biological Sciences"], "users"=>["Datsen George Wei", "Vicki Chiang", "Elizabeth Fyne", "Mini Balakrishnan", "Tiffany Barnes", "Michael Graupe", "Joseph Hesselgesser", "Alivelu Irrinki", "Jeffrey P. Murry", "George Stepan", "Kirsten M. Stray", "Angela Tsai", "Helen Yu", "Jonathan Spindler", "Mary Kearney", "Celsa A. Spina", "Deborah McMahon", "Jacob Lalezari", "Derek Sloan", "John Mellors", "Romas Geleziunas", "Tomas Cihlar"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004071.t002", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_RMD_VOR_and_PNB_on_the_activity_of_individual_human_HDAC_isoenzymes_/994316", "title"=>"Effect of RMD, VOR, and PNB on the activity of individual human HDAC isoenzymes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-04-10 02:46:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/1458574"], "description"=>"<p>PBMCs isolated from four HIV-infected patients on suppressive cART were treated with a 4-hour pulse of RMD or continuously with vehicle control (DMSO), VOR, or PMA+ionomycin and stained for surface markers 48 hours after the treatment initiation. Fractions of CD69−, CD25−, and HLA-DR-positive cells in subsets of CD4+ T cells, CD8+ T cells, and CD19+ B cells were analyzed by flow cytometry as described in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#s4\" target=\"_blank\">Materials and Methods</a>. Each symbol represents one donor.</p>", "links"=>[], "tags"=>["microbiology", "Medical microbiology", "Microbial pathogens", "Viral pathogens", "Immunodeficiency viruses", "hiv", "Infectious diseases", "Viral diseases", "induce", "activation"], "article_id"=>994312, "categories"=>["Biological Sciences"], "users"=>["Datsen George Wei", "Vicki Chiang", "Elizabeth Fyne", "Mini Balakrishnan", "Tiffany Barnes", "Michael Graupe", "Joseph Hesselgesser", "Alivelu Irrinki", "Jeffrey P. Murry", "George Stepan", "Kirsten M. Stray", "Angela Tsai", "Helen Yu", "Jonathan Spindler", "Mary Kearney", "Celsa A. Spina", "Deborah McMahon", "Jacob Lalezari", "Derek Sloan", "John Mellors", "Romas Geleziunas", "Tomas Cihlar"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004071.g006", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RMD_does_not_induce_global_activation_of_immune_cell_subsets_/994312", "title"=>"RMD does not induce global activation of immune cell subsets.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-10 02:46:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/1458572"], "description"=>"<p>Resting CD4 T cells were isolated from 3 cART-suppressed HIV-infected patients and pulse-treated with RMD for 4 hours with the indicated concentrations. Cell-associated HIV RNA levels were analyzed at each time point following the treatment initiation (t = 0 hour), and fold induction was determined relative to a background signal in vehicle-treated controls. Predicted i.v. dose and percentage of clinical exposure were calculated for each RMD concentration tested relative to the clinically approved dose of 14 mg/m<sup>2</sup>; calculations were performed based on the free fraction of drug in human plasma and cell culture media. Data represent mean ± SD from at least 3 HIV-infected donors. Data for each individual donor and condition including results of the statistical analysis are summarized in Supplementary <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#ppat.1004071.s008\" target=\"_blank\">Table S4</a>.</p>", "links"=>[], "tags"=>["microbiology", "Medical microbiology", "Microbial pathogens", "Viral pathogens", "Immunodeficiency viruses", "hiv", "Infectious diseases", "Viral diseases", "activates", "intracellular", "concentrations", "achieved"], "article_id"=>994310, "categories"=>["Biological Sciences"], "users"=>["Datsen George Wei", "Vicki Chiang", "Elizabeth Fyne", "Mini Balakrishnan", "Tiffany Barnes", "Michael Graupe", "Joseph Hesselgesser", "Alivelu Irrinki", "Jeffrey P. Murry", "George Stepan", "Kirsten M. Stray", "Angela Tsai", "Helen Yu", "Jonathan Spindler", "Mary Kearney", "Celsa A. Spina", "Deborah McMahon", "Jacob Lalezari", "Derek Sloan", "John Mellors", "Romas Geleziunas", "Tomas Cihlar"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004071.g005", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RMD_activates_intracellular_HIV_expression_at_concentrations_below_the_levels_achieved_by_clinical_dosing_/994310", "title"=>"RMD activates intracellular HIV expression at concentrations below the levels achieved by clinical dosing.