Potent Cell-Intrinsic Immune Responses in Dendritic Cells Facilitate HIV-1-Specific T Cell Immunity in HIV-1 Elite Controllers
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{"title"=>"Potent Cell-Intrinsic Immune Responses in Dendritic Cells Facilitate HIV-1-Specific T Cell Immunity in HIV-1 Elite Controllers", "type"=>"journal", "authors"=>[{"first_name"=>"Enrique", "last_name"=>"Martin-Gayo", "scopus_author_id"=>"16444765000"}, {"first_name"=>"Maria Jose", "last_name"=>"Buzon", "scopus_author_id"=>"25654516300"}, {"first_name"=>"Zhengyu", "last_name"=>"Ouyang", "scopus_author_id"=>"55786268000"}, {"first_name"=>"Taylor", "last_name"=>"Hickman", "scopus_author_id"=>"56715451500"}, {"first_name"=>"Jacqueline", "last_name"=>"Cronin", "scopus_author_id"=>"56715034100"}, {"first_name"=>"Dina", "last_name"=>"Pimenova", "scopus_author_id"=>"56716435200"}, {"first_name"=>"Bruce D.", "last_name"=>"Walker", "scopus_author_id"=>"7402209193"}, {"first_name"=>"Mathias", "last_name"=>"Lichterfeld", "scopus_author_id"=>"6602189737"}, {"first_name"=>"Xu G.", "last_name"=>"Yu", "scopus_author_id"=>"7404115518"}], "year"=>2015, "source"=>"PLoS Pathogens", "identifiers"=>{"scopus"=>"2-s2.0-84936741267", "pmid"=>"26067651", "isbn"=>"1553-7374 (Electronic)\\r1553-7366 (Linking)", "doi"=>"10.1371/journal.ppat.1004930", "issn"=>"15537374", "sgr"=>"84936741267", "pui"=>"605161842"}, "id"=>"7603061b-22bb-3a82-89dd-2488ec4bff52", "abstract"=>"The majority of HIV-1 elite controllers (EC) restrict HIV-1 replication through highly functional HIV-1-specific T cell responses, but mechanisms supporting the evolution of effective HIV-1-specific T cell immunity in these patients remain undefined. Cytosolic immune recognition of HIV-1 in conventional dendritic cells (cDC) can facilitate priming and expansion of HIV-1-specific T cells; however, HIV-1 seems to be able to avoid intracellular immune recognition in cDCs in most infected individuals. Here, we show that exposure of cDCs from EC to HIV-1 leads to a rapid and sustained production of type I interferons and upregulation of several interferon-stimulated effector genes. Emergence of these cell-intrinsic immune responses was associated with a reduced induction of SAMHD1 and LEDGF/p75, and an accumulation of viral reverse transcripts, but inhibited by pharmacological blockade of viral reverse transcription or siRNA-mediated silencing of the cytosolic DNA sensor cGAS. Importantly, improved cell-intrinsic immune recognition of HIV-1 in cDCs from elite controllers translated into stronger abilities to stimulate and expand HIV-1-specific CD8 T cell responses. These data suggest an important role of cell-intrinsic type I interferon secretion in dendritic cells for the induction of effective HIV-1-specific CD8 T cells, and may be helpful for eliciting functional T cell immunity against HIV-1 for preventative or therapeutic clinical purposes.", "link"=>"http://www.mendeley.com/research/potent-cellintrinsic-immune-responses-dendritic-cells-facilitate-hiv1specific-t-cell-immunity-hiv1-e", "reader_count"=>53, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Librarian"=>3, "Student > Doctoral Student"=>3, "Researcher"=>12, "Student > Ph. D. Student"=>12, "Student > Master"=>8, "Other"=>2, "Student > Bachelor"=>5, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Librarian"=>3, "Student > Doctoral Student"=>3, "Researcher"=>12, "Student > Ph. D. Student"=>12, "Student > Master"=>8, "Other"=>2, "Student > Bachelor"=>5, "Professor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>6, "Mathematics"=>1, "Agricultural and Biological Sciences"=>22, "Medicine and Dentistry"=>11, "Neuroscience"=>1, "Psychology"=>1, "Immunology and Microbiology"=>9, "Linguistics"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>11}, "Neuroscience"=>{"Neuroscience"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>9}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>22}, "Linguistics"=>{"Linguistics"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"United States"=>1, "Italy"=>1, "South Africa"=>1, "United Kingdom"=>1}, "group_count"=>1}

