Background
Brain health disorders (BHDs) remain prevalent among people with HIV (PWH) even when they take antiretroviral therapy (ART). The heterogeneity limits precision diagnostics and therapeutics. Nearly all PWH are also positive for herpesviruses (e.g., HSV-1, CMV) and can contribute to immune dysregulation and BHDs, yet their combined effects are poorly understood. We hypothesized that distinct antiviral antibody signatures in CSF and plasma would be associated with domain-specific cognitive impairment (CI).
Methods
Paired CSF and plasma from 88 ART-suppressed PWH were profiled with VirSIGHT, a Molecular Indexing of Proteins by Self-Assembly platform measuring IgG binding to 286,793 peptides from >500 viruses. Analyses included antibodies reactive in ≥10% of cohort. Associations with CI (global and seven cognitive domains) were evaluated using Welch’s T-tests and linear models adjusted for age, sex, and CD4+.
Results
Participants were predominantly male (81%) with mean age of 52, median CD4+ of 680 (current) and 200/µL (nadir). CSF IgG reactivity to 942 peptides were associated with working memory (WM) impairment (p<0.05), largely mapping to HSV-1/2, EBV, VZV, CMV, and HIV (Fig 1). Similar but less robust patterns emerged for executive function (EF), speed of information processing (SIP), and motor domains. Across domains, unimpaired people had higher antibody binding to most differentially reactive peptides, whereas impaired people had higher reactivity to HIV-1 envelope peptides. Few associations survived FDR correction in this small sample, but most effect sizes were medium-to-large (>0.5) and not substantially reduced by covariate adjustment. Plasma and CSF profiles were highly concordant. Total number of antibody reactivities did not differ for any domain CI.
Conclusions
High-resolution antibody profiling revealed associations between domain specific CI in PWH on ART and reactivities to multiple viruses especially HIV and herpesviruses. WM, SIP, and EF impairment showed the most differentially reactive peptides. HIV-1 env antibodies were consistently linked to worse cognition across domains, while higher most reactivities to multiple herpesvirus and HIV-1 non-env peptides were protective. Our findings support that individualized antiviral immune responses may contribute to BHDs. This pilot study generated testable hypotheses for mechanistic discovery and precision therapeutics – highlighting the value of unbiased antibody profiling to investigate viral-immune impacts on brain health.
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