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-10 02:46:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/1458569"], "description"=>"<p>CD4 T cells were isolated from virally suppressed HIV-infected patients and pulse-treated with RMD and VOR for 6 and 24 hours, respectively. Cell-associated total RNA was extracted, HIV RNA levels were quantified at the indicated time points, and fold increase in the cell-associated HIV RNA was determined relative to corresponding vehicle-treated control for each individual time point. The fold change for each donor and condition is based on mean number of HIV copies from 4 to 5 independent measurements. Red dashed line represents the mean fold HIV induction across all tested donors. Symbols # (p<0.01) and * (p<0.05) denote a statistically significant difference between fold HIV induction by RMD and VOR across all donors tested. Data for each individual donor and condition including results of statistical analysis are provided in Supplementary <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#ppat.1004071.s008\" target=\"_blank\">Table S4</a>. (<b>A</b>) Memory CD4 T cells were purified as the CD4(+)CD45RA(−) subset. (<b>B</b>) Resting CD4+ T cells were purified as the CD4(+)HLA-DR(−)CD69(−)CD25(−) subset.</p>", "links"=>[], "tags"=>["microbiology", "Medical microbiology", "Microbial pathogens", "Viral pathogens", "Immunodeficiency viruses", "hiv", "Infectious diseases", "Viral diseases", "vivo", "activation", "rmd"], "article_id"=>994307, "categories"=>["Biological Sciences"], "users"=>["Datsen George Wei", "Vicki Chiang", "Elizabeth Fyne", "Mini Balakrishnan", "Tiffany Barnes", "Michael Graupe", "Joseph Hesselgesser", "Alivelu Irrinki", "Jeffrey P. Murry", "George Stepan", "Kirsten M. Stray", "Angela Tsai", "Helen Yu", "Jonathan Spindler", "Mary Kearney", "Celsa A. Spina", "Deborah McMahon", "Jacob Lalezari", "Derek Sloan", "John Mellors", "Romas Geleziunas", "Tomas Cihlar"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004071.g002", "stats"=>{"downloads"=>1, "page_views"=>36, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ex_vivo_activation_of_HIV_expression_by_RMD_and_VOR_/994307", "title"=>"Ex vivo activation of HIV expression by RMD and VOR.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-10 02:46:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/1458568"], "description"=>"<p>Primary CD4 T cells latently infected in vitro with reporter HIV were established as previously described <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#ppat.1004071-Bosque1\" target=\"_blank\">[29]</a>, <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#ppat.1004071-Bosque2\" target=\"_blank\">[30]</a> with additional minor modifications described in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#s4\" target=\"_blank\">Materials and Methods</a>. The infected cells were incubated in the presence of the indicated HDACi. (<b>A</b>) A dose response of HIV activation by HDACi was determined by the quantification of luciferase reporter activity after a 48-hour treatment. <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#s2\" target=\"_blank\">Results</a> are mean ± SD from a representative experiment performed in quadruplicate. (<b>B</b>) Induction of p24 expression by RMD and VOR. Flow cytometry analysis of cells from a representative donor is shown with gating on the live cell population. Anti-CD3/CD28 antibodies conjugated to beads were used as a positive control. (<b>C</b>) Time course of the induction of p24 expression by RMD. Cells isolated from 2 independent donors were treated with 40 nM RMD or anti-CD3/CD28 antibodies for 24 to 72 hours in the presence of antiretrovirals. Percentage of p24-positive cells was determined by flow cytometry with gating on live cell population.