Homo sapiens strain:CD4+ T-Cells
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PROVIDER: PRJNA213846 | ENA |
REPOSITORIES: ENA
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Project description:The latent reservoir for HIV-1 in resting memory CD4+ T cells is the major barrier to curing HIV-1 infection. Studies of HIV-1 latency have focused on regulation of viral gene expression in cells in which latent infection is established. However, it remains unclear how infection initially becomes latent. Here we described a unique set of properties of CD4+ T cells undergoing effector-to-memory transition including temporary up-regulation of CCR5 expression and rapid down-regulation of cellular gene transcription. These cells allowed completion of steps in the HIV-1 life cycle through integration, but suppressed HIV-1 gene transcription, thus allowing the establishment of latency. CD4+ T cells in this stage were substantially more permissive for HIV-1 latent infection than other CD4+ T cells. Establishment of latent HIV-1 infection in CD4+ T could be inhibited by viral-specific CD8+ T cells, a result with implications for elimination of latent HIV-1 infection by T cell-based vaccines.
2017-09-27 | GSE104275 | GEO
Project description:BACKGROUND: Combination antiretroviral therapy (cART) is able to control HIV-1 viral replication, however long-lived latent infection in resting memory CD4+ T-cells persist. The mechanisms for establishment and maintenance of latent infection in resting memory CD4+ T-cells remain unclear. Previously we have shown that HIV-1 infection of resting CD4+ T-cells co-cultured with CD11c+ myeloid dendritic cells (mDC) produced a population of non-proliferating T-cells with latent infection. Here we asked whether different antigen presenting cells (APC), including subpopulations of DC and monocytes, were able to induce post-integration latent infection in resting CD4+ T-cells, and examined potential cell interactions that may be involved using RNA-seq. RESULTS: mDC (CD1c+), SLAN+ DC and CD14+ monocytes were most efficient in stimulating proliferation of CD4+ T-cells during syngeneic culture and in generating post-integration latent infection in non-proliferating CD4+ T-cells following HIV-1 infection of APC-T-cell co-cultures. In comparison, plasmacytoid DC (pDC) and B-cells did not induce latent infection in APC-T-cell co-cultures. We compared the RNA expression profiles of APC subpopulations that could and could not induce latency in non-proliferating CD4+ T-cells. Gene expression analysis, comparing the mDC, SLAN+ DC and CD14+ monocyte subpopulations to pDC identified 53 upregulated genes that encode proteins expressed on the plasma membrane that could signal to CD4+ T-cells via cell-cell interactions (32 genes), immune checkpoints (IC) (5 genes), T-cell activation (9 genes), regulation of apoptosis (5 genes), antigen presentation (1 gene) and through unknown ligands (1 gene). CONCLUSIONS: APC subpopulations from the myeloid lineage, specifically mDC subpopulations and CD14+ monocytes, were able to efficiently induce post-integration HIV-1 latency in non-proliferating CD4+ T-cells in vitro. Inhibition of key pathways involved in mDC-T-cell interactions and HIV-1 latency may provide novel targets to eliminate HIV latency. mRNA profiles of sorted, pure antigen presenting cells including, CD1c+ myleoid dendirtic cells (mDC), SLAN+ mDC, CD14+ monocytes and plasmacytoid DC (pDC), were generated using next generation sequencing in triplicate, using Illumina Illumina Hiseq 2000.
