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White Matter Abnormalities Linked to Interferon, Stress Response, and Energy Metabolism Gene Expression Changes in Older HIV-Positive Patients on Antiretroviral Therapy
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To better understand pathways underlying HAND pathogenesis, we assembled a cohort of 58 subjects (34 HIV+ and 24 HIV-) with available postmortem frozen brain tissue and evaluated gene expression patterns (n = 933 genes) in frontal lobe subcortical white matter using the NanoString nCounter platform.
HIV-positive and HIV-negative cases from four sites in the National NeuroAIDS Tissue Consortium were combined to form a cohort of 34 HIV+ subjects and 24 HIV- controls. HIV+ subjects were further divided into groups with (n = 18) or without (n = 16) neurocognitive impairment (NCI), based on the available clinical data and neuropsychological evaluations.
HIV-associated inflammation and oxidative stress are associated with elevated calcium levels, activation of the unfolded protein response, and mitochondrial dysfunction [27]
Taken together, the clinical, laboratory, histological, and gene expression data suggest a model in which chronic HIV infection and multiple comorbidities lead to cognitive deficits due in part to white matter damage. In HIV+ individuals, expression of inflammation and stress response genes is increased, while expression of oxidative phosphorylation genes is decreased, consistent with a model in which chronic inflammation and decreased mitochondrial function may both contribute to generation of increased reactive oxygen species (ROS) and stress responses. Increased ROS may further contribute to mitochondrial dysfunction by damaging mitochondrial DNA. Oligodendrocytes are particularly vulnerable to oxidative damage, providing a potential explanation for inflammation-mediated myelin pallor, which along with arteriosclerosis and vascular compromise leads to white matter damage and neurological dysfunction. Decreased oligodendrocytes and myelin density are associated with aging and vascular dementia, due in part to the susceptibility of myelin-associated glycoprotein (MAG) to ischemia, and accumulation of degenerating myelin basic protein (MBP) [19]. Comorbidities including vascular, neurodegenerative, and systemic/metabolic diseases are all expected to exacerbate the primary effects of HIV infection. Given this scenario, therapies that decrease chronic inflammation while promoting mitochondrial integrity may help to preserve white matter integrity in older HIV+ individuals.
This is the largest study to date to evaluate gene expression changes in frontal lobe white matter in HIV+ individuals on HAART. White matter dysfunction has emerged as a key component of normal aging and in neurodegenerative diseases, and our study supports a critical role in HIV pathogenesis in the brain of virally suppressed subjects. Differentially expressed genes were identified and mapped into pathways and networks, and a core signature predicting HIV status was identified and validated using results from prior studies.
These findings confirm the critical role of interferon response-, stress response-, energy metabolism-, MHC-1-, T cell-, myeloid-, and oligodendrocyte-associated genes in HAND pathogenesis. No differentially expressed genes or specific patterns distinguished HIV+ subjects by cognitive status, possibly reflecting heterogeneous subtypes within the NCI+ group, many of which were NPI-O rather than HAND.
Further studies with larger cohorts of individuals who have neuropsychologically confirmed impairment, multiple anatomic sites, and evaluation of specific cell types at the single-cell level will aid in better understanding of the cellular pathways involved and may lead to identification of drug targets or modifiable risk factors to preserve white matter integrity and cognitive function in the aging HIV+ population.


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