UC San Diego

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.