Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Drug repurposing for the treatment of HIV-Associated Neurocognitive Disorder by AI-based literature mining

ABSTRACT: HIV-1 Associated Neurocognitive Disorder (HAND) is a common and clinically detrimental complication of HIV infection. Viral proteins including Tat, released from infected cells, cause neuronal toxicity. Substance abuse in HIV-infected patients greatly exacerbates the severity of neuronal damage. To repurpose small molecule inhibitors for anti-HAND therapy, we employed MOLIERE, an AI-based literature mining system that we developed. All human genes were analyzed and prioritized by MOLIERE to find previously unknown targets connected to HAND. The list was narrowed to those with known small molecule inhibitors developed for other applications and lacking systemic toxicity in animal models. We tested the activity of small molecules targeted against the proteins of five prioritized genes to protect against the combined neurotoxicity of HIV-Tat and cocaine in primary neuronal cultures. Four prevented Tat and cocaine toxicity. The compounds are: the FDA approved drugs Amlexanox and Tazemetostat (EPZ-6438), Itaconate and Senicapoc. Despite the disparate molecular targets of these drugs, analysis revealed a common mechanism of neuroprotection; namely that modulation of astrocyte and microglia status prevents the toxicity of Tat and cocaine.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE269380 | GEO | 2024/10/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

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

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 neurons SH-SY5Y were chosen to examine the impact of HIV-1 Tat protein on gene expression

2013-01-17 | E-GEOD-43534 | biostudies-arrayexpress

A chronic, low-dose treatment with methamphetamine modulates genes implicated in neurodegeneration in a transgenic model of NeuroHIV

Project description:Methamphetamine (METH) is a frequently abused addictive psychostimulant. METH use is highly prevalent in people living with HIV (PLWH). The HIV and drug interaction may promote progression of HAND, as PLWH who uses METH reportedly have increased neuronal injury, cognitive impairment and viral load. However, low concentration of METH has an approved clinical use as a treatment for patients diagnosed with attention-deficit/hyperactivity disorder (ADHD). Recent studies have also reported potential non-injurious effects via low-dose METH exposure, that improved learning and memory, and limited neuronal injury. This suggests that the specific dosage of METH plays a key role in determining whether the psychostimulant effects will be associated with apparent neurotoxicity or not. This study explored in vivo the effects of a long-term, low-dose METH regimen (12 weeks) in the HAND animal model with inducible expression of HIV-1 transactivator of transcription (Tat). In our observation, low dose of METH has a modulatory effect on learning and memory in the presence of the pathology-inducing HIV regulatory protein Tat. The observations from this study create the framework for future identification of potential targets for the treatment of neuroHIV/HAND in the context of psychostimulant use.

2024-04-01 | GSE255016 | GEO

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

2013-02-12 | GSE44265 | GEO

Quantitative proteomic analysis of HIV-1 Tat-induced dysregulation in SH-SY5Y neuroblastoma cells

Project description:Despite affecting up to 70% of HIV+ patients and being the leading cause of dementia in patients under 40 years, the molecular mechanisms involved in the onset of HAND are not well understood. To address this, we performed SILAC-based quantitative proteomic analysis on HIV-Tat treated SH-SY5Y neuroblastoma cells. Isolated protein was fractionated by SDS-PAGE and analysed by nLC-MS/MS on an Orbitrap Velos. Using MaxQuant, we identified and quantitation 3077 unique protein groups. Statistical analysis identified 407 differentially regulated proteins, of which 29 were identified as highly significantly and stably dysregulated using an additional standard deviation-based cutoff. GO-term analysis shows dysregulation in both protein translation machinery as well as cytoskeletal regulation which have both been implicated in other dementias. In addition, several key cytoskeletal regulatory proteins such as ARHGEF17, the Rho GTPase, SHROOM3 and CMRP1 are down-regulated. Together, we show that HIV-Tat can dysregulate neuronal cytoskeletal regulatory proteins which could lead to the major HAND clinical manifestation - synapse loss.

