Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA328272 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3802511_1.fastq.gz | Fastqsanger.gz | |||
| SRR3802511_2.fastq.gz | Fastqsanger.gz | |||
| SRR3802521_1.fastq.gz | Fastqsanger.gz | |||
| SRR3802521_2.fastq.gz | Fastqsanger.gz | |||
| SRR3802513_1.fastq.gz | Fastqsanger.gz |
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Project description:Benzotriazoles reactivate latent HIV-1 through inactivation of STAT5 SUMOylation (ChIP-Seq)
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Project description:Benzotriazoles reactivate latent HIV-1 through inactivation of STAT5 SUMOylation
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Project description:We screened for small molecules that reactivated latent HIV-1 and identified benzotriazoles as latency-reducing agents. Here, we characterize the effects of HODHBt on gene expression in cultured T cells from three donors by polyA RNA-Seq and on STAT5A occupancy of the HIV-1 LTR promoter by ChIP-Seq. These and other results demonstrate that benzotriazoles block SUMOylation of phosphorylated STAT5, prolonging its transcriptional activity.
2017-01-11 | GSE84199 | GEO
Project description:We screened for small molecules that reactivated latent HIV-1 and identified benzotriazoles as latency-reducing agents. Here, we characterize the effects of HODHBt on gene expression in cultured T cells from three donors by polyA RNA-Seq and on STAT5A occupancy of the HIV-1 LTR promoter by ChIP-Seq. These and other results demonstrate that benzotriazoles block SUMOylation of phosphorylated STAT5, prolonging its transcriptional activity.
2017-01-11 | GSE84197 | GEO
Project description:The barrier to HIV-1 functional cure is caused by a small pool of latently infected resting CD4 T-cells that persist under antiretroviral therapy. Notably this latent reservoir of infected cells will produce replication-competent infectious virus once prolonged suppressive HAART is withdrawn. The reactivation of HIV-1 gene expression in T-cells harboring latent provirus in HIV-1 patients under HAART will likely result in depletion of this latent reservoir due to cytopathic effects and immune clearance. Many studies have investigated small molecules that reactivate HIV-1 gene expression but to date no latency reversal agent (LRA) has been identified to be specific, non-toxic, and effective in primary T-cells isolated from HIV-1 infected individuals undergoing long-term HAART. Stochastic fluctuations in HIV-1 tat gene expression have been attributed to be essential in the viral progression to latency. We hypothesized that exposing Tat to latently infected CD4 T-cells will result in potent latency reversal. Our results indicate the capacity of an engineered Tat to reactivate HIV-1 in latently infected cells from patients to a similar degree as the protein kinase C agonist PMA (Phorbol 12-Myristate 13-Acetate) while showing no T-cell activation nor any significant transcriptome perturbation in primary CD4 T-cells.
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Project description:Quiescence is a hallmark of CD4+ T cells latently infected with HIV-1. While reversing this quiescence is an effective approach to reactivate latent HIV from T cells in culture, it can cause deleterious cytokine dysregulation in patients. Here we report that FOXO1, a key regulator of T-cell quiescence, promotes latency and suppresses productive HIV infection. In resting T cells, FOXO1 inhibition induces ER stress and activates two associated transcription factors: activating transcription factor 4 (ATF4) and nuclear factor of activated T cells (NFAT). Thus, our studies uncover a novel link between FOXO1, ER stress, and HIV infection that could be therapeutically exploited to selectively reverse T-cell quiescence and reduce the size of the latent viral reservoir.
