HIV-1 Vpr activates microglia by upregulating m6A modification through ubiquitin-proteasome pathway-mediated degradation of the demethylase ALKBH5.

HIV-1 infection activates microglia and triggers neuroinflammation, which is the primary cause of HIV-associated neurological complications. Our previous study demonstrated that HIV-1 infection upregulates m6A modification in microglia, and in this study, we investigated the underlying regulatory mechanisms. Through viral protein screening, we identified Vpr as the protein responsible for increasing m6A modification. Further analysis revealed that HIV-1 infection reduces the level of the m6A demethylase ALKBH5. Vpr deleted HIV-1 infection and Q65R mutant Vpr expression experiments demonstrated that Vpr is capable of degrading ALKBH5 protein via the ubiquitin-proteasome pathway by interacting with ALKBH5. Addition of m6A inhibitors or overexpression of ALKBH5 inhibited Vpr-induced microglial activation and the production of inflammatory cytokines, suggesting that the upregulation of m6A modification might play a crucial role in microglial activation induced by Vpr. As microglial activation is a major cause of neuroinflammation leading to neuronal damage, this study provides new insights for understanding the interactions between HIV-1 and microglia, and might provide new ideas for the prevention strategies study on the neuroinflammation caused by HIV-1 infection.