The RNA-binding proteins SRP14 and HMGB3 control HIV-1 Tat mRNA processing and translation during HIV-1 latency
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Cell Suspension Culture
SUBMITTER: 
Sri Ramarathinam
LAB HEAD: Professor Anthony Purcell
PROVIDER: PXD025782 | Pride | 2021-06-14
REPOSITORIES: Pride
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Project description:The barrier to HIV-1 functional cure is caused by a small pool of latently infected resting CD4 T-cells that persist under antiretroviral therapy. Notably this latent reservoir of infected cells will produce replication-competent infectious virus once prolonged suppressive HAART is withdrawn. The reactivation of HIV-1 gene expression in T-cells harboring latent provirus in HIV-1 patients under HAART will likely result in depletion of this latent reservoir due to cytopathic effects and immune clearance. Many studies have investigated small molecules that reactivate HIV-1 gene expression but to date no latency reversal agent (LRA) has been identified to be specific, non-toxic, and effective in primary T-cells isolated from HIV-1 infected individuals undergoing long-term HAART. Stochastic fluctuations in HIV-1 tat gene expression have been attributed to be essential in the viral progression to latency. We hypothesized that exposing Tat to latently infected CD4 T-cells will result in potent latency reversal. Our results indicate the capacity of an engineered Tat to reactivate HIV-1 in latently infected cells from patients to a similar degree as the protein kinase C agonist PMA (Phorbol 12-Myristate 13-Acetate) while showing no T-cell activation nor any significant transcriptome perturbation in primary CD4 T-cells.
2023-09-05 | GSE235229 | GEO
Project description:HIV infection remains incurable due to the long-term persistence of latently infected cells, capable of refueling viremia upon antiretroviral therapy interruption. Shock-and-kill strategies aim to purge this latent reservoir by inducing the expression of viral genes, making infected cells visible for cleanup by the immune system. Here, we present a Tat mRNA formulation that, when combined with panobinostat, enables latency reversal at levels >3-fold higher than those reached with the most potent mitogens. We demonstrate that this mRNA formulation does not alter the transcriptome or phenotype of CD4 T cells, enabling the ex vivo assessment of infected cells upon latency reversal in a near-native state. Taking advantage of this characteristic, we show transcriptomic and proteomic differences between infected cells upon latency reversal and non-infected cells, including the upregulation of the cytotoxic protein granzyme A and a novel long non-coding RNA. Overall, we demonstrate that a Tat mRNA formulation enables potent reactivation of latent HIV, presenting a valuable research tool for studying the inducible HIV reservoir, as well as paving the way to a more effective shock-and-kill functional cure.
2023-11-09 | GSE247402 | GEO
Project description:Purpose: To investigate the impact of HIV protein Tat on macrophage transcriptome related to atherosclerosis development Methods: Peritoneal macrophages were isolated from myeloid specific IKKβ deficient LDLR-/- (IKKβΔMyeLDLR-/-) mice and their littermates (IKKβF/FLDLR-/-). Then the macrophages were treated with HIV protein Tat or control for 12 hr. Total RNA was extracted for RNAseq Results: HIV protein Tat treatment induces 2640 differentially expressed genes (DEGs) with false discovery rate (FDR) < 1 % and fold change > 3 in control macrophages. Those DEGs enriched in several biological processes that may contribute to atherogenesis. FAIME analysis demonstrated higher geneset scores of those GO terms in the Tat-treated macrophages from IKKβF/FLDLR-/- mice compared with the control ones. IKKβ deletion resulted in loss of geneset score in the macrophages of IKKβΔMyeLDLR-/- treated with HIV Tat. Conclusions: These results indicate that HIV protein Tat may affect many genes in macrophages related atherosclerosis development through IKKβ signaling.
2021-07-21 | GSE157833 | GEO
Project description:Our previous work demonstrated that HIV-1 infection progressively reduces TCR/CD3 expression due to a defect in CD3g gene transcripts. We further found that knocking down expression of the viral tat and/or nef genes was correlated with CD3g transcript and TCR/CD3 surface receptor levels on HIV-1 infected cells. This study was undertaken to investigate the direct effect of HIV-1 Tat expression on the TCR/CD3 machinery. Progressive downregulation from TCR/CD3hi to TCR/CD3lo to TCR/CD3− was observed on Tat expressing cells in a manner that emulated HIV-1 infection, with a lack of CD3g transcripts again responsible for the defect. When Tat cell cultures containing a mixture of TCR/CD3 surface densities were separated into TCR/CD3hi and TCR/CD3lo/− populations, they quickly reverted to a mixed CD3 phenotype. Thus, the progression TCR/CD3hi to TCR/CD3lo to TCR/CD3− is an active, reversible process with receptor levels fluctuating in response to intracellular dynamics. Examination of tat mutants found that the regions involved in Tat-mediated transactivation and TAR binding are required for TCR/CD3 downregulation while the lysine at position 28 and Tat exon 2 are dispensable. Global gene expression, assessed in association with TCR/CD3 downregulation in HIV-1 infected and Tat expressing cells, detected broad suppression of TCR/CD3 signaling, co-stimulation and negative regulatory genes along with target transcription factors, ligands and receptors. A significant subset of the genes altered in HIV-1 infected cells was specifically targeted by Tat in association with TCR/CD3 loss. Our finding that Tat negatively regulates many facets of the TCR/CD3 machinery has important implications for disease pathogenesis. We used microarrays to investigate changes in CD4+ T cell gene expression induced by expression of the HIV-1 Tat protein.
