Inflammatory mechanisms associated with HIV-1 dementia

HIV-1相关性痴呆（HAD）部分是由于脑内驻留的 巨噬细胞和小胶质细胞的病毒蛋白，造成神经元功能障碍和死亡超过 时间我们假设小胶质细胞和脑微血管内皮细胞中的CD 40信号传导 （BMVEC）可与候选HIV-1神经毒素（如达特或血小板）的作用协同作用。 活化因子（PAF）在HAD中起关键作用。我们将在三个具体目标中对此进行研究。 在目标1中，我们将分析候选HIV-1神经毒素和CD 40参与的协同效应。 对人类巨噬细胞和小胶质细胞中炎症基因表达的影响， 与CD 40接合相关的信号传导机制，包括抗- NF-κ B抑制剂、米诺环素和格列酮的炎症作用。在目标2中，我们将检查 CD 40参与单核细胞粘附和迁移通过人工血脑屏障的作用 HIV-1神经毒素的反应，通过确定特定的信号事件，导致增加 粘附和炎症分子在人BMVEC中的表达。此外，我们将 确定在CD 40特异性RNA干扰后是否下调CD 40表达 或暴露于药理学抑制剂（他汀类），拮抗通过BBB的细胞迁移。 最后，在目标3中，我们将使用用免疫抑制剂治疗的CD 40 KO小鼠、CD 40 L KO小鼠或野生型小鼠。 破坏CD 40-CD 40 L相互作用的小鼠CD 40 L特异性单克隆抗体， 研究CD 40和HIV-1神经毒素介导的信号传导之间的相互作用是否也 导致CMS炎症和体内受损的突触传递。总的来说，这些 研究将确定新的治疗策略，可以增强神经功能， 神经艾滋病的生存。

HIV-1 associated dementia (HAD) is due in part to aberrant activation of brain resident macrophages and microglial cells by viral proteins, causing neuronal dysfunction and death over time. We hypothesize that CD40 signaling in microglia and in brain microvascular endothelial cells (BMVEC) may synergize with the effects of candidate HIV-1 neurotoxins, such as Tat or platelet activating facotr (PAF), and play a pivotal role in HAD. We will investigate this in three specific aims. In Aim 1, we will analyze synergistic effects of candidate HIV-1 neurotoxins and CD40 engagement on inflammatory gene expression in human macrophages and microglial cells, by examining signaling mechanisms associated with CD40 engagement, including analyses of the anti- inflammatory effects of NF-KB inhibitors, minocycline and glitazones. In Aim 2, we will examine the role of CD40 engagement in monocyte adhesion and migration through an artificial BBB in response to HIV-1 neurotoxins, by determining specific signaling events that lead to increased expression of adhesion and inflammatory molecules in human BMVEC. Additionally, we will determine whether down-modulation of CD40 expression, following CD40-specific RNA interference or exposure to pharamcologic inhibitors (statins), antagonizes cellular migration through BBB. Finally, in Aim 3, we will use CD40 KO mice, CD40L KO mice or wild-type mice treated with a monoclonal antibody specific for mouse CD40L that disrupts CD40-CD40L interaction, to investigate whether the interplay between CD40- and HIV-1 neurotoxin-mediated signaling also contributes to the CMS inflammation and impaired synaptic transmission in vivo. Collectively, these investigations will identify novel therapeutic strategies that may enhance neuronal function and survival in neuroAIDS.