Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA369087 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5209820.fastq.gz | Fastqsanger.gz | |||
| SRR5209830.fastq.gz | Fastqsanger.gz | |||
| SRR5209840.fastq.gz | Fastqsanger.gz | |||
| SRR5209850.fastq.gz | Fastqsanger.gz | |||
| SRR5209821.fastq.gz | Fastqsanger.gz |
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Project description:Memory CD4+ T cell subsets show differential responses to HIV latency reversing agents
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Project description:Memory CD4+ T cell subsets show differential responses to HIV latency reversing agents [LARA]
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Project description:HIV-1 persists in individuals on ART in infected central (CM), transitional (TM) and effector memory (EM) CD4+ T cells. We developed LARA (latency and reversion assay), which facilitates the examination of HIV latency reversal in CM, TM and EM subsets in a single assay. Studies with latency reversing agents (LRAs) revealed responses specific to each subset, including compounds that significantly reversed latency in all subsets but with a range of efficiency (bryostatin) to those that demonstrated subset specificity (IL-15). Significantly, LARA has allowed the demonstration that EM cells display a more activated profile compared to CM, which translated to enhanced efficiency in responsiveness to multiple LRAs and allowed the identification of mechanisms associated with the compounds that reactivate latent HIV in all subsets. Understanding the responsiveness of memory CD4+ T cells subsets to LRAs will accelerate the development of anti-latency therapy to interfering with viral persistence in vivo.
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Project description:CD4 T cells with latent HIV-1 infection persist despite treatment with currently available antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may increase the immunological vulnerability of HIV-1-infected cells, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized, controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-a2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target site for panobinostat. In contrast, proviruses near H3K27ac marks appeared to be actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment with panobinostat can accelerate immune selection of HIV-1 proviruses.
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Project description:CD4 T cells with latent HIV-1 infection persist despite treatment with currently available antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may increase the immunological vulnerability of HIV-1-infected cells, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized, controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-a2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target site for panobinostat. In contrast, proviruses near H3K27ac marks appeared to be actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment with panobinostat can accelerate immune selection of HIV-1 proviruses.
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Project description:Despite the success of antiretroviral therapy, HIV cannot be cured because of a reservoir of latently infected cells that evades therapy. To understand the mechanisms of HIV latency, we employed an integrated single-cell RNA-seq/ATAC-seq approach to simultaneously profile the transcriptomic and epigenomic characteristics of ~125,000 latently infected primary CD4 cells after reactivation using three different latency-reversing agents.
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Project description:HIV-1 infected patients virally suppressed by antiviral treatment harbor a persistent reservoir of replication competent latent HIV-1 infected cells, which constitute the main roadblock to a cure. A main strategy for HIV cure aims to stimulate viral gene expression in latently infected cells so that they can be cleared. Crucial for the design of drugs referred to as “latency-reversing agents” (LRAs) is the identification of molecular targets for latency reversal. The regulatory factors physically associated with and repressing the latent HIV-1 promoter or 5’LTR would provide ideal putative molecular targets for latency reversal. However, due to technical limitations, the comprehensive and unbiased identification of host proteins associated with the latent or active integrated HIV LTR in infected cells not been possible. Here we use dCas9 targeted chromatin and histone enrichment strategy coupled to mass spectrometry (Catchet-MS), to purify the locus-associated dCas9 bait, guided downstream of the HIV-1 transcriptional start site (TSS) in latent and activated HIV-1 infected T cells to identify the 5’LTR bound latent and active regulatory complexes. Catchet-MS identified both previously described as well as novel host factors distinctly associated with the latent versus transcriptionally active HIV-1 5’LTR. Within the identified factors we find the transcription factor IKZF1 to be a novel repressor of the HIV-1 promoter required for maintenance of latency, and thus a molecular target for latency reversal. Finally, we identify the FDA approved drug, Iberdomide, which targets IKZF1 for degradation to be a novel LRA, which reversed latency in latent ex vivo HIV-1 infected primary CD4+ T cells and in cells isolated from HIV-1 infected, aviremic participants.
2022-05-31 | PXD032975 | Pride
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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