Targeted plasma proteomics reveals a central role of upregulated TNFRSF proteins in HIV-associated stroke

Chronic inflammation drives vascular aging and stroke risk, yet circulating proteins linking immune activation to cerebrovascular events remain elusive. People with HIV (PWH) face elevated stroke risk beyond traditional vascular risk factors, even under antiretroviral therapy. We aimed to identify circulating proteomic signatures of HIV-associated stroke, characterize underlying biological pathways, and assess their longitudinal stability. We conducted a nested case-control study of 135 PWH with stroke (HIV + /Stroke + , mean age 64.2 years, 85.9% ischemic) and two matched control groups (HIV + /Stroke- and HIV - /Stroke - , n = 135 each), with longitudinal validation in 37 PWH who subsequently developed stroke (78.4% ischemic). Among 184 plasma proteins measured using Olink Cardiovascular panels, 16 were associated with stroke in PWH, centrally involving the tumor necrosis factor receptor superfamily (TNFRSF). TNFRSF proteins (TNFRSF10A, TRAIL-R2, TNFRSF14, and TNF-R1) were strongly inter-correlated (ρ > 0.77), with their co-expression module associated with stroke (adjusted OR = 1.75, P = 0.018). TNFRSF expression increased monotonically across HIV - /Stroke - , HIV + /Stroke - , and HIV + /Stroke+ groups. Longitudinal analysis confirmed post-stroke upregulation of these TNFRSF members, alongside MMP12 and TFF3, particularly in ischemic subtypes. These findings suggest coordinated TNFRSF upregulation as a potential signature associated with both HIV-related inflammation and cerebrovascular events, providing candidate biomarkers for future investigation.