HIV-1 Tat mediates microglial NLRP3 inflammasome activation and neurotoxicity by inducing cytosolic mtDNA stress.

Tat, a regulatory protein of human immunodeficiency virus (HIV)-1, is a potent viral neurotoxin which can activate the NLRP3 inflammasome in microglia and contribute to neurotoxicity. Here, we found that HIV Tat induces mitochondrial dysfunction in microglia and promotes mtDNA leakage into the cytoplasm to activate the NLRP3 inflammasome. Degrading mtDNA with DNase I significantly blocks the activation of NLRP3 inflammasome and IL-1β secretion. Interestingly, we found that HIV Tat promotes the translocation of TDP-43 from nucleus to mitochondria. Furthermore, we found that ROS accumulation mediated by HIV Tat could activate NF-κB signaling pathway to facilitate the transcription of IL-1β precursor. Scavenging intracellular ROS significantly inhibits the activation of the NF-κB signaling pathway, thereby reducing the transcription and secretion of IL-1β. Conditioned medium from microglia treated with Tat significantly induces SH-SY5Y and primary neuronal cell apoptosis, which can be alleviated by GIBH-130. In conclusion, our results suggest that HIV-1 Tat promotes TDP-43 abnormal localization to mitochondria and mitochondrial dysfunction, inducing cytosolic mtDNA stress and ROS accumulation. These events respectively activate the NLRP3 inflammasome and NF-κB signaling pathway, thereby promoting IL-1β secretion and neuronal damage. This study reveals a new underlying mechanism for neuroinflammation mediated by HIV infection.