</p>", "links"=>[], "tags"=>["microbiology", "Medical microbiology", "Microbial pathogens", "Viral pathogens", "Immunodeficiency viruses", "hiv", "Infectious diseases", "Viral diseases", "vitro", "activation", "hdac", "inhibitors", "latency"], "article_id"=>994306, "categories"=>["Biological Sciences"], "users"=>["Datsen George Wei", "Vicki Chiang", "Elizabeth Fyne", "Mini Balakrishnan", "Tiffany Barnes", "Michael Graupe", "Joseph Hesselgesser", "Alivelu Irrinki", "Jeffrey P. Murry", "George Stepan", "Kirsten M. Stray", "Angela Tsai", "Helen Yu", "Jonathan Spindler", "Mary Kearney", "Celsa A. Spina", "Deborah McMahon", "Jacob Lalezari", "Derek Sloan", "John Mellors", "Romas Geleziunas", "Tomas Cihlar"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004071.g001", "stats"=>{"downloads"=>5, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vitro_activation_of_HIV_expression_by_HDAC_inhibitors_in_an_in_vitro_latency_model_/994306", "title"=>"In vitro activation of HIV expression by HDAC inhibitors in an in vitro latency model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-10 02:46:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/1458581", "https://ndownloader.figshare.com/files/1458582", "https://ndownloader.figshare.com/files/1458583", "https://ndownloader.figshare.com/files/1458584", "https://ndownloader.figshare.com/files/1458585", "https://ndownloader.figshare.com/files/1458586", "https://ndownloader.figshare.com/files/1458587", "https://ndownloader.figshare.com/files/1458588"], "description"=>"<div><p>Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC<sub>50</sub> = 4.5 nM) compared with vorinostat (VOR; EC<sub>50</sub> = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC<sub>50</sub> = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART.</p></div>", "links"=>[], "tags"=>["microbiology", "Medical microbiology", "Microbial pathogens", "Viral pathogens", "Immunodeficiency viruses", "hiv", "Infectious diseases", "Viral diseases", "deacetylase", "inhibitor", "romidepsin", "cd4", "cells", "patients", "suppressive", "antiretroviral", "concentrations", "achieved"], "article_id"=>994319, "categories"=>["Biological Sciences"], "users"=>["Datsen George Wei", "Vicki Chiang", "Elizabeth Fyne", "Mini Balakrishnan", "Tiffany Barnes", "Michael Graupe", "Joseph Hesselgesser", "Alivelu Irrinki", "Jeffrey P. Murry", "George Stepan", "Kirsten M. Stray", "Angela Tsai", "Helen Yu", "Jonathan Spindler", "Mary Kearney", "Celsa A. Spina", "Deborah McMahon", "Jacob Lalezari", "Derek Sloan", "John Mellors", "Romas Geleziunas", "Tomas Cihlar"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1004071.s001", "https://dx.doi.org/10.1371/journal.ppat.1004071.s002", "https://dx.doi.org/10.1371/journal.ppat.1004071.s003", "https://dx.doi.org/10.1371/journal.ppat.1004071.s004", "https://dx.doi.org/10.1371/journal.ppat.1004071.s005", "https://dx.doi.org/10.1371/journal.ppat.1004071.s006", "https://dx.doi.org/10.1371/journal.ppat.1004071.s007", "https://dx.doi.org/10.1371/journal.ppat.1004071.s008"], "stats"=>{"downloads"=>4, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Histone_Deacetylase_Inhibitor_Romidepsin_Induces_HIV_Expression_in_CD4_T_Cells_from_Patients_on_Suppressive_Antiretroviral_Therapy_at_Concentrations_Achieved_by_Clinical_Dosing_/994319", "title"=>"Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-04-10 02:46:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/1458577"], "description"=>"<p>Resting CD4 T cells isolated from a cART-suppressed HIV-infected patient (high-responding patient from <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#ppat-1004071-g007\" target=\"_blank\">Fig. 7</a>) were treated continuously with RMD or activation control (anti-CD3/CD28 antibodies). Single-genome sequencing was used to analyze patient HIV proviral DNA and plasma RNA at the initiation of treatment (day 0), together with the ex vivo induced HIV RNA in cell culture supernatants at the end of treatment (day 7). Total of 43 sequences were recovered for proviral DNA. Eighty-eight, 11, and 4 sequences of HIV RNA were collected in culture supernatants following the treatment with activation control, 7.5 nM RMD, and 2.5 nM RMD, respectively. Grey arrows indicate examples of full concordance between the sequence of proviral DNA and viral RNA induced either by RMD or activation control. No HIV RNA sequences were recovered in supernatants from cultures treated with control vehicle or 2 µM SAHA. Identified HIV DNA and RNA sequences were aligned and the phylogenetic tree was constructed using Clustal W and MEAG5.