Linking neuroinflammation and neurodegeneration to cognitive decline in HIV

Background and objectives: We investigated the relationship between cerebrospinal fluid (CSF) and plasma biomarkers of inflammation, neurodegeneration, and neurocognitive performance in people with HIV (PWH), using longitudinal samples from two previously published cohorts: ACTG A5090 (virally suppressed on antiretroviral therapy, ART) and A736 (ART-naïve or failing). Methods: We analyzed paired CSF and plasma samples, as well as 7-domain standardized neurocognitive test scores, at baseline and 24 weeks. Biomarkers included markers of inflammation (e.g., TNF-α, IL-6, IP-10) and neurodegeneration (e.g., NFL, p-Tau217, Aβ42), which were quantified via high-sensitivity immunoassays. Associations with cognition were tested using regression, mediation, and interaction models. Results: < 0.15). Exploratory mediation analysis suggested CSF TNFα, but not plasma TNFα, partially mediated the effect of CSF HIV RNA on cognition (indirect β = 0.14, 95% CI: 0.045-0.235, p = 0.006), though this finding requires replication in larger cohorts. Within-compartment biomarker correlations were stronger in CSF than plasma, and cross-compartment agreement was highest for TNFα, GFAP, and NFL. ART initiation in A736 led to significant declines in CSF IL-6, IL-10, and TNFα; no changes were observed in A5090. Exploratory interaction models suggested that astrocytic activation may amplify tau-related cognitive risk, but these effects were not statistically reliable when analyses were restricted to participants with complete data for GFAP, tau biomarkers, and cognitive scores. Discussion: These results suggest a potential role of CSF TNFα in mediating the neurocognitive effects of HIV and highlight compartment-specific inflammatory dynamics. Plasma TNFα, GFAP, and NFL may serve as peripheral indicators of CNS pathology, though with only moderate concordance. Astrocyte-tau interactions require cautious interpretation pending replication in larger cohorts.