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Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal [CRISPR]

ABSTRACT: Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal [CRISPR]

PROVIDER: PRJNA1158849 | ENA |

REPOSITORIES: ENA

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Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal

Project description:Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal

| PRJNA1161690 | ENA

Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal [RNA-seq]

Project description:Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal [RNA-seq]

| PRJNA1158793 | ENA

Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal [AutoCUT&Tag]

Project description:Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal [AutoCUT&Tag]

| PRJNA1161694 | ENA

Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal [CRISPR]

Project description:The latent HIV reservoir is a major barrier to HIV cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, a non-canonical NF-kB activator, and I-BET151, a bromodomain inhibitor is appealing towards inducing HIV-1 reactivation. However, even this LRA combination needs improvement as it is inefficient at activating proviruses in cells from people living with HIV (PLWH). We performed a CRISPR screen in conjunction with AZD5582 & I-BET151 and identified a member of the Integrator complex as a target to improve this LRA combination, specifically Integrator complex subunit 12 (INTS12). Integrator functions as a genome-wide attenuator of transcription that acts on elongation through its RNA cleavage and phosphatase modules. Knockout of INTS12 improved latency reactivation at the transcriptional level and is more specific to the HIV-1 provirus than AZD5582 & I-BET151 treatment alone. We found that INTS12 is present on chromatin at the promoter of HIV and therefore its effect on HIV may be direct. Additionally, we observed more RNAPII in the gene body of HIV only with the combination of INTS12 knockout with AZD5582 & I-BET151, indicating that INTS12 induces a transcriptional elongation block to viral reactivation. Moreover, knockout of INTS12 increased HIV-1 reactivation in CD4 T cells from virally suppressed PLWH ex vivo. We also detected viral RNA in the supernatant from CD4 T cells of all three virally suppressed PLWH tested upon INTS12 knockout suggesting that INTS12 prevents full-length HIV RNA production in primary T cells.

2024-09-17 | GSE276777 | GEO

Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal [AutoCUT&Tag]

Project description:The latent HIV reservoir is a major barrier to HIV cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, a non-canonical NF-kB activator, and I-BET151, a bromodomain inhibitor are appealing towards inducing HIV reactivation. However, even this LRA combination needs improvement as it is inefficient at activating proviruses in cells from people living with HIV (PLWH). We performed a CRISPR screen in conjunction with AZD5582 & I-BET151 and identified a member of the Integrator complex as a target to improve this LRA combination, specifically Integrator complex subunit 12 (INTS12). Integrator functions as a genome-wide attenuator of transcription that acts on elongation through its RNA cleavage and phosphatase modules. Knockout of INTS12 in both cell line models and in CD4 T cells from virally suppressed PLWH improves reactivation at the transcriptional level and is more specific than AZD5582 & I-BET151 treatment alone. INTS12 is present on chromatin at the promoter of HIV and therefore its effect on HIV may be direct. Additionally, we observe more RNAPII in the gene body of HIV only with the combination of INTS12 knockout with AZD5582 & I-BET151 indicating the combination may specifically overcome an elongation block to reactivation. We also observe viral RNA in the supernatant from CD4 T cells of all three virally suppressed PLWH tested upon INTS12 knockout suggesting that INTS12 controls full-length HIV RNA and virus production ex vivo.

2024-09-17 | GSE277305 | GEO

Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal [RNA-seq]

Project description:The latent HIV reservoir is a major barrier to HIV cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, a non-canonical NF-kB activator, and I-BET151, a bromodomain inhibitor are appealing towards inducing HIV reactivation. However, even this LRA combination needs improvement as it is inefficient at activating proviruses in cells from people living with HIV (PLWH). We performed a CRISPR screen in conjunction with AZD5582 & I-BET151 and identified a member of the Integrator complex as a target to improve this LRA combination, specifically Integrator complex subunit 12 (INTS12). Integrator functions as a genome-wide attenuator of transcription that acts on elongation through its RNA cleavage and phosphatase modules. Knockout of INTS12 in both cell line models and in CD4 T cells from virally suppressed PLWH improves reactivation at the transcriptional level and is more specific than AZD5582 & I-BET151 treatment alone. INTS12 is present on chromatin at the promoter of HIV and therefore its effect on HIV may be direct. Additionally, we observe more RNAPII in the gene body of HIV only with the combination of INTS12 knockout with AZD5582 & I-BET151 indicating the combination may specifically overcome an elongation block to reactivation. We also observe viral RNA in the supernatant from CD4 T cells of all three virally suppressed PLWH tested upon INTS12 knockout suggesting that INTS12 controls full-length HIV RNA and virus production ex vivo.

2024-09-17 | GSE276747 | GEO

Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-09-17 | GSE277306 | GEO

CaptureSeq to study HIV-1 transcription after reversal of latency

Project description:The goal of this study was to utilize CaptureSeq to be able to measure HIV-1 transcription after reversal of latency in primary cells from antiretroviral-treated HIV-1 infected individuals.

2021-06-01 | GSE152377 | GEO

Systemic HIV/SIV latency reversal via non-canonical NF-κB signaling in vivo

Project description:Molecules mimicking the active N-terminal tetrapeptide of the second mitochondrial-derived activator of caspases (SMACm) potently reverse HIV latency in vitro and ex vivo without the pleotropic cellular effects seen with other LRAs. We verified that SMACm facilitate latency reversal through activation of the non-canonical NFκB pathway as exemplified by rapid degradation of cIAP1, followed by a slower conversion of inactive p100 into active p52. A potent representative of this class, AZD5582, increases cell-associated HIV gag RNA expression in resting CD4+ T cells from ART-suppressed, HIV-infected donors while altering the expression of a restricted number of human genes. These findings represent the first demonstration that SMACm have single agent latency reversal activity in patient-derived cells and support evaluation of SMACm in preclinical animal models.

2020-01-11 | GSE142774 | GEO

Single-cell RNA-seq in a model for HIV latency reversal

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

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