Neuronal immune checkpoint HVEM in neuroHIV pathogenesis: implications for biomarkers and neuroinflammation 2482

Description HVEM (Herpesvirus Entry Mediator) is an immune checkpoint (ICP) that plays a crucial role in immune regulation, exerting both stimulatory and inhibitory effects depending on the specific ligands or receptors it engages. Although HVEM’s function in modulating immunity is well-recognized in the peripheral immune system and tumor microenvironments, its role and clinical relevance in the central nervous system (CNS) remain largely unexplored. In this study, we measured soluble HVEM (sHVEM) and other ICPs in cerebrospinal fluid (CSF) and plasma samples from people living with HIV (PLWH), both with and without HIV-associated neurocognitive disorders (HAND). We observed that sHVEM levels were elevated in PLWH, particularly in those with HAND, and positively correlated in the CSF with pro-inflammatory cytokines, including IFN-γ, IL-1β, and TNF-α. In vitro, HVEM expression was significantly upregulated in human neural cell lines, including neurons, in response to treatment with IFN-γ, IL-1β, and TNF-α. Additionally, recombinant HVEM-Ig could enhance T cell production of inflammatory cytokines, such as IFN-γ and TNF-α. In rhesus macaques (RMs), HVEM was constitutively expressed in brain neurons and showed marked upregulation in response to SIV infection. These findings suggest that neuronal HVEM may contribute to sHVEM levels and neuroinflammation in the CNS. Therefore, sHVEM holds potential as a biomarker for HAND and as a therapeutic target for neuroinflammatory conditions in PLWH.