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Significant Effects of Antiretroviral Therapy on Global Gene Expression in Brain Tissues of Patients with HIV-Associated Neurocognitive Disorders

ABSTRACT: Antiretroviral therapy (ART) has reduced morbidity and mortality in HIV infection; however HIV-1-associated neurocognitive disorders (HAND) persist despite treatment. We used microarray analysis in post-mortem brain tissues to determine ART effectiveness in the brain and to identify molecular signatures of HAND under ART.

ORGANISM(S): Homo sapiens

PROVIDER: GSE28160 | GEO | 2011/09/25

SECONDARY ACCESSION(S): PRJNA139681

REPOSITORIES: GEO

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Significant Effects of Antiretroviral Therapy on Global Gene Expression in Brain Tissues of Patients with HIV-Associated Neurocognitive Disorders

Project description:Antiretroviral therapy (ART) has reduced morbidity and mortality in HIV infection; however HIV-1-associated neurocognitive disorders (HAND) persist despite treatment. We used microarray analysis in post-mortem brain tissues to determine ART effectiveness in the brain and to identify molecular signatures of HAND under ART. We performed microarray analysis using Affymetrix Arrays in portmortem brain tissues from seven treated and eight untreated HAND patients and six uninfected controls.

2011-09-24 | E-GEOD-28160 | biostudies-arrayexpress

Single-cell RNA sequencing study of brain-derived cells from two individuals with HIV-associated neurocognitive dysfunction

Project description:The high prevalence of cognitive alterations in persons with HIV (PWH) despite effective antiretroviral therapy (ART) is associated with sustained neuroinflammation. Here, we uncover the signaling pathways that are essential for persistent immune activation and might underly development of HIV associated Neurocognitive Disorder (HAND). We analyze the brain proteome from PWH on ART during HAND progression. We observe that 73.3% of the significantly upregulated proteins in brains from PWH and HAND (compared to PWH with normal cognition) belong to immune pathways. Among them, 36.4% of upregulated innate immune-related proteins are within the type I interferon (IFN-I) signaling, suggesting that persistent IFN-I activation is central to HAND-associated brain immune activation. Single cell (sc)RNA-seq analysis confirmed that FN-I occurs mainly in astrocytes during acute HIV infection in the microglia-containing organoid (MCO) model of HIV infection and persistent in microglia in the brain of PLWH on ART. Of note, IFN-I persistence is independent of HIV status but associated with the induction of human endogenous retroviruses-W (HERV-W) Env during HAND progression after initial HIV infection and its associated immune activation. When induced, HERV-W Env directly activates IFN-I signaling in astrocytes, but not in microglia. Together, IFN-I signaling may be initiated directly in the astrocytes after acute HIV infection then sustained in the microglia during ART. IFN-I persists due to expression of HERV-W Env, thereby contributing to the persistent immune activation in the HAND brain on ART, independent of HIV and insensitive to ART. Our data link the neuroinflammation of persistent IFN-I signaling to the HAND brain on ART.

2024-05-25 | GSE233717 | GEO

Neuroinflammation and EIF2 signaling persist despite antiretroviral treatment in an HiPSC tri-culture model of HIV infection [scRNA-seq]

Project description:HIV-Associated Neurocognitive Disorders (HAND) affect over half of HIV-infected individuals, despite antiretroviral therapy (ART). Therapeutically targetable mechanisms underlying HAND remain elusive, partly due to a lack of a proper model. We developed a human-induced pluripotent stem cell (HiPSC) based model, independently differentiating HiPSCs into neurons, astrocytes, and microglia, and systematically combining to generate a tri-culture with or without HIV-infection and ART. Single cell RNAseq analysis on tri-cultures with HIV-infected microglia revealed inflammatory signatures in the microglia and EIF2 signaling in all three cell types. Treatment with the antiretroviral compound EFZ mostly resolved these signatures. However, EFZ increased RhoGDI and CD40 signaling in the HIV-infected microglia. This activation was associated with a persistent increase in TNFa production by microglia. This work establishes a tri-culture that recapitulates key features of HIV infection in the CNS and provides a new model to examine the effects of infection, its treatment, and other co-morbid conditions.

