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Single-Nucleus Multiomic Analysis Reveals Immune-Metabolic Reprogramming Consistent With Maladaptive Trained Immunity
Siera Martinez1, Anelia Horvath1, Luke Johnson1
1The George Washington University School of Medicine and Health Sciences, Washington, Washington, DC, USA.
Glia
|June 26, 2026
Summary
Maladaptive trained immunity may drive neuroinflammation in people with HIV, causing persistent cognitive issues despite treatment. This involves immune cell reprogramming, metabolic changes, and epigenetic alterations in the brain.
Area of Science:
- Neuroimmunology
- Neurovirology
- Epigenetics
Background:
- HIV-associated neurocognitive disorders (HAND) persist in people with HIV (PWH) even with effective antiretroviral therapy.
- Persistent immune activation is suspected to cause ongoing neurological dysfunction in PWH.
- Maladaptive trained immunity (TRIM), a form of innate immune reprogramming, is a proposed mechanism for sustained inflammation in HAND.
Purpose of the Study:
- To investigate the role of maladaptive trained immunity in the pathogenesis of HAND.
- To compare multiomic profiles of brain tissue from PWH with different HAND severities and HIV-uninfected individuals.
Main Methods:
- Single-nucleus RNA sequencing (snRNA-seq) and ATAC sequencing (snATAC-seq) on post-mortem brain tissue.
- Comparison of PWH (with HIV-associated dementia or asymptomatic neurocognitive impairment) and HIV-uninfected (PWoH) datasets.
- Analysis focused on glial and neuronal cell types, examining immune signaling, metabolism, and epigenetic modifications.
Main Results:
- Glia, particularly microglia, in PWH showed enhanced innate immune signaling (NLRP3, TLR2/4) and inflammatory mediator upregulation.
- Coordinated cholesterol remodeling and partial glycolytic reprogramming were observed in glia.
- Epigenetic analysis revealed increased chromatin accessibility at inflammatory, cholesterol regulatory (RXRA, APOE), and glycolytic loci.
- Distinct patterns were observed between HIV-associated dementia and asymptomatic neurocognitive impairment, suggesting selective reorganization.
- Neurons showed primarily bystander epigenetic changes.
Conclusions:
- Multiomic data support the hypothesis of maladaptive trained immunity sustaining neuroinflammation in HAND.
- Key features align with trained immunity hallmarks: concordant transcriptional/epigenetic priming, metabolic rewiring, and persistence despite viral suppression.
- Further functional studies are needed to validate these findings.
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