Abstract
To generate new mechanistic hypotheses on the pathogenesis and disease progression of neuroHIV and identify novel therapeutic targets to improve neuropsychological function in people with HIV, we investigated host genes and pathway dysregulations associated with brain HIV RNA load in gene expression profiles of the frontal cortex, basal ganglia, and white matter of HIV+ patients. Pathway analyses showed that host genes correlated with HIV expression in all three brain regions were predominantly related to inflammation, neurodegeneration, and bioenergetics. HIV RNA load directly correlated particularly with inflammation genesets representative of cytokine signaling, and this was more prominent in white matter and the basal ganglia. Increases in interferon signaling were correlated with high brain HIV RNA load in the basal ganglia and the white matter although not in the frontal cortex. Brain HIV RNA load was inversely correlated with genesets that are indicative of neuronal and synaptic genes, particularly in the cortex, indicative of synaptic injury and neurodegeneration. Brain HIV RNA load was inversely correlated with genesets that are representative of oxidative phosphorylation, electron transfer, and the tricarboxylic acid cycle in all three brain regions. Mitochondrial dysfunction has been implicated in the toxicity of some antiretrovirals, and these results indicate that mitochondrial dysfunction is also associated with productive HIV infection. Genes and pathways correlated with brain HIV RNA load suggest potential therapeutic targets to ameliorate neuropsychological functioning in people living with HIV.
Highlights
The prevalence of severe human immunodeficiency virus (HIV)-associated dementia (HAD) has decreased since the introduction of antiretrovirals, but the incidence of milder and chronic forms of HIV-associated neurocognitive disorder (HAND) and HIV-associated major depressive disorder have increased[1,2,3,4,5,6,7,8,9,10]
We applied gene set enrichment analysis (GSEA), a computational method that assesses whether a priori-defined genesets show statistically significant differences between biological states[31], to compare gene expression profiles associated with high brain HIV RNA loads
Pathways that are representative of cytokine signaling were correlated with brain HIV RNA load in all three brain regions, consistent with the contribution of inflammatory processes to cortical, subcortical, and white matter injury[47]
Summary
The prevalence of severe human immunodeficiency virus (HIV)-associated dementia (HAD) has decreased since the introduction of antiretrovirals, but the incidence of milder and chronic forms of HIV-associated neurocognitive disorder (HAND) and HIV-associated major depressive disorder have increased[1,2,3,4,5,6,7,8,9,10]. We used gene set enrichment analysis (GSEA) for pathway analysis[31] in conjunction with genesets from the Molecular Signatures Database (MSigDb), including canonical pathways in the C2 collection, including Kyoto Encyclopedia of Genes and Genomes (KEGG)[32,33]. This approach aids interpretations of genome-wide expression profiles by revealing common biological processes that are dysregulated in pathological conditions. Genesets that correlated with brain HIV RNA load and were concordantly dysregulated in the three brain regions studied could mostly be grouped into three broad biological processes: greater inflammation, increased transcriptional evidence of neurodegeneration, and bioenergetics dysfunction. Results indicate that HIV expression is itself associated with mitochondrial dysfunction and that impairments in brain energetics are a central aspect of the progression and severity of neuroHIV
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