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HIV-1 Tat protein promotes neuronal dysfunction through disruption of microRNAs [differentiated SH-5Y cells]

ABSTRACT: Over the last decade, small noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators in the expression and function of eukaryotic genomes. It has been suggested that viral infections and neurological disease outcome may also be shaped by the influence of small RNAs. This has prompted us to suggest that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. Therefore, using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs due to its characteristic features such as release from the infected cells and taken up by noninfected cells. Using microRNA array assay, we demonstrated that Tat deregulates the levels of several miRNAs. Interestingly, miR-34a was among the most highly induced miRNAs in Tat-treated neurons. Tat also decreases the levels of miR-34a target genes such as CREB protein as shown by real time PCR. The effect of Tat was neutralized in the presence of anti-miR-34a. Using in situ hybridization assay, we found that the levels of miR-34a increase in Tat transgenic mice when compared with the parental mice. Therefore, we conclude that deregulation of neuronal functions by HIV-1 Tat protein is miRNA-dependent. Human neurons SH-SY5Y were chosen to examine the impact of HIV-1 Tat protein on gene expression

ORGANISM(S): Homo sapiens

SUBMITTER: Bassel Sawaya

PROVIDER: E-GEOD-43534 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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HIV-1 Tat protein promotes neuronal dysfunction through disruption of microRNAs.

Project description:Over the last decade, small noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators in the expression and function of eukaryotic genomes. It has been suggested that viral infections and neurological disease outcome may also be shaped by the influence of small RNAs. This has prompted us to suggest that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. Therefore, using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs due to its characteristic features such as release from the infected cells and taken up by noninfected cells. Using microRNA array assay, we demonstrated that Tat deregulates the levels of several miRNAs. Interestingly, miR-34a was among the most highly induced miRNAs in Tat-treated neurons. Tat also decreases the levels of miR-34a target genes such as CREB protein as shown by real time PCR. The effect of Tat was neutralized in the presence of anti-miR-34a. Using in situ hybridization assay, we found that the levels of miR-34a increase in Tat transgenic mice when compared with the parental mice. Therefore, we conclude that deregulation of neuronal functions by HIV-1 Tat protein is miRNA-dependent. Using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs and mRNAs.

2013-02-12 | E-GEOD-44265 | biostudies-arrayexpress

HIV-1 Tat protein promotes neuronal dysfunction through disruption of microRNAs

Project description:Over the last decade, small noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators in the expression and function of eukaryotic genomes. It has been suggested that viral infections and neurological disease outcome may also be shaped by the influence of small RNAs. This has prompted us to suggest that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. Therefore, using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs due to its characteristic features such as release from the infected cells and taken up by noninfected cells. Using microRNA array assay, we demonstrated that Tat deregulates the levels of several miRNAs. Interestingly, miR-34a was among the most highly induced miRNAs in Tat-treated neurons. Tat also decreases the levels of miR-34a target genes such as CREB protein as shown by real time PCR. The effect of Tat was neutralized in the presence of anti-miR-34a. Using in situ hybridization assay, we found that the levels of miR-34a increase in Tat transgenic mice when compared with the parental mice. Therefore, we conclude that deregulation of neuronal functions by HIV-1 Tat protein is miRNA-dependent. Human fetal neurons were chosen to examine the impact of HIV-1 Tat protein on gene expression

2012-12-07 | E-GEOD-42423 | biostudies-arrayexpress

Deregulation of microRNAs by HIV-1 Vpr protein leads to the development of neurocognitive disorders [differentiated SH-5Y cells]

Project description:Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction. The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic reticulum-calcium release, (iii) activation of the oxidative stress pathway, (iv) mitochondrial dysfunction and v- synaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several microRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr plays a major role in neuronal dysfunction through deregulating microRNAs and their target genes, a phenomenon that could lead to the development of neurocognitive disorders. Human neurons SH-SY5Y were chosen to examine the impact of HIV-1 Vpr protein on gene expression

2013-01-17 | E-GEOD-43535 | biostudies-arrayexpress

Deregulation of microRNAs by HIV-1 Vpr protein leads to the development of neurocognitive disorders.

Project description:Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction. The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic reticulum-calcium release, (iii) activation of the oxidative stress pathway, (iv) mitochondrial dysfunction and v- synaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several microRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr plays a major role in neuronal dysfunction through deregulating microRNAs and their target genes, a phenomenon that could lead to the development of neurocognitive disorders. Using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Vpr) on the expression of miRNAs and mRNAs.

2013-02-12 | E-GEOD-44266 | biostudies-arrayexpress

HIV-1 Tat protein promotes neuronal dysfunction through disruption of microRNAs.

