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Neuro-immune deconvolution analysis of OAS3 as a transcriptomic central node in HIV-associated neurocognitive disorders

Published:January 19, 2023DOI:https://doi.org/10.1016/j.jns.2023.120562

      Highlights

      • Microglia activation play a key role in progression of HIV-associated Neurocognitive Disorder (HAND).
      • Deconvolution method represents a new approach to define the brain cells' architecture HAND.
      • OAS3 is a 2′-5′-oligoadenylate synthetases high modulated in HIV infection.
      • In HAND/HIVE brains the high expression levels of OAS3 were associated with an inflammatory profile.
      • Neuronal activation profile is significantly activated in HAND patients with low OAS3 expression.

      Abstract

      Neurological complications of AIDS (NeuroAIDS) include primary HIV-associated neurocognitive disorder (HAND). OAS3 is an enzyme belonging to the 2′, 5′ oligoadenylate synthase family induced by type I interferons and involved in the degradation of both viral and endogenous RNA. Here, we used microarray datasets from NCBI of brain samples of non-demented HIV-negative controls (NDC), HIV, deceased patients with HAND and encephalitis (HIVE) (treated and untreated with antiretroviral therapy, ART), and with HAND without HIVE. The HAND/HIVE patients were stratified according to the OAS3 gene expression. The genes positively and negatively correlated to the OAS3 gene expression were used to perform a genomic deconvolution analysis using neuroimmune signatures (NIS) belonging to sixteen signatures. Expression analysis revealed significantly higher OAS3 expression in HAND/HIVE and HAND/HIVE/ART compared with NDC. OAS3 expressed an excellent diagnostic ability to discriminate NDC from HAND/HIVE, HAND from HAND/HIVE, HAND from HAND/HIVE/ART, and HIV from HAND/HIVE. Noteworthy, OAS3 expression levels in the brains of HAND/HIVE patients were positively correlated with viral load in both peripheral blood and cerebrospinal fluid (CSF). Furthermore, deconvolution analysis revealed that the genes positively correlated to OAS3 expression were associated with inflammatory signatures. Neuronal activation profiles were significantly activated by the genes negatively correlated to OAS3 expression levels. Moreover, gene ontology analysis performed on genes characterizing the microglia signature highlighted an immune response as a main biological process. According to our results, genes positively correlated to OAS3 gene expression in the brains of HAND/HIVE patients are associated with inflammatory transcriptomic signatures and likely worse cognitive impairment.

      Keywords

      Abbreviations:

      MD (microarray datasets), MeV (MultiExperiment Viewer), FDR (false discovery rate), CNS (central nervous system), NDC (non-demented HIV-negative controls), GSPC (genes significant positive correlated), GSNC (genes significant negative correlated), SDEG (Significantly Different Expressed Genes), AUC (area under the ROC curve), GSPC-OAS3 (genes significantly positively correlated to OAS3), GSNC-OAS3 (genes significantly negatively correlated to OAS3), HAND (HIV-associated neurocognitive disorder), ANI (asymptomatic neurocognitive impairment), MND (mild neurocognitive disorder), HAD (HIV associated dementia), ART (antiretroviral therapy), CSF (Cerebrospinal fluid), HIVE (HIV encephalitis)
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