2015-12-23 | E-GEOD-70106 | biostudies-arrayexpress
Project description:BACKGROUND: Combination antiretroviral therapy (cART) is able to control HIV-1 viral replication, however long-lived latent infection in resting memory CD4+ T-cells persist. The mechanisms for establishment and maintenance of latent infection in resting memory CD4+ T-cells remain unclear. Previously we have shown that HIV-1 infection of resting CD4+ T-cells co-cultured with CD11c+ myeloid dendritic cells (mDC) produced a population of non-proliferating T-cells with latent infection. Here we asked whether different antigen presenting cells (APC), including subpopulations of DC and monocytes, were able to induce post-integration latent infection in resting CD4+ T-cells, and examined potential cell interactions that may be involved using RNA-seq. RESULTS: mDC (CD1c+), SLAN+ DC and CD14+ monocytes were most efficient in stimulating proliferation of CD4+ T-cells during syngeneic culture and in generating post-integration latent infection in non-proliferating CD4+ T-cells following HIV-1 infection of APC-T-cell co-cultures. In comparison, plasmacytoid DC (pDC) and B-cells did not induce latent infection in APC-T-cell co-cultures. We compared the RNA expression profiles of APC subpopulations that could and could not induce latency in non-proliferating CD4+ T-cells. Gene expression analysis, comparing the mDC, SLAN+ DC and CD14+ monocyte subpopulations to pDC identified 53 upregulated genes that encode proteins expressed on the plasma membrane that could signal to CD4+ T-cells via cell-cell interactions (32 genes), immune checkpoints (IC) (5 genes), T-cell activation (9 genes), regulation of apoptosis (5 genes), antigen presentation (1 gene) and through unknown ligands (1 gene). CONCLUSIONS: APC subpopulations from the myeloid lineage, specifically mDC subpopulations and CD14+ monocytes, were able to efficiently induce post-integration HIV-1 latency in non-proliferating CD4+ T-cells in vitro. Inhibition of key pathways involved in mDC-T-cell interactions and HIV-1 latency may provide novel targets to eliminate HIV latency.
2015-12-23 | GSE70106 | GEO
Project description:Latently infected resting CD4+ T cells are a major barrier to HIV cure. Understanding how latency is established, maintained and reversed is critical to identifying novel strategies to eliminate latently infected cells. We demonstrate here that co-culture of resting CD4+ T cells and syngeneic myeloid dendritic cells (mDC) can dramatically increase the frequency of HIV DNA integration and latent HIV infection in non-proliferating memory, but not naïve, CD4+ T cells. Gene expression in non-proliferating CD4+ T cells, enriched for latent infection, showed significant changes in the expression of genes involved in cellular activation and interferon regulated pathways, including the down-regulation of genes controlling both NF-κB and cell cycle. We conclude that mDC play a key role in the establishment of HIV latency in resting memory CD4+ T cells, which is predominantly mediated through signalling during DC-T cell contact. Resting (CD69-CD25-HLA-DR-) CD4+ T cells were enriched from the blood of 4 normal donors by magnetic bead depletion and labelled with the proliferation dye SNARF. SNARFhiEGFP- CD4+ T cells cultured with (+DC) or without syngeneic bulk DC (lin-HLA-DR+), in the presence (HIV T) or absence (Mock T) of HIV, were sorted 5 days following infection with NL(AD8)-nef/EGFP (MOI 5).Culture media was supplemented with 10ng/mL of IL-7. The gene expression profile of the 4 cell populations: 1. HIV T (+DC); 2. Mock T (+DC); 3. HIV T; and 4. Mock T, was determined.
2014-11-01 | E-GEOD-52344 | biostudies-arrayexpress
Project description:Latently infected resting CD4+ T cells are a major barrier to HIV cure. Understanding how latency is established, maintained and reversed is critical to identifying novel strategies to eliminate latently infected cells. We demonstrate here that co-culture of resting CD4+ T cells and syngeneic myeloid dendritic cells (mDC) can dramatically increase the frequency of HIV DNA integration and latent HIV infection in non-proliferating memory, but not naïve, CD4+ T cells. Gene expression in non-proliferating CD4+ T cells, enriched for latent infection, showed significant changes in the expression of genes involved in cellular activation and interferon regulated pathways, including the down-regulation of genes controlling both NF-κB and cell cycle. We conclude that mDC play a key role in the establishment of HIV latency in resting memory CD4+ T cells, which is predominantly mediated through signalling during DC-T cell contact.
