Intrathecal production of anti-EBV Viral Capsid Antigen IgG is associated with Neurocognition and tau pathology in people with HIV

Objective: HIV and EBV co-infection has been linked to increased immune activation and larger HIV reservoir. We assessed whether anti-EBV humoral responses are associated with increased cerebrospinal fluid (CSF) inflammation and with neurocognitive impairment (NCI) in people with HIV (PWH). Design: Cross-sectional analysis in 123 EBV-seropositive PWH either on antiretroviral therapy (n = 70) or not. Methods: Serum and CSF anti-EBV Viral Capsid Antigen Immunoglobulin G (anti-EVI) and CSF EBV DNA were measured by commercial immunoassay and RT-PCR. Seventy-eight participants without neurological confounding factors underwent neurocognitive assessment (Global Deficit Score, GDS). CSF total tau and 181-phosphorylated-tau (ptau) were measured by immunoassays together with biomarkers of blood-brain barrier (BBB) integrity, immune activation, astrocytosis, and intrathecal synthesis. Logistic and linear regressions and moderation analysis were used to investigate the relationships between CSF anti-EVI, GDS, and biomarkers. Results: Twenty-one (17.1%) and twenty-two participants (17.9%) had detectable CSF anti-EVI (10.5-416.0 U/mL) and CSF EBV DNA (25-971 cp/mL). After adjusting for BBB integrity, age, and clinical factors, the presence of CSF anti-EVI was only associated with serum levels of anti-EVI, and not with CSF EBV DNA. CSF anti-EVI and tau and ptau showed reciprocal interactions affecting their associations with GDS. After adjusting for demographics and clinical parameters, higher CSF anti-EVI levels were associated with worse GDS (aβ 0.45, p < 0.001), and CSF levels of tau and ptau had moderate the strength of this association (models'p < 0.001). Conclusions: Humoral immune responses against EBV within the central nervous system may contribute to NCI of PWH through mechanisms that involve neuronal injury.