2017-01-24 | PXD004241 | Pride

Quantitative proteomic analysis of HIV-1 Tat-induced dysregulation in SH-SY5Y neuroblastoma cells

2019-03-18 | MSV000083590 | MassIVE

Tat RNA silencing suppressor activity contributes to perturbation of lymphocyte miRNAs by HIV-1

Project description:Herein expression trends of host miRNA were measured in CEMx174 lymphocytes infected with HIV-1NL4-3 or derivative strains deficient in Tat RSS activity (RSS) or vif-/vpr (VV), or unexposed to virus. As expected from previous studies, miRNA trends were different in naive and HIV-1 infected cells. Moreover, miRNA expression trends were similar for HIV-1 and vif-/vpr-deficient HIV-1, but diverged for RSS. Rather than generalized changes in miRNA levels, HIV-1 bearing the Tat K51A RSS mutation changed the steady state of a subset of miRNAs. The results are attributable to reduction in miRNA stability or change in miRNAs activity that altered steady state expression. Comparison of the miRNA expression trends in patient PBMC and the CEMx174 lymphocytes determined >50% overlap with a subset of miRNAs identified in patients, supporting the utility of HIV-1 cell culture model to refine experimental design with patient samples, which represent miRNA profiles of co-isolated infected and uninfected cells. Our results indicate that ablation of Tat RNA silencing suppressor activity in HIV-1 changes the steady state of a subset of host mature miRNA. The observation reinforces the concept of active HIV-1 interplay with host small RNAs that modulate replication and spread. The study validated the utility of derivative HIV-1 strains to explore the interface of viral genes with host small RNA activity. In this study the microRNA profiles of CEMx174 cells infected with HIV-1 NL4-3 or derivative viruses deficient in Vif/Vpr or Tat RNA silencing suppressor activity were compared to mock infected cells. The samples were analyzed in duplicate.

2011-03-01 | E-GEOD-21892 | biostudies-arrayexpress

T cell stimulation alters the HIV-1 reservoir by differential activation of proviral chromatin

Project description:The reservoir of latently HIV-1 infected cells is heterogeneous. To achieve an HIV-1 cure the reservoir of activatable proviruses should be removed, whereas permanently silenced proviruses may be tolerated. We have developed a method to assess the proviral nuclear microenvironment in single cells. Latently HIV-1 infected cells were transduced with a zinc finger protein specifically binding to the HIV-1 promoter, producing a fluorescent signal as the viral transactivator Tat is recruited to the HIV-1 promoter. In these cells we assessed the proviral chromatin composition simultaneously with the proviral activation. By linking the Tat promoter recruitment to viral activation, we dissected the mechanisms of HIV-1 reactivation and the consequences of HIV-1 production. A pulse of promoter-associated Tat was identified that contrasts to the continuous production of viral proteins. As expected, promoter H3K4me3 led to massive expression of the provirus following T cell stimulation. However, the activation induced cell cycle arrest and death resulted in an expanded surviving cell fraction with proviruses encapsulated in repressive chromatin. Further, this model can be used to reveal mechanisms of action of small molecules. In a proof-of-concept study we determine the effect of CBP/P300-inhibitor GNE049. We found that only active enhancers, associated with H3K4me1 and H3K27ac, efficiently recruit Tat, as GNE049 that specifically inhibits enhancer H3K27ac also depletes promoter Tat. Despite the absence of Tat, HIV-1 latency reversal still occurred. Single cell assessment of the chromatin composition of the latent HIV-1 proviruses revealed how T cell stimulation modulates the proviral activity and the subsequent fate of the infected cell.

2021-10-04 | GSE183275 | GEO

Human iPSC-derived neurons reveal NMDAR-independent dysfunction following HIV-associated insults

Project description:The central nervous system encounters a number of challenges following HIV infection, leading to increased risk for a collection of neurocognitive symptoms clinically classified as HIV-associated neurocognitive disorders (HAND). Studies attempting to identify causal mechanisms and potential therapeutic interventions have historically relied on primary rodent neurons, but a number of recent reports take advantage of iPSC-derived neurons in order to study these mechanisms in a readily-reproducible, human model. We found that iPSC-derived neurons differentiated via an inducible neurogenin-2 transcription factor were resistant to gross toxicity from a number of HIV-associated insults previously reported to be toxic in rodent models, including HIV-infected myeloid cell supernatants and the integrase inhibitor antiretroviral drug, elvitegravir. Further examination of these cultures revealed robust resistance to NMDA receptor-mediated toxicity. We then performed a comparative analysis of iPSC neurons exposed to integrase inhibitors and activated microglial supernatants to study sub-cytotoxic alterations in micro electrode array (MEA)-measured neuronal activity and gene expression, identifying extracellular matrix interaction/morphogenesis as the most consistently altered pathways across HIV-associated insults. These findings illustrate that HIV-associated insults dysregulate human neuronal activity and organization even in the absence of gross NMDA-mediated neurotoxicity, which has important implications on the effects of these insults in neurodevelopment and on the interpretation of primary vs. iPSC in vitro neuronal studies.

2024-01-20 | GSE250609 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data