HIV-1 Transactivator of Transcription Protein Induces Mitochondrial Hyperpolarization and Synaptic Stress Leading to Apoptosis

摘要: Despite the efficacy of highly active antiretroviral therapy in reducing viral burden, neurologic disease associated with HIV-1 infection CNS has not decreased prevalence. does induce by direct neurons, although extensive data suggest that intra-CNS burden correlates both severity virally induced disease, and generation neurotoxic metabolites. Many these molecules are capable inducing neuronal apoptosis vitro, but vivo correlate dysfunction, thus prompting us to investigate cellular synaptic events occurring before cell death may contribute HIV-1-associated disease. We now report regulatory protein transactivator transcription (Tat) increased oxidative stress, ATP levels, mitochondrial membrane potential primary rodent cortical neurons. Additionally, a proinflammatory metabolite up-regulated Tat, platelet-activating factor, also stress hyperpolarization suggesting this type metabolic dysfunction occur on chronic basis during CNS. Tat-induced could be blocked low dose protonophore FCCP, or KATP channel antagonist, tolbutamide. Importantly, blocking attenuated apoptosis, causal event precipitating culture. Finally, Tat factor vesicular release, which related bioenergetics serve as biomarker for early damage