</p>", "links"=>[], "tags"=>["microbiology", "Medical microbiology", "Microbial pathogens", "Viral pathogens", "Immunodeficiency viruses", "hiv", "Infectious diseases", "Viral diseases", "sequences", "ex", "vivo", "latency"], "article_id"=>994315, "categories"=>["Biological Sciences"], "users"=>["Datsen George Wei", "Vicki Chiang", "Elizabeth Fyne", "Mini Balakrishnan", "Tiffany Barnes", "Michael Graupe", "Joseph Hesselgesser", "Alivelu Irrinki", "Jeffrey P. Murry", "George Stepan", "Kirsten M. Stray", "Angela Tsai", "Helen Yu", "Jonathan Spindler", "Mary Kearney", "Celsa A. Spina", "Deborah McMahon", "Jacob Lalezari", "Derek Sloan", "John Mellors", "Romas Geleziunas", "Tomas Cihlar"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004071.g008", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Phylogenetic_analysis_of_HIV_sequences_expressed_ex_vivo_following_the_latency_reversal_/994315", "title"=>"Phylogenetic analysis of HIV sequences expressed ex vivo following the latency reversal.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-10 02:46:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/1458576"], "description"=>"<p>Resting CD4 T cells isolated from 2 cART-suppressed HIV-infected patients were treated continuously with RMD or with anti-CD3/CD28 antibodies (AC, activation control) for 7 days. HIV RNA in cell culture supernatants was quantified by COBAS on day 7. Data for a high-responding (<b>A</b>) and a low-responding donor (<b>B</b>) to RMD is shown; each donor was tested at 3 different time points separated by at least 2 weeks (Exp 1–3). VC/NDC, vehicle control/no-drug control. Asterisk (*) indicates no value due to COBAS analysis failure. Dashed lines indicate the limit of HIV quantification by COBAS (20 copies/ml). Data for each individual donor and condition including results of the statistical analysis are summarized in Supplementary <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#ppat.1004071.s008\" target=\"_blank\">Table S4</a>.</p>", "links"=>[], "tags"=>["microbiology", "Medical microbiology", "Microbial pathogens", "Viral pathogens", "Immunodeficiency viruses", "hiv", "Infectious diseases", "Viral diseases", "vivo", "rmd", "longitudinal", "samples"], "article_id"=>994314, "categories"=>["Biological Sciences"], "users"=>["Datsen George Wei", "Vicki Chiang", "Elizabeth Fyne", "Mini Balakrishnan", "Tiffany Barnes", "Michael Graupe", "Joseph Hesselgesser", "Alivelu Irrinki", "Jeffrey P. Murry", "George Stepan", "Kirsten M. Stray", "Angela Tsai", "Helen Yu", "Jonathan Spindler", "Mary Kearney", "Celsa A. Spina", "Deborah McMahon", "Jacob Lalezari", "Derek Sloan", "John Mellors", "Romas Geleziunas", "Tomas Cihlar"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004071.g007", "stats"=>{"downloads"=>1, "page_views"=>37, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ex_vivo_response_to_RMD_in_multiple_longitudinal_samples_from_the_same_donors_/994314", "title"=>"Ex vivo response to RMD in multiple longitudinal samples from the same donors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-10 02:46:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/1458571"], "description"=>"<p>Resting CD4 T cells isolated from cART-suppressed HIV-infected patients were pulse-treated with RMD (4 hours), VOR (24 hours), and PNB (24 hours). Viral RNA was determined 48 hours after the initiation of the treatment. Data represent mean ± SD from two independent donors. (<b>A</b>) Cell-associated total RNA was extracted at the indicated time points, and HIV RNA levels were quantified. Data for each individual donor and condition including results of the statistical analysis are summarized in Supplementary <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#ppat.1004071.s008\" target=\"_blank\">Table S4</a>. (<b>B</b>) Total class I and II HDAC enzyme activity was measured in total cell extracts of treated cells relative to vehicle-treated cells (representing 100% activity) using a model substrate described in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#s4\" target=\"_blank\">Materials and Methods</a>.