2015-12-31 | GSE33705 | GEO
Project description:Our previous work demonstrated that HIV-1 infection progressively reduces TCR/CD3 expression due to a defect in CD3g gene transcripts. We further found that knocking down expression of the viral tat and/or nef genes was correlated with CD3g transcript and TCR/CD3 surface receptor levels on HIV-1 infected cells. This study was undertaken to investigate the direct effect of HIV-1 Tat expression on the TCR/CD3 machinery. Progressive downregulation from TCR/CD3hi to TCR/CD3lo to TCR/CD3â was observed on Tat expressing cells in a manner that emulated HIV-1 infection, with a lack of CD3g transcripts again responsible for the defect. When Tat cell cultures containing a mixture of TCR/CD3 surface densities were separated into TCR/CD3hi and TCR/CD3lo/â populations, they quickly reverted to a mixed CD3 phenotype. Thus, the progression TCR/CD3hi to TCR/CD3lo to TCR/CD3â is an active, reversible process with receptor levels fluctuating in response to intracellular dynamics. Examination of tat mutants found that the regions involved in Tat-mediated transactivation and TAR binding are required for TCR/CD3 downregulation while the lysine at position 28 and Tat exon 2 are dispensable. Global gene expression, assessed in association with TCR/CD3 downregulation in HIV-1 infected and Tat expressing cells, detected broad suppression of TCR/CD3 signaling, co-stimulation and negative regulatory genes along with target transcription factors, ligands and receptors. A significant subset of the genes altered in HIV-1 infected cells was specifically targeted by Tat in association with TCR/CD3 loss. Our finding that Tat negatively regulates many facets of the TCR/CD3 machinery has important implications for disease pathogenesis. We used microarrays to investigate changes in CD4+ T cell gene expression induced by expression of the HIV-1 Tat protein. Examine changes in gene expression in HIV-1 Tat transduced cells compared with cells transduced with an antisense Tat sequence used as a control.
2015-12-31 | E-GEOD-33705 | biostudies-arrayexpress
Project description:Our previous work demonstrated that HIV-1 infection progressively reduces TCR/CD3 expression due to a defect in CD3g gene transcripts. We further found that knocking down expression of the viral tat and/or nef genes was correlated with CD3g transcript and TCR/CD3 surface receptor levels on HIV-1 infected cells. This study was undertaken to investigate the direct effect of HIV-1 Tat expression on the TCR/CD3 machinery. Progressive downregulation from TCR/CD3hi to TCR/CD3lo to TCR/CD3− was observed on Tat expressing cells in a manner that emulated HIV-1 infection, with a lack of CD3g transcripts again responsible for the defect. When Tat cell cultures containing a mixture of TCR/CD3 surface densities were separated into TCR/CD3hi and TCR/CD3lo/− populations, they quickly reverted to a mixed CD3 phenotype. Thus, the progression TCR/CD3hi to TCR/CD3lo to TCR/CD3− is an active, reversible process with receptor levels fluctuating in response to intracellular dynamics. Examination of tat mutants found that the regions involved in Tat-mediated transactivation and TAR binding are required for TCR/CD3 downregulation while the lysine at position 28 and Tat exon 2 are dispensable. Global gene expression, assessed in association with TCR/CD3 downregulation in HIV-1 infected and Tat expressing cells, detected broad suppression of TCR/CD3 signaling, co-stimulation and negative regulatory genes along with target transcription factors, ligands and receptors. A significant subset of the genes altered in HIV-1 infected cells was specifically targeted by Tat in association with TCR/CD3 loss. Our finding that Tat negatively regulates many facets of the TCR/CD3 machinery has important implications for disease pathogenesis. We used microarrays to investigate changes in CD4+ T cell gene expression induced by HIV-1 infection for comparison with the Tat expressing cells.
2015-12-31 | GSE33706 | GEO
Project description:HIV-1 Tat can modulate the expression of both HIV and cellular genes. In antigen-presenting cells Tat induces the expression of a subset of interferon-stimulated genes (ISGs) in the absence of interferons (IFNs). We investigated the genome-wide Tat association with cellular promoters in immature dendritic cells (iDC) and in monocyte derived macrophages (MDM). Chromatin immunoprecipitation (ChIP) of Tat together with chromatin profiling by ChIP-on-chip analysis demonstrated that Tat associates with the MAP2K6 and MAP2K3 promoters and mediates its increase, which also affects the induction of some ISGs.