2013-02-12 | GSE44265 | GEO

Deregulation of genes in SH-SY5Y treated with supernatant from U-937-HIV-1 infected cells

Project description:It is well known that HIV-1 does not infect neurons, however neurons are the most affected cells by the virus. Several studies linked the deregulation of neuronal transcriptional machinery to single HIV proteins, however the impact of the all the viral proteins on neurons remain unknown. In here we infected U-937 cells with JR-FL strain of HIV-1. 21 days later, the supernatants were collected and subjected to p24ELISA to measure the level of the virus. Supernatant was then added to SH-SY5Y cells in culture for 24hrs. The cells were then collected, RNA isolated and subjected to gene array analysis. Human neuronal cell line, SH-SY5Y were chosen to examine the impact of HIV-1 supernatant prepared from U-937 infected cells on gene expression in neuronal cells.

2012-12-07 | E-GEOD-42615 | biostudies-arrayexpress

Deregulation of microRNAs by HIV-1 Vpr protein leads to the development of neurocognitive disorders

Project description:Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction. The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic reticulum-calcium release, (iii) activation of the oxidative stress pathway, (iv) mitochondrial dysfunction and v- synaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several microRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr plays a major role in neuronal dysfunction through deregulating microRNAs and their target genes, a phenomenon that could lead to the development of neurocognitive disorders. Human fetal neurons were chosen to examine the impact of HIV-1 Vpr protein on gene expression

2012-12-07 | E-GEOD-42424 | biostudies-arrayexpress

Identification of SART3 as a pre-miR-34a–binding protein

Project description:MicroRNAs (miRNAs or miRs) are small, noncoding RNAs that are implicated in the regulation of nearly all biological processes. Global miRNA biogenesis is altered in many cancers and RNA-binding proteins (RBPs) have been shown to play a role in this process, presenting a promising avenue for targeting miRNA dysregulation in disease. miR-34a exhibits tumor-suppressive functions by targeting cell cycle regulators CDK4/6 and anti-apoptotic factor Bcl-2, among other regulatory pathways such as Wnt, TGF-, and Notch signaling. Many cancers show downregulation or loss of miR-34a, and synthetic miR-34a supplementation has been shown to inhibit tumor growth in vivo; however, the post-transcriptional mechanisms by which miR-34a is lost in cancer are not entirely understood. Here, we have used a proteomics-mediated approach to identify Squamous cell carcinoma antigen recognized by T-cells 3 (SART3) as a putative pre-miR-34a-binding protein. SART3 is a spliceosome recycling factor and nuclear RBP with no previously reported role in miRNA regulation. We demonstrate that SART3 binds pre-miR-34a with specificity over pre-let-7d and begin to elucidate a new functional role for this protein in non-small lung cancer cells. Overexpression of SART3 led to increased miR-34a levels, downregulation of the miR-34a target genes CDK4 and CDK6, and cell cycle arrest in the G1 phase. In vitro binding studies showed that the RNA-recognition motifs within the SART3 sequence are responsible for selective pre-miR-34a binding. Collectively, our results present evidence for an influential role of SART3 in miR-34a biogenesis and cell cycle progression.

2019-10-14 | PXD015278 | Pride

Deregulation of microRNAs by HIV-1 Vpr protein leads to the development of neurocognitive disorders.

2013-02-12 | GSE44266 | GEO

Changes in the MicroRNA Expression Pattern Contribute to HIV-1 Tat-mediated Protection against Apoptosis and Impaired Cell Proliferation in CD4+ T Cells

Project description:HIV-1 infection changes the miRNA expression pattern in CD4+ T lymphocytes and its main regulator, Tat, has been appointed as an RNA silencing suppressor (RSS). Our group previously described that full-length Tat protects CD4+ T cells against FasL-mediated apoptosis and delays T-cell proliferation. Now we analyzed by microarrays and qRT-PCR the changes in the miRNA expression pattern of Jurkat cells induced by the intracellular expression of the two-exon Tat101 protein or the first-exon Tat72 in order to elucidate their role in the anti-apoptotic and anergic state exerted by Tat. It was determined that the expression of specific miRNAs such as hsa-miR-21, hsa-miR-222, hsa-miR-29a, and hsa-miR-1290 was up-regulated in Jurkat-Tat101. These miRNAs were related to the high activity of several transcription factors related to Tat such as NF-kB, SP1 and STAT3, and they repressed the expression of target mRNAs encoding proteins related to apoptosis and cell proliferation such as PTEN, PDCD4 and CDKN1B. In fact, mostly Jurkat-Tat101 showed an arrest at G2 phase and an impaired cytokinesis, resulting in giant, multilobulated nuclear cells. All these mechanisms would contribute to the role of Tat in HIV-1 immunosuppression and persistent infection, and the presence of Tat second exon would be essential.

2017-11-09 | GSE48800 | GEO

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