2019-04-10 | GSE129522 | GEO
Project description:Resting CD4+ T cells that are both persistent and latently infected with HIV represent the most important challenge to HIV eradication. Estimates indicate the need for >70 years of continuous, fully suppressive, antiretroviral therapy (ART) to eliminate the HIV reservoir. Alternatively, induction of HIV from its latent state could accelerate the decline of the reservoir, thereby shortening the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in peripheral blood with minimal focus on tissue reservoirs and had limited effect. We found that activation of the non-canonical NF-B signaling pathway via AZD5582 results in induction of HIV- and SIV-RNA expression in the blood and tissues of ART-suppressed humanized mice and rhesus macaques. Analysis of resting CD4+ T cells from tissues after AZD55852 treatment revealed increased SIV-RNA in lymph nodes in macaques and robust induction of HIV in virtually all tissues analyzed in humanized mice including lymph nodes, thymus, bone marrow, liver, and lung. This promising new approach to latency reversal, in combination with the appropriate tools for systemic clearance of persistent HIV infection, greatly increases opportunities for HIV eradication.
2020-01-07 | GSE141546 | GEO
Project description:The switch between HIV latency and productive transcription is regulated by an auto-feedback mechanism initiated by the viral trans-activator Tat, which functions to recruit the host transcription elongation factor P-TEFb to proviral HIV. A heterodimeric complex of CDK9 and one of three cyclin T subunits, P-TEFb is expressed at vanishingly low levels in latently infected memory CD4+ T cells and cellular mechanisms controlling its availability for proviral transcription are not well-defined. Using a well-characterized primary T-cell model of HIV latency alongside healthy donor memory CD4+ T cells, we sought to identify specific T-cell receptor (TCR) signaling pathways that regulate the generation of transcriptionally active P-TEFb, defined as the coordinate expression of cyclin T1 and phospho-Ser175 CDK9. Unexpectedly, cellular treatment with diacylglycerol-mimicking protein kinase C (PKC) agonists in the absence of intracellular calcium mobilization with an ionophore was sufficient to stimulate active P-TEFb expression and reactivate latent HIV with minimal cytotoxicity. Furthermore, inhibition-based experiments demonstrated that PKC agonists and TCR-mobilized diacylglycerol signal through MAP kinases ERK1/2 rather than through PKC to effect the reactivation of both P-TEFb and latent HIV. Single-cell RNA-seq analysis revealed that of the four known isoforms of RasGRP, the diacylglycerol-dependent Ras guanine nucleotide exchange factor RasGRP1 is by far the predominantly expressed isoform in memory CD4+ T cells and should therefore mediate the activation of ERK1/2 upon TCR co-stimulation or PKC agonist challenge. Combined inhibition of the PI3K-AKT-mTORC1/2 pathway alongside the ERK1/2 activator MEK prior to TCR co-stimulation abrogated active P-TEFb expression and strongly suppressed latent HIV reactivation. Therefore, contrary to prevailing models, the coordinate reactivation of P-TEFb and latent HIV in primary T cells in response to either TCR co-stimulation or PKC agonist challenge is largely independent of PKC activity but rather primarily involves two complementary signaling arms of the TCR cascade namely RasGRP1-Ras-Raf-MEK-ERK1/2 and PI3K-AKT-mTORC1/2.
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Project description:Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1
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Project description:Molecular mechanisms of HIV-1 latency have been studied extensively to achieve a functional cure for the acquired immunodeficiency syndrome (AIDS). To develop more promising latency-reversing agents (LRAs) to efficiently reactivate the latent reservoir which is subsequently eliminated by immune surveillance, new therapeutic targets need to be evaluated. Here, we found that the Polycomb group (PcG) protein CBX4 contributes to HIV-1 latency in many latency models and primary CD4+ T cells. CBX4 forms nuclear bodies with liquid–liquid phase separation (LLPS) properties on the HIV-1 long terminal repeat (LTR). Further proteomics analysis revealed that CBX4 recruits EZH2 to CBX4 bodies and SUMOylates EZH2 utilizing its SUMO E3 ligase activity, which enhances the H3K27 methyltransferase activity of EZH2. Our results indicated that CBX4 bridges the Polycomb repressive complex 1 (PRC1) and PRC2, resulting in synergistically maintaining HIV-1 latency. Dissolution of phase-separated CBX4 bodies could be a potential intervention to reactivate latent HIV-1.
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