2014-11-01 | GSE52344 | GEO
Project description:HIV-1 encounters the hierarchically organized host chromatin to stably integrate and persist in anatomically distinct latent reservoirs. The contribution of genome organization in HIV-1 infection has been largely understudied across different HIV-1 targets. Here we determine HIV-1 integration sites (IS), associate them to chromatin and expression signatures at different genomic scales in a microglia cell model and profile them together with the primary T cell reservoir. HIV-1 insertions into introns of actively transcribed genes with IS hotspots in genic- and super-enhancers, characteristic of blood cells, are maintained in the microglia cell model. Genome organization analysis reveals dynamic CCCTC-binding factor (CTCF) clusters in cells with active and repressed HIV-1 transcription, while CTCF removal impairs viral integration. We identify CTCF-enriched topologically associated domain (TAD) boundaries with signatures of transcriptionally active chromatin as HIV-1 integration determinant in microglia and CD4+ T cells, highlighting the importance of the host genome organization in HIV-1 infection.
2023-01-24 | GSE223638 | GEO
Project description:HIV integrates semi-randomly into the genome of immune cells and thus proviruses that persist in patients under long-term, highly active suppressive therapy can be detected in various positions (inside and outside) and orientations (same, convergent and divergent) respective to genes, promoters, and enhancers. Thus, this integration landscape heterogeneity can influence HIV transcription activity thereby dictating proviral fate (active vs latent). However, the effect of the integration site to proviral transcription activity has so far remained elusive. Here we integrate open-source, large-scale datasets including epigenetics, transcriptome, and 3D genome architecture to interrogate the chromatin states, transcription activity landscape, nuclear sub-compartments, and topological associated domains around HIV integration sites in CD4+ T cell-based models to decipher ‘codes’ in the human genome shaping proviral transcription. As part of this integrated approach, here we collect nucleosome occupancy profiles in Jurkat CD4+ T cells.
2021-05-05 | GSE144753 | GEO
Project description:Antiretroviral therapy controls but does not cure HIV-1 infection due to a reservoir of rare CD4 + T cells harboring latent proviruses. Little is known about the transcriptional program of latent cells. Here we report a novel strategy to enrich clones of latent cells carrying intact, replication-competent HIV-1 proviruses from blood based on their expression of unique T cell receptors. Latent cell enrichment enabled single cell transcriptomic analysis of 1,050 CD4 + T cells belonging to expanded clones harboring intact HIV-1 proviruses from 6 different individuals. The analysis revealed that most of these cells are T effector memory cells that are enriched for expression of HLA-DR, HLA-DP, CD74, CCL5, Granzymes A and K, cystatin F, LYAR and DUSP2. We conclude that expanded clones of latent cells carrying intact HIV-1 proviruses persist preferentially in a distinct CD4 + T cell population opening new possibilities for eradication.
2022-06-03 | GSE204756 | GEO
Project description:Latent HIV reservoirs are extremely stable which pose a tremendous challenge to eradicate HIV. Here, we show that HIV explores the integrated stress response (ISR) signaling to establish its quiescent infection, refractory to the clearance for its persistence. HA15, a recently characterized specific ISR agonist, activates ATF4/CHOP signaling to not only disrupt HIV latency but also reduce HIV+ cells in the primary CD4+ T cell model of HIV latency without the induction of cell death in the HIV negative primary CD4+ T cells and the impact of viability in resting CD4+ T cells isolated from people living with HIV (PLWH). Mechanistically, the reduction of HIV+ cells by ISR/ATF4 activation is associated with the enhancement of cellular apoptosis. However, this mainly occurs in the HIV translation negative CD4+ T cells. In fact, ISR/ATF4 activation-induced cell death largely occurs in HIV transcription active (HIV gag-pol) CD4+ T cells. This is involved in HIV RNA-induced innate immune IFIT signaling. During the acute SIV infection in the rhesus macaques, the induction of ATF4 is associated with decrease of SIV reservoir in the intestine in vivo. When further tested in the resting CD4+ T cells isolated from PLWH on ART, the induction of ISR/ATF4 signaling by HA15 reduced HIV DNA reservoir. These findings support that inactivation of ISR/ATF4 signaling is associated with the maintenance of the stable and quiescent HIV reservoirs while enforced ISR/ATF4 signaling reduces translation quiescent HIV reservoirs in CD4+ T cells.
2022-12-05 | GSE210824 | GEO
Project description:This study examines the sites of HIV integration in quiescent CD4 T cells and compares them to activated T cells. The expression patterns of the sites hosting integration events were determined using microarray analysis data from quiescent and activated CD4 T cells.
2009-05-30 | GSE14596 | GEO