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

## TL;DR

This study shows that an HIV protein causes changes in DNA that increase alpha-synuclein levels, leading to brain problems in HIV patients.

## Contribution

The first study to show that an HIV protein epigenetically activates the SNCA antisense promoter.

## Key findings

- HIV-1 Vpr demethylates the SNCA antisense promoter, increasing alpha-synuclein expression.
- Vpr-induced demethylation is reversed by Tet inhibitors like DMOG, reducing SNCA activation.
- Alpha-synuclein dysregulation contributes to synaptic dysfunction and HIV-related neurodegeneration.

## Abstract

Human immunodeficiency virus type 1 (HIV-1) alpha-synuclein (α-Syn) aggregation is a hallmark of neurodegenerative diseases. Accumulation and aggregation of α-Syn are often observed in individuals with HIV-1 cognitive impairments. The direct mechanistic link between α-Syn dysregulation and HIV-associated neurocognitive disorders (HAND) remains unclear. Emerging evidence suggests that epigenetic changes, particularly deoxyribonucleic acid (DNA) demethylation, influence α-Syn regulation. We show that the HIV-1 protein viral protein R (Vpr) demethylates the antisense promoter within intron 1 of the alpha-synuclein gene (SNCA), potentially contributing to increased α-Syn expression. Elevated α-Syn promotes aggregation, causing synaptic dysfunction and impaired mitochondrial transport. These processes contribute to the development of HAND. Furthermore, we find that Vpr’s activation of the SNCA antisense promoter depends on demethylation; dimethyloxaloylglycine (DMOG), a ten-eleven translocation (Tet) inhibitor, reverses this demethylation and reduces Vpr-induced SNCA antisense activation. Our findings suggest that α-Syn dysregulation plays a role in cognitive decline among people living with HIV and that targeting α-Syn regulatory pathways could help reduce HIV-related neurodegeneration. To our knowledge, this is the first study to show that an HIV protein epigenetically activates the SNCA antisense promoter, linking viral infection to α-synuclein deregulation. Future research should explore how SNCA antisense promoter demethylation leads to neuronal dysfunction and examine the broader impact of α-Syn dysregulation on neuronal health.

The online version contains supplementary material available at 10.1038/s41598-026-35691-3.