Cerebrospinal Fluid Cytokine Expression and Relationships With Neurological Measures in Virologically Controlled People With HIV

Objective Quantify cytokines in cerebrospinal fluid (CSF) of virologically suppressed people with HIV (PWH) and people without HIV (PWoH) and correlate these with neuroimaging, neuropsychometric (NP), and neurodegenerative measurements. Methods CSF samples were collected from virologically suppressed PWH and demographically matched PWoH under a natural history protocol. Participants underwent annual lumbar puncture, magnetic resonance imaging (MRI) brain scans, and NP testing at the National Institutes of Health (NIH). Using a magnetic bead assay, concentrations of 30 cytokines were measured in 136 PWH and 30 PWoH CSF samples, from 82 PWH and 25 unique PWoH participants. Results Thirteen cytokines – IP‐10/CXCL10, G‐CSF, GM‐CSF, IL‐7, IL‐1ra, IL‐1α, MIP‐1β/CCL4, IL‐15, TNF‐α, IFN‐α2, IL‐10, IL‐8/CXCL8, and IL‐β – were significantly higher ( p < 0.05) in the CSF of PWH compared to PWoH. Five others were elevated, and one decreased, in PWH ( p = 0.05–0.10). Seven cytokines (EGF, IL‐15, IL‐6, IP‐10/CXCL10, MCP‐1/CCL2, MIP‐1α/CCL3, and TNF‐α) positively correlated with white matter lesion burden and 4 (eotaxin/CCL11, G‐CSF, GM‐CSF, and IL‐1ra) with white matter volume in PWH. Significant positive correlations were seen between cytokines, including IP‐10/CXCL10, MIP‐1α/CCL3, MIP‐1β/CCL4, IL‐15, IL‐6, and TNF‐α, and NP scores. IL‐10, IL‐15, IL‐8/CXCL8, IP‐10/CXCL10, MCP‐1/CCL2, MIP‐1α/CCL3, and VEGF positively correlated with CSF total tau and neurofilament light levels. Principal component analysis revealed discrete subsets of PWH. Demographics and comorbidities did not significantly impact differences between PWH and PWoH. Interpretation Elevated expression of several cytokines in the CSF of virologically suppressed PWH indicates persistent immune activity and supports the existence of a central nervous system (CNS) reservoir. Numerous cytokines showed favorable associations with NP data, including “proinflammatory” cytokines such as IL‐6 and TNF‐α and several chemotactic cytokines, whereas some “anti‐inflammatory” cytokines such as IL‐10 correlated positively with unfavorable neurodegenerative markers. Our findings suggest that cytokine functions in the CNS of PWH vary from the periphery, are pleiotropic and potentially protective, and evolve over time. ANN NEUROL 2026