HIV Vpr induces demethylation of the SNCA antisense promoter leading to neurocognitive impairment

Alpha-synuclein (α-Syn) aggregation is a hallmark of neurodegenerative diseases. In individuals with HIV-1, cognitive impairments are associated with α-Syn accumulation and aggregation. The direct mechanistic link between α-Syn dysregulation and HIV-associated neurocognitive disorders (HAND) remains unclear. Emerging evidence suggests epigenetic changes, particularly DNA demethylation, play a role in α-Syn regulation. We show that the HIV-1 protein Vpr demethylates the antisense promoter (AS-1) within intron 1 of the SNCA gene, leading to increased α-Syn expression. Elevated α-Syn levels promote its aggregation, resulting in synaptic dysfunction and impaired mitochondrial transport. These processes contribute to the development of HAND. Additionally, we find that Vpr's activation of AS-1 depends on demethylation; DMOG, a Tet inhibitor, reverses this demethylation and reduces Vpr-induced activation of AS-1. Our results indicate that α-Syn dysregulation contributes to cognitive decline in people living with HIV and imply that targeting α-Syn regulatory pathways could mitigate HIV-related neurodegeneration. To our knowledge, this is the first study to demonstrate that an HIV protein epigenetically activates the SNCA antisense promoter, linking viral infection to α-synuclein deregulation. Future research should explore how AS-1 demethylation causes neuronal dysfunction and examine the broader effects of α-Syn dysregulation on neuronal health.