Increased Levels of GDF15 Protein in the Brain are Associated with Neurocognitive Dysfunction in People with HIV
Ali Boustani1, Mary Ford1, Jacqueline kulbe1, Anna Laird1, Leeann Shu1, Matthew Spencer1, Ronald Ellis1, Jerel Fields1
1UC San Diego
Objective:
To investigate the relationship between GDF15 expression and HIV-associated NCI
Background:
HIV-associated neurocognitive impairment (NCI) remains a prevalent issue among people with HIV (PWH) despite advancements in antiretroviral therapy (ART). The pathogenesis of HIV-associated NCI is linked to chronic neuroinflammation caused by HIV and ART, which can lead to neuronal damage and neurodegeneration. Growth Differentiation Factor 15 (GDF15), a protein involved in inflammatory and metabolic stress responses, has emerged as a potential biomarker for various neurological conditions. Cannabidiol (CBD) is linked to anti-inflammation in cell culture and animal models. This study investigates the relationship between GDF15 expression and HIV-associated NCI.
Design/Methods:
We investigated its relationship with HIV-associated NCI in 22 PWH from the CNTN. Subjects underwent comprehensive neuropsychological exams within 12 months before death and were categorized based on cognitive performance. We examined GDF15 expression in brain tissues using immunoblotting, immunohistochemistry, and double immunolabeling and conducted in vitro experiments with brain cell models exposed to HIV-relevant stimuli.
Results:
The cohort was of similar age across HIV-associated NCI statuses (Mean=40.5), with a predominance of males (77%). The mean plasma viral load was 3627.3 copies/ml for cognitively normal PWH and 238200 copies/ml for people with HIV-associated NCI. GDF15 protein levels were significantly elevated in the frontal cortices of PWH with NCI compared to those without NCI. Increased GDF15 expression was observed in both gray and white matter, particularly in microglia, neurons, and astrocytes. In vitro experiments revealed that CBD, interleukin-1 beta, and ART modulated GDF15 expression.
Conclusions:
Findings indicate that GDF15 may play a role in the pathogenesis of HIV-associated NCI, possibly through neuroinflammatory mechanisms. The strong association between GDF15 levels and cognitive impairment severity suggests its potential as a biomarker for early detection and monitoring of NCI in PWH. Additionally, the modulatory effects of cannabidiol on GDF15 expression warrant further investigation as potential intervention strategy.
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