Distinct inflammatory marker profiles of adolescents and young adults among the HIV risk, infection, and treatment spectrum

Abstract Youth living with or at HIV-risk exhibit distinct immune perturbations during HIV exposure, infection, and antiretroviral therapy (ART). Understanding immune perturbations is critical for development of tailored prevention and enhanced therapeutic strategies. We performed plasma proteomic profiling of 49 biomarkers using Luminex multiplex assay in 262 participants (mean age of 21.9 years), including healthy controls, high-risk youth without HIV (HRY), newly diagnosed youth living with HIV (NY), and previously diagnosed youth on ART for over 24 months (PY), and report distinct immune landscapes. Among HRY, we observe dysregulation of circulating interferon-driven inflammation. NY display overt systemic inflammation at diagnosis, which partially resolves but does not fully normalize within 24 months of ART. PY display largely normalized immune profiles, though circulating signatures consistent with residual checkpoint activation persist. Our results identify conserved and stage-specific, circulating inflammatory modulators and key transcriptional regulators delineating HIV susceptibility, progression, and long-term treatment responses.