Brain inflammation underlies the neuropathogenesis of HIV-1 infection. What triggers neuronal death and the inflammatory mechanism driving neurological disease affects multiple neurodegenerative disorders including HIV-1-associated dementia (HAD). One important and newly discovered inflammatory mediator implicated in the pathogenesis of HAD is TRAIL. TRAIL, a member of the TNF superfamily, mediates immunoregulatory and inflammatory responses through its interaction with TRAIL receptor one (R1) and two (R2), decoy receptors (R3 and R4), and a soluble receptor, osteoprotegerin (OPG). Recently, we demonstrated that TRAIL is upregulated on HIV-infected, immune-activated macrophages. Importantly, TRAIL induces neuronal cell death by binding to neuronal death receptors. Of further importance to HAD are the described links between glutamate and TRAIL. HIV-1 infection of macrophage leads to the upregulation of glutaminase C (the GAC isoform of the glutaminase gene) and consequently increased glutamate production. Recombinant TRAIL enhances HIV-1 infected macrophage death leading to the significant increase of glutamate production that affects macrophage mediated neuronal injury. Based on these preliminary results, this competitive renewal proposal will examine the hypothesis that an important inflammatory event in HAD is the upregulation of TRAIL expression. We argue that this is a significant pathogenic event that triggers macrophage-neuron and macrophage-macrophage interactions engaging death receptors and affecting signaling events eventually leading to generalized cell death. Moreover, we hypothesize that a specific consequence of TRAIL mediated MP death is glutaminase release, increasing drain glutamate levels and leading to secondary neuronal death. This project will develop assays that mimic brain macrophage activation, neuronal injury and apoptotic signaling that occur in HAD. The elucidation of the mechanisms by which TRAIL-TRAIL receptors and glutaminase interact during MP mediated neuronal injury may open up new therapeutic ideas for disease treatment or prevention.