Inflammatory mechanisms associated with HIV-1 dementia

HIV-1相关性痴呆(HAD)的部分原因是大脑驻留的异常激活 巨噬细胞和小胶质细胞由病毒蛋白引起的神经元功能障碍和死亡 时间到了。我们假设CD40信号在小胶质细胞和脑微血管内皮细胞中 (BMVEC)可能与候选HIV-1神经毒素，如TAT或血小板的作用协同作用 激活因子(PAF)，在HAD中起着举足轻重的作用。我们将从三个具体目标来调查这一点。 在目标1中，我们将分析候选HIV-1神经毒素和CD40参与的协同效应 人巨噬细胞和小胶质细胞炎症基因表达的研究 与CD40结合相关的信号机制，包括对抗CD40结合的分析 核因子-kB抑制剂、米诺环素和格列酮的炎症效应。在目标2中，我们将研究 CD40参与单核细胞通过人工血脑屏障黏附和迁移的作用 对HIV-1神经毒素的反应，通过确定导致增加的特定信号事件 黏附分子和炎性分子在人BMVEC中的表达此外，我们还将 确定在CD40特异性RNA干扰后，CD40表达是否下调 或暴露于药物抑制剂(他汀类)，通过血脑屏障对抗细胞迁移。 最后，在目标3中，我们将使用CD40 KO小鼠、CD40L KO小鼠或野生型小鼠 针对小鼠CD40L的单抗可破坏CD40-CD40L相互作用，以 研究CD40和HIV-1神经毒素之间的相互作用是否也 在体内导致CMS炎症和突触传递受损。总而言之，这些 研究将确定新的治疗策略，可以增强神经元功能和 神经艾滋病患者的存活率。

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.