Memory CD4+ T cell subsets show differential responses to HIV latency reversing agents
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PROVIDER: PRJNA369088 | ENA |
REPOSITORIES: ENA
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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.
2018-01-26 | GSE94149 | GEO
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.
2018-01-26 | GSE94150 | GEO
Project description:The latent viral reservoir represents one of the major barriers of curing HIV. Focus on the “kick and kill” approach, in which virus expression is reactivated then cells producing virus are selectively depleted, has led to the discovery of many latency reversing agents (LRAs) that can reactivate latently integrated virus and further our understanding of the mechanisms driving HIV latency and latency reversal. Thus far, individual compounds have yet to be robust enough to work as a therapy, highlighting the importance of identifying new compounds that target novel pathways and synergize with known LRAs. In this study, we identified a promising LRA, NSC95397, from a screen of ~4250 compounds in J-Lat cell lines. We validated that NSC95397 reactivates latent viral transcription and protein expression from cells with unique integration events. Co-treating cells with NSC95397 and known LRAs demonstrated that NSC95397 has the potential to synergize with different drugs under both standard normoxic and physiological hypoxic conditions. We showed that NSC95397 does not globally increase open chromatin, and bulk RNA sequencing revealed that NSC95397 does not greatly change cellular transcription. Instead, NSC95397 downregulates many pathways key to metabolism, cell growth, and DNA repair – highlighting the potential of these pathways in regulating HIV latency. Overall, we identified NSC95397 as a novel LRA that does not alter global transcription, that shows potential for synergy with known LRAs, and that may act through novel pathways not previously recognized for their ability to modulate HIV latency.
2024-08-31 | GSE241617 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-01-26 | GSE94152 | GEO
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.
2023-12-28 | GSE242997 | GEO
Project description:To delineate the mechanism driving JAK2 inhibitors´ induced effects on HIV-1 latency, whole transcriptome profiling was performed in the HIV-1 latency model HL-HIG, treated with the LRA fedratinib, the LPA pacritinib, the pan-JAKi ruxolitinib and PMA as a positive control of latency reactivation and immune activation.
2022-08-24 | GSE195855 | GEO
Project description:HIV-1 latency is a major obstacle to achieve a functional cure for AIDS. To eradicate the viral reservoir, one of the strategies is to specifically reactivate HIV-1-infected cells and followed by elimination with potent immune surveillance. However, present latency-reversing agents (LRAs) are quite dissatisfactory because of their high toxicity and low efficiency. New targets need to be identified to develop more promising LRAs. Here, we found that histone chaperone chromatin assembly factor 1 (CAF-1) promotes HIV-1 latency by forming versatile suppressive nuclear bodies. CAF-1 plays a leading role for the formation of bodies recruiting multi-layer suppressive epigenetic modifiers and maintainers, and is of the characteristic of liquid-liquid phase separation (LLPS). Three distinct disordered regions of CHAF1A subunit coalesce CAF-1 body components by forming LLPS and play a key in maintaining HIV-1 latency. Therefore, disruptive induction of phase-separated CAF-1 body could be an important strategy to reactivate latent HIV-1.
2021-02-09 | GSE166337 | GEO
Project description:Different classes of latency reversing agents (LRAs) are being evaluated to measure their effects in reactivating HIV replication from latently infected cells. A limited number of studies have demonstrated additive effects of LRAs with the viral protein Tat in initiating transcription, but less is known about how LRAs interact with Tat, particularly through basic residues that may be post-translationally modified to alter the behaviour of Tat for processive transcription and co-transcriptional RNA processing.Here we show that various lysine and arginine mutations reduce the capacity of Tat to induce both transcription and mRNA splicing. The lysine 28 and lysine 50 residues of Tat, or the acetylation and methylation modifications of these basic amino acids, were essential for Tat transcriptional control, and also for the proviral expression effects elicited by histone deacetylase inhibitors (HDACi) or the bromodomain inhibitor JQ1. We also found that JQ1 was the only LRA tested that could induce HIV mRNA splicing in the absence of Tat, or rescue splicing for Tat lysine mutants in a BRD4-dependent manner.Our data provide evidence that Tat activities in both co-transcriptional RNA processing together with transcriptional initiation and processivity are crucial during reactivation of latent HIV infection. The HDACi and JQ1 LRAs act with Tat to increase transcription, but JQ1 also enables post-transcriptional mRNA splicing. Tat residues K28 and K50, or their modifications through acetylation or methylation, are critical for LRAs that function in conjunction with Tat.
| S-EPMC5948896 | biostudies-other
Project description:The presence of a reservoir of latently infected cells in HIV-infected patients is a major barrier towards finding a cure. One active cure strategy is to find latency-reversing agents that induce viral reactivation, thus leading to immune cell recognition and elimination of latently infected cells, known as the shock-and-kill strategy. Therefore, the identification of molecules that reactivate latent HIV and increase immune activation has the potential to further these strategies into the clinic. Here, we characterized synthetic molecules composed of a TLR2 and a TLR7 agonist (dual TLR2/7 agonists) as latency-reversing agents and compared their activity with that of the TLR2 agonist Pam2CSK4 and the TLR7 agonist GS-9620. We found that these dual TLR2/7 agonists reactivate latency by 2 complementary mechanisms. The TLR2 component reactivates HIV by inducing NF-?B activation in memory CD4+ T cells, while the TLR7 component induces the secretion of TNF-? by monocytes and plasmacytoid dendritic cells, promoting viral reactivation in CD4+ T cells. Furthermore, the TLR2 component induces the secretion of IL-22, which promotes an antiviral state and blocks HIV infection in CD4+ T cells. Our study provides insight into the use of these agonists as a multipronged approach targeting eradication of latent HIV.
| S-EPMC6237480 | biostudies-literature
Project description:T cells are the primary target of the virus HIV-1. Upon infection, the expression of the virus may come to a complete shutdown, a phenomenon known as latency. The molecular mechanisms responsible for the latency of HIV-1 are still poorly understood. To shed light on those mechanisms, we used the J-Lat A2 model for latency reversal, that consists of a Jurkat T cell clone containing a mini HIV construct that is transcriptionally silent. We treated J-Lat A2 and Jurkat cells with the latency-reversing drugs SAHA (suberoylanilide hydroxamic acid) and PMA (phorbol 12-myristate 13-acetate), and we performed single-cell RNA-seq to identify transcriptional signatures shared among the cells where HIV is reactivated.
2021-07-15 | GSE180133 | GEO