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  • {"files"=>["https://ndownloader.figshare.com/files/2108109"], "description"=>"<p>(A): Representative flow cytometry plots reflecting proliferation of CD4<sup>+</sup> T cells after stimulation with allogeneic uninfected (Med) or HIV-1 infected (HIV) cDCs from Neg, CP, EC and HAART patients. Numbers in flow cytometry plots represent the proportion of proliferating CFSE<sup>low</sup> T cells. (B–C): Induction of allogeneic CD4 (B; n = 8) and CD8 T (C; n = 7) cell proliferation after exposure to HIV-1 infected cDC from indicated study cohorts. Horizontal lines represent the median for each specific cohort and experimental condition. (D): Representative flow cytometry dot plots reflecting IFN-γ secretion in an HLA-A2-SL9 (SLYNTVATL)-specific CTL cell line after 16 hours of co-culture with uninfected or HIV-1-infected cDCs from Neg, CP, EC and HAART individuals. (E): Proportion of IFNγ<sup>+</sup> cells in the SL9 CTL cell line after exposure to HIV-1-infected cDCs from indicated study groups. Cumulative data from n = 8 experiments are shown. (B,C,E): Differences within and among study groups were tested for statistical significance using a Wilcoxon matched-pairs signed-rank test rank test or a Mann Whitney test corrected for multiple comparisons using Bonferroni method, respectively. * p<0.05; ** p<0.01. (F): Induction of allogeneic CD4 (left; n = 7) and CD8 (right; n = 7) T cell proliferation after exposure to cDC from EC cultured in the presence of media (Med) or infected with HIV-1 in the presence or absence of AZT or RAL. Statistical significance of differences was tested using a Wilcoxon matched-pairs signed rank test. Bonferroni correction was applied for multiple comparisons.* p<0.05. (E-F): Horizontal lines represent the median for each specific cohort and experimental condition.</p>", "links"=>[], "tags"=>["hiv", "SAMHD", "cytosolic DNA sensor cGAS", "T Cell Immunity", "ec", "elite controllers", "Dendritic cells", "ledgf"], "article_id"=>1447102, "categories"=>["Biological Sciences"], "users"=>["Enrique Martin-Gayo", "Maria Jose Buzon", "Zhengyu Ouyang", "Taylor Hickman", "Jacqueline Cronin", "Dina Pimenova", "Bruce D. Walker", "Mathias Lichterfeld", "Xu G. Yu"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004930.g006", "stats"=>{"downloads"=>8, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Antigen_presenting_properties_of_cDCs_after_exposure_to_HIV_1_/1447102", "title"=>"Antigen-presenting properties of cDCs after exposure to HIV-1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-11 03:58:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/2108106"], "description"=>"<p>(A) SAMHD1 mRNA expression levels in cDCs from Neg (n = 11), CP (n = 11), EC (n = 11) and HAART-treated (n = 11) subjects at 48 hours after exposure to HIV-1 (HIV) or to media only (Med). (B): mRNA levels of TREX1 in cDCs from Neg (n = 11), CP (n = 11), EC (n = 11) and HAART (n = 11) individuals at 48 hours after exposure to HIV-1 (HIV), or to media only (Med). (A–B): Horizontal lines represent the median for each specific cohort and experimental condition. (C): Efficiency of siRNA-mediated SAMHD1 protein knock-down in primary cDCs 24h after treatment with scramble (SC) or SAMHD1-specific (SAM) siRNAs. Left panel shows a representative western blot analysis of SAMHD1 and β-actin expression on cDCs, right panel represents cumulative SAMHD1 expression data after normalization to β -actin in DCs nucleofected with SC (blue; n = 4) or SAM (brown; n = 4) siRNAs. The number above the bar represents the mean inhibition (%) in SAMHD1 protein expression after treatment with specific siRNAs. (D): Relative expression of early (left panel) and late (right panel) HIV-1 reverse transcripts in cDCs after <i>ex vivo</i> infection in the presence or absence of siRNA-mediated SAMHD1 silencing. Statistical significance was calculated using a Wilcoxon matched-pairs signed rank test. (E-F): mRNA levels of TPNO3 (E) and LEDGF/p75 (F) in cDCs from the indicated study cohorts at 48 hours after exposure to HIV-1 (HIV), or to media only (Med). Differences within cohorts were calculated using a Wilcoxon matched-pairs signed rank test * p<0.05; ** p<0.01; *** p<0.001. (D-E-F): Horizontal lines represent the median for each specific cohort and experimental condition.