Persistent Type I Interferon Signaling in the Brain of People with HIV under ART with Cognitive Impairment

To examine the mechanisms that drive persistent neuroinflammation, we analyzed the proteome from 27 HIV-infected brains on antiretroviral therapy (ART) with different stages of HIV-associated neurocognitive disorders (HAND) by tandem mass tag quantitative proteomics. We observed that 73.3% of the upregulated proteins were from immune pathways, among which 36.4% were within the type I interferon (IFN-I) signaling. Single-cell RNA-seq analysis revealed that IFN-I signaling persisted in the brain microglia isolated from people with HIV (PWH) on suppressive ART. During the acute HIV infection, IFN-I signaling was activated in astrocytes in the brain organoids while it remained activated in the HAND brains even with undetectable HIV. HAND progression was associated with human endogenous retroviruses-W (HERV-W) Env expression in the HAND brains on suppressive ART. When overexpressed, HERV-W Env induced IFNβ in astrocytes. These findings point to a persistent IFN-I activation in the glial cells in HAND brains, suggesting a mechanistic link of sustained neuroinflammation with the prevalence of cognitive impairment in HAND receiving effective ART.