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A CRISPR screen of HIV dependency factors reveals CCNT1 is non-essential in T cells but required for HIV-1 reactivation from latency

ABSTRACT: A CRISPR screen of HIV dependency factors reveals CCNT1 is non-essential in T cells but required for HIV-1 reactivation from latency

PROVIDER: PRJNA1005655 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25648800.fastq.gz	Fastqsanger.gz
	SRR25648801.fastq.gz	Fastqsanger.gz
	SRR25648802.fastq.gz	Fastqsanger.gz
	SRR25648803.fastq.gz	Fastqsanger.gz
	SRR25648804.fastq.gz	Fastqsanger.gz

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A CRISPR screen of HIV dependency factors reveals CCNT1 is non-essential in T cells but required for HIV-1 reactivation from latency [CRISPR]

Project description:We sought to explore the hypothesis that host factors required for HIV-1 replication also play a role in latency reversal. Using a CRISPR gene library of putative HIV dependency factors, we performed a screen to identify genes required for latency reactivation. We identified several HIV- 1 dependency factors that play a key role in HIV-1 latency reactivation including ELL, UBE2M, TBL1XR1, HDAC3, AMBRA1, and ALYREF. Knockout of Cyclin T1 (CCNT1), a component of the P-TEFb complex important for transcription elongation, was the top hit in the screen and had the largest effect on HIV latency reversal with a wide variety of latency reversal agents. Moreover, CCNT1 knockout prevents latency reactivation in a primary CD4+ T cell model of HIV latency without affecting activation of these cells. RNA sequencing data showed that CCNT1 regulates HIV-1 proviral genes to a larger extent than any other host gene and had no significant effects on RNA transcripts in primary T cells after activation. We conclude that CCNT1 function is redundant in T cells but is absolutely required for HIV latency reversal.

2023-08-15 | GSE240894 | GEO

A CRISPR screen of HIV dependency factors reveals CCNT1 is non-essential in T cells but required for HIV-1 reactivation from latency [RNA-Seq]

2023-08-15 | GSE240896 | GEO

A CRISPR screen of HIV dependency factors reveals CCNT1 is non-essential in T cells but required for HIV-1 reactivation from latency [CRISPR]

Project description:A CRISPR screen of HIV dependency factors reveals CCNT1 is non-essential in T cells but required for HIV-1 reactivation from latency [CRISPR]

| PRJNA1005659 | ENA

A CRISPR screen of HIV dependency factors reveals CCNT1 is non-essential in T cells but required for HIV-1 reactivation from latency [RNA-Seq]

Project description:A CRISPR screen of HIV dependency factors reveals CCNT1 is non-essential in T cells but required for HIV-1 reactivation from latency [RNA-Seq]

| PRJNA1005661 | ENA

Integrated single-cell multiomic analysis of HIV latency reversal reveals novel regulators of viral reactivation

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

Dynamics of HIV Latency and Reactivation in a Primary CD4+ T Cell Model

Project description:HIV latency is a major obstacle to curing infection. Current strategies to eradicate HIV aim at increasing transcription of the latent provirus. In the present study we observed that latently infected CD4+ T cells from HIV-infected individuals failed to produce viral particles upon ex vivo exposure to SAHA (vorinostat), despite effective inhibition of histone deacetylases. To identify steps that were not susceptible to the action of SAHA or other latency reverting agents, we used a primary CD4+ T cell model, joint host and viral RNA sequencing, and a viral-encoded reporter. This model served to investigate the characteristics of latently infected cells, the dynamics of HIV latency, and the process of reactivation induced by various stimuli. During latency, we observed persistence of viral transcripts but only limited viral translation. Similarly, the reactivating agents SAHA and disulfiram successfully increased viral transcription, but failed to effectively enhance viral translation, mirroring the ex vivo data. This study highlights the importance of post-transcriptional blocks as one mechanism leading to HIV latency that needs to be relieved in order to purge the viral reservoir.

2017-02-24 | GSE95297 | GEO

Gene expression changes following latency reversal agents screening in a cellular model of HIV-1 latency

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.