2013-05-31 | GSE42191 | GEO
Project description:Our previous work demonstrated that HIV-1 infection progressively reduces TCR/CD3 expression due to a defect in CD3g gene transcripts. We further found that knocking down expression of the viral tat and/or nef genes was correlated with CD3g transcript and TCR/CD3 surface receptor levels on HIV-1 infected cells. This study was undertaken to investigate the direct effect of HIV-1 Tat expression on the TCR/CD3 machinery. Progressive downregulation from TCR/CD3hi to TCR/CD3lo to TCR/CD3â was observed on Tat expressing cells in a manner that emulated HIV-1 infection, with a lack of CD3g transcripts again responsible for the defect. When Tat cell cultures containing a mixture of TCR/CD3 surface densities were separated into TCR/CD3hi and TCR/CD3lo/â populations, they quickly reverted to a mixed CD3 phenotype. Thus, the progression TCR/CD3hi to TCR/CD3lo to TCR/CD3â is an active, reversible process with receptor levels fluctuating in response to intracellular dynamics. Examination of tat mutants found that the regions involved in Tat-mediated transactivation and TAR binding are required for TCR/CD3 downregulation while the lysine at position 28 and Tat exon 2 are dispensable. Global gene expression, assessed in association with TCR/CD3 downregulation in HIV-1 infected and Tat expressing cells, detected broad suppression of TCR/CD3 signaling, co-stimulation and negative regulatory genes along with target transcription factors, ligands and receptors. A significant subset of the genes altered in HIV-1 infected cells was specifically targeted by Tat in association with TCR/CD3 loss. Our finding that Tat negatively regulates many facets of the TCR/CD3 machinery has important implications for disease pathogenesis. We used microarrays to investigate changes in CD4+ T cell gene expression induced by HIV-1 infection for comparison with the Tat expressing cells. Examine changes in gene expression in TCR/CD3 negative HIV-1 infected cells compared to TCR/CD3 positive uninfected controls.
2015-12-31 | E-GEOD-33706 | biostudies-arrayexpress
Project description:HIV-1 Tat can modulate the expression of both HIV and cellular genes. In antigen-presenting cells Tat induces the expression of a subset of interferon-stimulated genes (ISGs) in the absence of interferons (IFNs). We investigated the genome-wide Tat association with cellular promoters in immature dendritic cells (iDC) and in monocyte derived macrophages (MDM). Chromatin immunoprecipitation (ChIP) of Tat together with chromatin profiling by ChIP-on-chip analysis demonstrated that Tat associates with the MAP2K6 and MAP2K3 promoters and mediates its increase, which also affects the induction of some ISGs. comparison of KG-1 cells expressing tTA control vs Tat or mutant TatSF2G48R57A
2013-05-31 | E-GEOD-42191 | biostudies-arrayexpress
Project description:HIV-1 Tat induces the expression of interferon (IFN)-inducible genes in immature dendritic cells (iDC) in the absence of IFN production. We evaluated how three alleles of Tat and some Tat mutants differ in cellular gene modulation and whether a similar gene induction pattern could be detected by treating cells with IFNM-bM-^@M-^Ys. The three alleles and mutants, with the exception of mutants TatSF21-47 and TatSF2G48-R57A that do not localize in the nucleous, modulated to different degrees IFN-inducible genes without concomitant induction of IFNM-bM-^@M-^Ys. The first exon TatSF21-72 and the minimal transactivator TatSF21-58, all induced genes to a significantly greater extent than full-length Tat. The 2nd exon appears to diminish the gene modulation that can be observed when the first exon alone is expressed. To investigate what domain of Tat are critical to the host-pathogen interactions that are Tat-dependent during HIV infection, we evaluated a variety of Tat-mutants and found that in antigen presenting cells, blood-derived myeloid iDC and macrophages, the second exon of Tat reduces innate immunological responses which are maximal when a Single exon Tat is expressed. 1X10e6 macrophages were infected with HIVBal (20 ng of p24/ 106 cells) for 10 days and with adenoviruses expressing TatHXB2 or LacZ control (5 pfu per cell). Cells infected with Ad-Tat or Ad-LacZ were collected at 24 hours and cells infected with HIV or treated with medium were harvested at 7d and 10d post-infection. THP-Mac were infected with Ad-Tat or Ad-tTA control for 24 hours. RNA was isolated and mRNA expression levels were analyzed by microarrays. adenovirus expressing HIV Tat for 30 hours. and then RNA was isolated, labeled, and prepared for hybridization on Affymetrix microarrays.
2013-06-01 | E-GEOD-42925 | biostudies-arrayexpress