</p>", "links"=>[], "tags"=>["hiv", "SAMHD", "cytosolic DNA sensor cGAS", "T Cell Immunity", "ec", "elite controllers", "Dendritic cells", "ledgf"], "article_id"=>1447099, "categories"=>["Biological Sciences"], "users"=>["Enrique Martin-Gayo", "Maria Jose Buzon", "Zhengyu Ouyang", "Taylor Hickman", "Jacqueline Cronin", "Dina Pimenova", "Bruce D. Walker", "Mathias Lichterfeld", "Xu G. Yu"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004930.g004", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_host_restriction_factors_in_cDCs_from_EC_/1447099", "title"=>"Expression of host restriction factors in cDCs from EC.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-11 03:58:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/2108096"], "description"=>"<p>(A): IFNα and IFNβ mRNA levels in isolated BDCA1<sup>+</sup> cDCs from HIV-negative persons (Neg), individuals with chronic progressive HIV-1 infection (CP), Elite controllers (EC) and HAART-treated HIV-1 patients (HAART) at 24 and 48 hours after exposure to HIV-1 (HIV) or to media only (Med) as negative control. Horizontal lines represent the median for each specific cohort and experimental condition. (B): Mean Fluorescence Intensity (MFI) reflecting surface expression of CD86, CD83 and CD40 in cDCs from the different study cohorts at 24 hours after infection with HIV-1 (HIV) or after exposure to poly(I:C) (PIC). MFI values are expressed as fold-changes in comparison to baseline levels. Intra-individual differences were tested for statistical significance using Wilcoxon matched-pairs signed rank tests (above each cohort), differences between cohorts were tested using a Kruskal-Wallis test with post-hoc Dunn’s test; * p<0.05; ** p<0.01; *** p < 0.001; **** p< 0.0001. Horizontal lines represent the median for each specific cohort and experimental condition. (C): Heatmaps reflecting gene expression patterns of 28 interferon-stimulated genes (ISG) in cDCs from Neg (n = 6), CP (n = 6) and EC (n = 6) at 48 hours after infection with HIV-1. (D): Heatmaps reflecting correlations among gene expression intensities of all 28 ISGs in indicated study cohorts. Color-coding reflects Pearson’s correlation coefficient indicating strengths of statistical association between expression intensities of given gene pairs.</p>", "links"=>[], "tags"=>["hiv", "SAMHD", "cytosolic DNA sensor cGAS", "T Cell Immunity", "ec", "elite controllers", "Dendritic cells", "ledgf"], "article_id"=>1447093, "categories"=>["Biological Sciences"], "users"=>["Enrique Martin-Gayo", "Maria Jose Buzon", "Zhengyu Ouyang", "Taylor Hickman", "Jacqueline Cronin", "Dina Pimenova", "Bruce D. Walker", "Mathias Lichterfeld", "Xu G. Yu"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004930.g001", "stats"=>{"downloads"=>5, "page_views"=>31, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Type_I_IFN_secretion_and_activation_in_cDCs_after_ex_vivo_exposure_to_HIV_1_/1447093", "title"=>"Type I IFN secretion and activation in cDCs after <i>ex-vivo</i> exposure to HIV-1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-11 03:58:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/2108107"], "description"=>"<p>(A): Fold change in cGAS, STING and IFI16 mRNA expression levels in indicated study cohorts at 24 (upper panels) and 48 (lower panels) hours after <i>ex-vivo</i> infection with HIV-1. Induction of mRNA expression in comparison to baseline levels was tested for statistical significance using Wilcoxon matched-pairs signed-rank test tests. Significant differences between distinct cohorts were calculated using a Mann Whitney test. No correction for multiple comparisons was applied (B): IFNα and IFNβ expression in primary cDCs nucleofected with scrambled (SC) or cGAS-specific siRNAs, followed by infection with HIV-1. Data from n = 4 experiments are shown. Data were normalized to results from experiments with scrambled siRNA sequences. Differences in type I IFN responses between untreated or SC- or cGAS-nucleofected cDCs were tested for statistical significance using a Kruskal-Wallis test with post-hoc Dunn’s test * p<0.05; ** p<0.01.