Central nervous system (CNS) transcriptomic correlates of human immunodeficiency virus (HIV) brain RNA load in HIV-infected individuals

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.

Osteopontin/secreted phosphoprotein‐1 harnesses glial‐, immune‐, and neuronal cell ligand‐receptor interactions to sense and regulate acute and chronic neuroinflammation

“…Moreover, dysregulation of dopaminergic signaling by chronic, even low‐grade system‐wide inflammation is strongly associated with psychiatric disorders 138,139 . A study in 2021 found that brain levels of HIV RNA in human tissue from the National NeuroAIDS Tissue Consortium (NNTC) correlate with increased inflammation in the basal ganglia and white matter 140 . Recognizing the limitations of the available human studies, variation in radioligands, and how radiotracer uptake was measured, 2,141 several TSPO neuroimaging studies in people with HIV found evidence of microglial activation 142‐145 .…”

Neurodegenerative phagocytes mediate synaptic stripping in Neuro-HIV

“…We found that the neuronal Janus Kinase-STAT1 signalling pathway is activated in Neuro-HIV cases with dense CD8 + T-cell infiltration, suggesting that even in the absence of viral infection in neurons, bystander exposure to IFN-γ may participate in neuronal damage and phagocyte-mediated synaptic loss. The absence of pSTAT1 in the other samples might reflect different disease stages, changes in viral load 107 or complementary pathways leading to synaptic loss and cognitive decline.…”

The potential role of HIV-1 latency in promoting neuroinflammation and HIV-1-associated neurocognitive disorder

“…In a new approach to measure the relationship between HIV-1 replication, inflammation, and neurodegeneration, correlations were established between host gene expression patterns and brain HIV-1 RNA in transcriptional profiles derived from postmortem samples obtained from the National NeuroHIV Tissue Consortium [36]. Viral load directly correlated with increased expression of cytokine and IFN signaling pathways, but was inversely correlated with gene pathways that were relevant to oxidative phosphorylation, electron transfer, and the tricarboxylic acid cycle, suggesting that mitochondrial dysfunction might have also been linked to productive HIV-1 infection [36]. Similarly, histological studies of brain sections of PLWH revealed the elevated expression and functional activation of p53 in microglia, whereas deletion or functional suppression of p53 appeared to suggest reduced inflammation relative to controls, based on transcriptional profiles [37].…”

“…To reconcile the contradictory observations that virus persistence, neuroinflammation, and systemic inflammation are all associated with HAND but do not correlate well with each other, we propose that the central molecular mechanism underlying HAND may be the emergence of HIV-1 from proviral latency due to inflammation and microglial dysregulation. This type of intermittent viral growth at the cellular level can be considered to be a specialized form of arising viral persistence since none of the existing ART drugs target proviral transcription or prevent reactivation of the latent HIV-1 provirus [36].…”