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Benzotriazoles reactivate latent HIV-1 through inactivation of STAT5 SUMOylation (RNA-Seq)

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE84197 | GEO | 2017/01/11

SECONDARY ACCESSION(S): PRJNA328272

REPOSITORIES: GEO

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Benzotriazoles reactivate latent HIV-1 through inactivation of STAT5 SUMOylation (ChIP-Seq)

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.

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Benzotriazoles reactivate latent HIV-1 through inactivation of STAT5 SUMOylation

Project description:Benzotriazoles reactivate latent HIV-1 through inactivation of STAT5 SUMOylation

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Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation.

Project description:The presence of latent HIV-1 in infected individuals represents a major barrier preventing viral eradication. For that reason, reactivation of latent viruses in the presence of antiretroviral regimens has been proposed as a therapeutic strategy to achieve remission. We screened for small molecules and identified several benzotriazole derivatives with the ability to reactivate latent HIV-1. In the presence of IL-2, benzotriazoles reactivated and reduced the latent reservoir in primary cells, and, remarkably, viral reactivation was achieved without inducing cell proliferation, T cell activation, or cytokine release. Mechanistic studies showed that benzotriazoles block SUMOylation of phosphorylated STAT5, increasing STAT5's activity and occupancy of the HIV-1 LTR. Our results identify benzotriazoles as latency reversing agents and STAT5 signaling and SUMOylation as targets for HIV-1 eradication strategies. These compounds represent a different direction in the search for "shock and kill" therapies.

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Benzotriazoles reactivate latent HIV-1 through inactivation of STAT5 SUMOylation

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

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Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1

Project description:Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy 1. Current research efforts to cure HIV-1 infection include “shock and kill” strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells 2. However, the modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy 3,4. Aminobisphosphonates that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies 5. Here, we show the use of aminobisphosphonates as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that aminobisphosphonates induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin. RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further of alendronate-mediated latency reversal and activation of immune effector cells.Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of aminobisphosphonates to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.

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Project description:Surface expression of the viral Envelope protein (Env) was used to enrich reactivated latent T cells producing HIV-RNA, and single cell RNASeq was performed to study gene expression differences between latent cells and controls.

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Unrestricted SUMOylation drives lymphomagenesis

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Transcriptome analysis in sumoylation deficient (ubc9-6) budding yeast and in a strain with a sumoylation-impairing mutation in the TFIIF subunit, Tfg1

Project description:Transcription related proteins are among the most frequently identified targets of SUMO post-translational modification, but the gene-specific and genome-wide effects of transcription machinery sumoylation are not well-understood. To explore this, we examined whether dramatically reducing cellular sumoylation levels affects the levels of mRNAs in budding yeast. RNA-seq was performed using polyadenylate (polyA)-enriched RNAs from the sumoylation-deficient ubc9-6 strain and its wild-type parent. Indeed, the abundance of hundreds of mRNAs were upregulated or downregulated in the mutant strain, implying that sumoylation has a widespread influence on RNA polymerase II (RNAPII) transcription or mRNA stability. Interestingly, about one third of mRNAs that were significantly upregulated in the ubc9-6 strain encode proteins that are involved in small molecule metabolic processes, suggesting that sumoylation is normally involved in restricting these pathways. As part of our analysis of transcription-related sumoylation, we determined that the large subunit of TFIIF, Tfg1, is a major target of sumoylation among the general transcription factors (GTFs) of RNAPII. To determine whether sumoylation of Tfg1 specifically is involved in regulating mRNA levels, we performed RNA-seq on polyA-enriched RNAs derived from strains expressing wild-type (Tfg1-HA) or sumoylation-deficient (Tfg1-K60,61R-HA) forms of Tfg1. However, with few exceptions, impairing Tfg1 sumoylation had no effect on the mRNA transcriptome. Together, our data demonstrate that gene expression is extensively regulated by sumoylation, but this likely involves the coordinated modification of multiple proteins at multiple levels.

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