</p>", "links"=>[], "tags"=>["hiv", "SAMHD", "cytosolic DNA sensor cGAS", "T Cell Immunity", "ec", "elite controllers", "Dendritic cells", "ledgf"], "article_id"=>1447100, "categories"=>["Biological Sciences"], "users"=>["Enrique Martin-Gayo", "Maria Jose Buzon", "Zhengyu Ouyang", "Taylor Hickman", "Jacqueline Cronin", "Dina Pimenova", "Bruce D. Walker", "Mathias Lichterfeld", "Xu G. Yu"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004930.g005", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Induction_of_cytosolic_DNA_sensors_in_cDCs_from_EC_/1447100", "title"=>"Induction of cytosolic DNA sensors in cDCs from EC.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-11 03:58:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/2108098"], "description"=>"<p>(A): Flow cytometry gating strategy for defining cDCs in bulk PBMC cultures. (B): Representative flow cytometry dot plots indicating GFP expression in gated CD11c<sup>+</sup> HLA-DR<sup>+</sup> cDCs from Neg, CP, EC and HAART individuals after 24, 48 and 96 hours of <i>ex-vivo</i> infection with GFP-encoding HIV-1. Numbers in dot plots reflect the proportion of GFP-positive cells within gated cDCs. (C–D): Proportion (C) and GFP MFI (D) of GFP<sup>+</sup> cDCs from Neg, CP, EC and HAART subjects at 96 hours after infection with HIV-1 (n = 20 tested subjects for each cohort). Horizontal lines represent the median for each specific cohort and experimental condition. Differences among cohorts were tested using a Kruskal-Wallis test with post-hoc Dunn’s test (* p<0.05; *** p<0.001) or using Mann Whitney U test (# p<0.05; ## p<0.01).</p>", "links"=>[], "tags"=>["hiv", "SAMHD", "cytosolic DNA sensor cGAS", "T Cell Immunity", "ec", "elite controllers", "Dendritic cells", "ledgf"], "article_id"=>1447095, "categories"=>["Biological Sciences"], "users"=>["Enrique Martin-Gayo", "Maria Jose Buzon", "Zhengyu Ouyang", "Taylor Hickman", "Jacqueline Cronin", "Dina Pimenova", "Bruce D. Walker", "Mathias Lichterfeld", "Xu G. Yu"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004930.g002", "stats"=>{"downloads"=>1, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Susceptibility_of_primary_cDCs_to_ex_vivo_infection_with_HIV_1_/1447095", "title"=>"Susceptibility of primary cDCs to <i>ex-vivo</i> infection with HIV-1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-11 03:58:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/2108099"], "description"=>"<p>(A): Early and late HIV-1 reverse transcripts (RT) and 2-LTR circles in cDCs from indicated study subjects at 48 hours after <i>ex vivo</i> infection with HIV-1. (B): Analysis of integrated HIV-1 DNA in primary cDCs from the different study cohorts. Basal levels of integrated HIV-1 DNA are shown in the left panel, right panel shows <i>de novo</i> HIV-1 integration in cDCs after subtraction of baseline levels of integrated HIV-1 DNA. (C): Analysis of late HIV-1 RT products and 2-LTR circles normalized to levels of <i>de novo</i> integrated HIV-1 DNA in cDCs at 48 hours after infection. (A–C): Differences between different cohorts were tested for statistical significance using a Kruskal-Wallis test with post-hoc Dunn’s test or using Mann Whitney U test (# p<0.05; ## p<0.01). (A,B,C). Horizontal lines represent the median for each specific cohort and experimental condition. (D): Inhibition of IFNα and IFNβ mRNA expression in cDCs from EC cultured in media (Med) or infected with HIV-1 (HIV) in the presence or absence of AZT, Efavirenz (EFV) or Raltegavir (Ral). Data reflect mean and standard error from qPCR values of IFNα and IFNβ mRNA levels after normalization to β-actin endogenous expression from n = 5 experiments. Numbers above bars represent the mean percentage of inhibition induced by each drug. Differences were tested for statistical significance using a one-tailed Wilcoxon matched-pairs signed rank test, * p<0.05.