2020-04-27 | GSE143686 | GEO

Neuroinflammation and EIF2 signaling persist despite antiretroviral treatment in an HiPSC tri-culture model of HIV infection [bulk RNA-seq]

2020-04-27 | GSE143685 | GEO

HIV Infection and Antiretroviral Therapy Have Divergent Effects on Mitochondria in Adipose Tissue

Project description:Exploratory microarray analysis identified significant changes in gene expression in adipose tissue. These included changes in genes regulating lipid and steroid metabolic processes and electron carrier activity in HIV-infected patients receiving antiretroviral therapy (ART). Additional genes involved in metabolic processes and mitochondrial function were found to be up-regulated in the adipose tissue of HIV-positive patients compared with HIV-negative controls. To identify differential gene expression in different tissues (PBMC, muscle, adipose tissue) between HIV patient groups (HIV negative, HIV positive with ART, HIV positive without ART).

2011-07-07 | E-GEOD-30310 | biostudies-arrayexpress

Novel RNA-Seq Signatures Post-Methamphetamine and Oxycodone Use in a Model of HIV-Associated Neurocognitive Disorders

Project description:In the 21st century, the effects of HIV-associated neurocognitive disorders (HAND) have been significantly reduced in individuals due to the development of antiretroviral therapies (ARTs). However, the growing epidemic of polysubstance use (PSU) has led to concern for the effects of PSU on HIV-seropositive individuals. To effectively treat individuals affected by HAND, it is critical to understand the biological mechanisms affected by PSU including identification of novel markers. To fill this important knowledge gap, we used an in vivo HIV-Transgenic (HIV-Tg) animal model, to investigate the effects of the combined use of chronic methamphetamine (METH) and oxycodone (oxy). RNA-Seq analysis on the striatum - a brain region that is primarily targeted by both HIV and drugs of abuse - identified key differentially expressed markers post-METH and oxy exposure. Furthermore, ClueGO analysis and Ingenuity Pathway Analysis (IPA) revealed crucial molecular and biological functions associated with ATP-activated adenosine receptor, neuropeptide hormone activity, and the oxytocin signaling pathway to be altered between the different treatment groups. The current study further reveals the harmful effects of chronic PSU and HIV infection that can subsequently impact neurological outcomes in polysubstance users with HAND.

2024-06-30 | GSE236466 | GEO

Effect of HIV infection and antiretroviral therapy initiation on genome-wide DNA methylation patterns.

Project description:Background. Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) affects the HIV-induced epigenetic modifications. Methods. 184 individuals with HIV from the NEAT001/ANRS143 clinical trial (with pre-ART and post-ART samples [96 weeks of follow-up]) and 44 age-and-sex matched individuals without HIV were included. We compared genome-wide DNA methylation profiles in whole blood between groups adjusting for age, sex, batch effects, and leucocyte type heterogeneity. Findings. We identified 430 differentially methylated positions (DMPs) between HIV+ pre-ART individuals and HIV-uninfected controls. In participants with HIV, ART initiation modified the DNA methylation levels at 845 CpG positions and restored 49.3% of the changes found between HIV+ pre-ART and HIV-uninfected individuals. We only found 15 DMPs when comparing DNA methylation profiles between HIV+ post-ART individuals and participants without HIV. The Gene Ontology enrichment analysis of DMPs associated with untreated HIV infection revealed an enrichment in biological processes regulating the immune system and antiviral responses. In participants with untreated HIV infection, DNA methylation levels at top HIV-related DMPs were associated with CD4/CD8 ratios and viral loads. Changes in DNA methylation levels after ART initiation were weakly correlated with changes in CD4+ cell counts and the CD4/CD8 ratio. Interpretation. Control of HIV viraemia after 96 weeks of ART initiation restores most of the host DNA methylation changes that occurred before antiretroviral treatment of HIV infection.

2023-01-16 | GSE217633 | GEO

No reliable gene expression biomarkers of current or impending neurocognitive impairment in peripheral blood monocytes of persons living with HIV

Project description:Analysis of HIV-associated neurocognitive disorder (HAND) in peripheral monocytes at the gene expression level. The hypothesis tested in the present study was that monocyte gene expression would be predictive of HAND. Results provide information of the associations between monocytes and global neurocognitive function.

2017-10-07 | GSE104640 | GEO

Effect of Analytic Treatment Interruption of Antiretroviral Therapy on HIV Reservoirs and Immunological Parameters

Project description:We compared transcriptional profiles of CD4+ and CD8+ T lymphocytes from HIV infected individuals before and 1 year after interruption of antiretroviral therapy (ART).

2018-01-01 | GSE98902 | GEO

The National NeuroAIDS Tissue Consortium Brain Gene Array: Two types of HIV-associated neurocognitive impairment

Project description:Finding the differences in gene expression in three regions of the brain, basal ganglia, white matter, and frontal cortex, in normal, HIV infected, HIV infected with neurocognitive impairment, and HIV infected with both neurocognitive impairment and encephalitis patients.

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