Dataset Information

Transcriptomic analysis of brain tissues identifies a role for CCAAT enhancer binding protein β in HIV-associated neurocognitive disorder.

ABSTRACT:

Background

HIV-associated neurocognitive disorders (HAND) persist in the era of combined antiretroviral therapy (ART) despite reductions in viral load (VL) and overall disease severity. The mechanisms underlying HAND in the ART era are not well understood but are likely multifactorial, involving alterations in common pathways such as inflammation, autophagy, neurogenesis, and mitochondrial function. Newly developed omics approaches hold potential to identify mechanisms driving neuropathogenesis of HIV in the ART era.

Methods

In this study, using 33 postmortem frontal cortex (FC) tissues, neuropathological, molecular, and biochemical analyses were used to determine cellular localization and validate expression levels of the prolific transcription factor (TF), CCAAT enhancer binding protein (C/EBP) β, in brain tissues from HIV+ cognitively normal and HAND cases. RNA sequencing (seq) and transcriptomic analyses were performed on FC tissues including 24 specimens from well-characterized people with HIV that had undergone neurocognitive assessments. In vitro models for brain cells were used to investigate the role of C/EBPβ in mediating gene expression.

Results

The most robust signal for TF dysregulation was observed in cases diagnosed with minor neurocognitive disorder (MND) compared to cognitive normal (CN) cases. Of particular interest, due to its role in inflammation, autophagy and neurogenesis, C/EBPβ was significantly upregulated in MND compared to CN brains. C/EBPβ was increased at the protein level in HAND brains. C/EBPβ levels were significantly reduced in neurons and increased in astroglia in HAND brains compared to CN. Transfection of human astroglial cells with a plasmid expressing C/EBPβ induced expression of multiple targets identified in the transcriptomic analysis of HAND brains, including dynamin-1-like protein (DNM1L) and interleukin-1 receptor-associated kinase 1. Recombinant HIV-Tat reduced and increased C/EBPβ levels in neuronal and astroglial cells, respectively.

Conclusions

These findings are the first to present RNAseq-based transcriptomic analyses of HIV+ brain tissues, providing further evidence of altered neuroinflammation, neurogenesis, mitochondrial function, and autophagy in HAND. Interestingly, these studies confirm a role for CEBPβ in regulating inflammation, metabolism, and autophagy in astroglia. Therapeutic strategies aimed at transcriptional regulation of astroglia or downstream pathways may provide relief to HIV+ patients at risk for HAND and other neurological disorders.

SUBMITTER: Canchi S

PROVIDER: S-EPMC7149918 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeThis study aimed to determine if people living with HIV (PLWH) in preclinical human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), with no clinical symptoms and without decreased daily functioning, suffer from brain volumetric alterations and its patterns.MethodFifty-nine male PLWH at the HAND preclinical stage were evaluated, including 19 subjects with asymptomatic neurocognitive impairment (ANI), 17 subjects with cognitive abnormality that does not reach ANI (Not reach ANI), and 23 subjects with cognitive integrity. Moreover, 23 healthy volunteers were set as the seronegative normal controls (NCs). These individuals underwent sagittal three-dimensional T1-weighted imaging (3D T1WI). Quantified data and volumetric measures of brain structures were automatically segmented and extracted using AccuBrain®. In addition, the multiple linear regression analysis was performed to analyze the relationship of volumes of brain structures and clinical variables in preclinical HAND, and the correlations of the brain volume parameters with different cognitive function states were assessed by Pearson's correlation analysis.ResultsThe significant difference was shown in the relative volumes of the ventricular system, bilateral lateral ventricle, thalamus, caudate, and left parietal lobe gray matter between the preclinical HAND and NCs. Furthermore, the relative volumes of the bilateral thalamus in preclinical HAND were negatively correlated with attention/working memory (left: r = -0.271, p = 0.042; right: r = -0.273, p = 0.040). Higher age was associated with increased relative volumes of the bilateral lateral ventricle and ventricular system and reduced relative volumes of the left thalamus and parietal lobe gray matter. The lower CD4+/CD8+ ratio was associated with increased relative volumes of the left lateral ventricle and ventricular system. Longer disease course was associated with increased relative volumes of the bilateral thalamus. No significant difference was found among preclinical HAND subgroups in all indices, and the difference between the individual groups (Not reach ANI and Cognitive integrity groups) and NCs was also insignificant. However, there was a significant difference between ANI and NCs in the relative volumes of the bilateral caudate and lateral ventricle.ConclusionMale PLWH at the HAND preclinical stage suffer from brain volumetric alterations. AccuBrain® provides potential value in evaluating HIV-related neurocognitive dysfunction.