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Single-cell CRISPR Screen for HIV Host Dependency Factors Involved in Latency Reversal

Project description:Single-cell CRISPR Screen for HIV Host Dependency Factors Involved in Latency Reversal

| PRJNA1039800 | ENA

The XPB Subunit of the TFIIH Complex Plays a Critical Role in HIV-1 Transcription, and XPB Inhibition by Spironolactone Prevents HIV-1 Reactivation from Latency

Project description:Human immunodeficiency virus (HIV) transcription requires assembly of cellular transcription factors at the human immunodeficiency virus type 1 (HIV-1) promoter. The TFIIH general transcription factor facilitates transcription initiation by opening the DNA strands around the transcription start site and phosphorylating the C-terminal domain of RNA polymerase II (RNAPII) for activation. Spironolactone (SP), an FDA approved aldosterone antagonist, triggers the proteasomal degradation of the XPB subunit of TFIIH and concurrently suppresses acute HIV infection in vitro. Here, we investigated SP as a possible block-and-lock agent for a functional cure, aimed at the transcriptional silencing of the viral reservoir. The long-term activity of SP was investigated in primary and cell line models of HIV-1 latency and reactivation. We show that SP rapidly inhibits HIV-1 transcription by reducing RNAPII recruitment to the HIV-1 genome. Short hairpin RNA (shRNA) knockdown of XPB confirmed XPB loss as the mechanism of action of HIV inhibition. Unfortunately, long-term pretreatment with SP does not result in long-term epigenetic suppression of HIV upon SP treatment interruption, since the virus rapidly rebounds when XPB reemerges; however, SP alone without antiretroviral therapy (ART) maintains transcriptional silencing of HIV. Importantly, SP inhibits HIV reactivation from latency in both cell line models and resting CD4+ T cells isolated from aviremic individuals living with HIV upon cell stimulation with latency-reversing agents. Furthermore, long-term treatment with concentrations of SP that potently degrade XPB does not lead to global dysregulation of cellular mRNA expression. Overall, these results suggest that XPB plays a key role in HIV transcriptional regulation, and XPB degradation by SP strengthens the potential of HIV transcriptional inhibitors in block-and-lock cure approaches.

2021-03-02 | GSE167997 | GEO

An integrated systems biology approach reveals positive and negative effects of suberoylanilide hydroxamic acid (SAHA) on HIV reactivation from latency

Project description:Suberoylanilide hydroxamic acid (SAHA) has been assessed in clinical trials as part of a “shock and kill” strategy to cure HIV-infected patients. While it was effective at inducing expression of HIV RNA "shock" , treatment with SAHA did not result in the reduction of reservoir size "kill". We therefore utilized a systems biology approach to dissect the mechanisms of action of SAHA that may explain its limited success in “shock and kill” strategies. CD4+ T cells from HIV seronegative donors were treated with 1 uM SAHA or its solvent dimethyl sulfoxide for 24 hours. Differential protein expression and post-translational modification was measured with two-dimensional liquid chromatography - tandem mass spectrometry iTRAQ proteomics. Gene expression changes were assessed by Illumina microarrays. Using limma package in the R computing environment, we identified 185 proteins, 18 phosphorylated forms, 4 acetylated forms and 2,982 genes, whose expression was modulated by SAHA. A protein interaction network integrating these 4 data types identified the transcriptional regulator HMGA1 to be upregulated by SAHA at the transcript, protein and acetylated protein levels. HMGA1 has been shown to repress HIV transcription, which is not optimal with respect to a shock and kill strategy. Further functional category assessment of proteins and genes modulated by SAHA identified gene ontology terms related to NFB signaling, protein folding and autophagy, which are all relevant to HIV reactivation. In summary, this study identified a number of host factors that may be therapeutically targeted to achieve more potent HIV reactivation in the “shock and kill” treatment, when using SAHA, either through modification of SAHA itself or through combination with other latency reversing agents. Finally, proteome profiling highlighted a number of potential adverse effects of SAHA, which transcriptome profiling alone would not have identified.

2015-09-10 | PXD002150 | Pride

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