</p>", "links"=>[], "tags"=>["microbiology", "Medical microbiology", "Microbial pathogens", "Viral pathogens", "Immunodeficiency viruses", "hiv", "Infectious diseases", "Viral diseases", "inhibition", "cell-associated", "hdac"], "article_id"=>994309, "categories"=>["Biological Sciences"], "users"=>["Datsen George Wei", "Vicki Chiang", "Elizabeth Fyne", "Mini Balakrishnan", "Tiffany Barnes", "Michael Graupe", "Joseph Hesselgesser", "Alivelu Irrinki", "Jeffrey P. Murry", "George Stepan", "Kirsten M. Stray", "Angela Tsai", "Helen Yu", "Jonathan Spindler", "Mary Kearney", "Celsa A. Spina", "Deborah McMahon", "Jacob Lalezari", "Derek Sloan", "John Mellors", "Romas Geleziunas", "Tomas Cihlar"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004071.g004", "stats"=>{"downloads"=>7, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Induction_of_HIV_expression_and_inhibition_of_cell_associated_HDAC_activity_by_HDACi_/994309", "title"=>"Induction of HIV expression and inhibition of cell-associated HDAC activity by HDACi.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-10 02:46:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/1458570"], "description"=>"<p>Memory or resting CD4 T cells isolated from HIV-infected patients on suppressive cART were treated with RMD or VOR, and viral RNA was quantified in cell culture supernatants 6 days after the addition of drugs. <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#s2\" target=\"_blank\">Results</a> are depicted as fold increase in viral RNA relative to control cultures. Each symbol represents one HIV subject. Solid circles, p<0.05; open circles, p>0.05 compared to vehicle-treated controls from the same donors; solid squares, p value not calculated. Red lines represent the mean fold HIV induction across all analyzed donors. Symbols # and * denote a statistically significant difference (p<0.05) for RMD-mediated HIV induction vs. 0.5 and 1 µM VOR, respectively, across all tested donors. Data for each individual donor and condition including results of the statistical analysis are summarized in Supplementary <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004071#ppat.1004071.s008\" target=\"_blank\">Table S4</a>. (<b>A</b>) Memory CD4 T cells were treated with RMD and VOR for 4 and 24 hours, respectively. (<b>B</b>) Memory CD4 T cells were treated continuously for 6 days. (<b>C</b>) Resting CD4 T cells were treated continuously for 6 days.</p>", "links"=>[], "tags"=>["microbiology", "Medical microbiology", "Microbial pathogens", "Viral pathogens", "Immunodeficiency viruses", "hiv", "Infectious diseases", "Viral diseases", "extracellular", "viral", "rna", "cd4", "cells", "treated", "rmd"], "article_id"=>994308, "categories"=>["Biological Sciences"], "users"=>["Datsen George Wei", "Vicki Chiang", "Elizabeth Fyne", "Mini Balakrishnan", "Tiffany Barnes", "Michael Graupe", "Joseph Hesselgesser", "Alivelu Irrinki", "Jeffrey P. Murry", "George Stepan", "Kirsten M. Stray", "Angela Tsai", "Helen Yu", "Jonathan Spindler", "Mary Kearney", "Celsa A. Spina", "Deborah McMahon", "Jacob Lalezari", "Derek Sloan", "John Mellors", "Romas Geleziunas", "Tomas Cihlar"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004071.g003", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Induction_of_extracellular_viral_RNA_release_from_CD4_T_cells_treated_with_RMD_and_VOR_/994308", "title"=>"Induction of extracellular viral RNA release from CD4 T cells treated with RMD and VOR.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-10 02:46:27"}

PMC Usage Stats | Further Information

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