</p>", "links"=>[], "tags"=>["hiv", "SAMHD", "cytosolic DNA sensor cGAS", "T Cell Immunity", "ec", "elite controllers", "Dendritic cells", "ledgf"], "article_id"=>1447096, "categories"=>["Biological Sciences"], "users"=>["Enrique Martin-Gayo", "Maria Jose Buzon", "Zhengyu Ouyang", "Taylor Hickman", "Jacqueline Cronin", "Dina Pimenova", "Bruce D. Walker", "Mathias Lichterfeld", "Xu G. Yu"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004930.g003", "stats"=>{"downloads"=>1, "page_views"=>30, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HIV_1_replication_patterns_in_cDCs_from_EC_/1447096", "title"=>"HIV-1 replication patterns in cDCs from EC.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-11 03:58:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/2108116", "https://ndownloader.figshare.com/files/2108117", "https://ndownloader.figshare.com/files/2108118", "https://ndownloader.figshare.com/files/2108119", "https://ndownloader.figshare.com/files/2108120", "https://ndownloader.figshare.com/files/2108121", "https://ndownloader.figshare.com/files/2108122"], "description"=>"<div><p>The majority of HIV-1 elite controllers (EC) restrict HIV-1 replication through highly functional HIV-1-specific T cell responses, but mechanisms supporting the evolution of effective HIV-1-specific T cell immunity in these patients remain undefined. Cytosolic immune recognition of HIV-1 in conventional dendritic cells (cDC) can facilitate priming and expansion of HIV-1-specific T cells; however, HIV-1 seems to be able to avoid intracellular immune recognition in cDCs in most infected individuals. Here, we show that exposure of cDCs from EC to HIV-1 leads to a rapid and sustained production of type I interferons and upregulation of several interferon-stimulated effector genes. Emergence of these cell-intrinsic immune responses was associated with a reduced induction of SAMHD1 and LEDGF/p75, and an accumulation of viral reverse transcripts, but inhibited by pharmacological blockade of viral reverse transcription or siRNA-mediated silencing of the cytosolic DNA sensor cGAS. Importantly, improved cell-intrinsic immune recognition of HIV-1 in cDCs from elite controllers translated into stronger abilities to stimulate and expand HIV-1-specific CD8 T cell responses. These data suggest an important role of cell-intrinsic type I interferon secretion in dendritic cells for the induction of effective HIV-1-specific CD8 T cells, and may be helpful for eliciting functional T cell immunity against HIV-1 for preventative or therapeutic clinical purposes.</p></div>", "links"=>[], "tags"=>["hiv", "SAMHD", "cytosolic DNA sensor cGAS", "T Cell Immunity", "ec", "elite controllers", "Dendritic cells", "ledgf"], "article_id"=>1447109, "categories"=>["Biological Sciences"], "users"=>["Enrique Martin-Gayo", "Maria Jose Buzon", "Zhengyu Ouyang", "Taylor Hickman", "Jacqueline Cronin", "Dina Pimenova", "Bruce D. Walker", "Mathias Lichterfeld", "Xu G. Yu"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1004930.s001", "https://dx.doi.org/10.1371/journal.ppat.1004930.s002", "https://dx.doi.org/10.1371/journal.ppat.1004930.s003", "https://dx.doi.org/10.1371/journal.ppat.1004930.s004", "https://dx.doi.org/10.1371/journal.ppat.1004930.s005", "https://dx.doi.org/10.1371/journal.ppat.1004930.s006", "https://dx.doi.org/10.1371/journal.ppat.1004930.s007"], "stats"=>{"downloads"=>4, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Potent_Cell_Intrinsic_Immune_Responses_in_Dendritic_Cells_Facilitate_HIV_1_Specific_T_Cell_Immunity_in_HIV_1_Elite_Controllers_/1447109", "title"=>"Potent Cell-Intrinsic Immune Responses in Dendritic Cells Facilitate HIV-1-Specific T Cell Immunity in HIV-1 Elite Controllers", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-06-11 03:58:06"}

PMC Usage Stats | Further Information

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Relative Metric

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