Gp120, Macrophage Activation & TNF in HIV Encephalopathy

HIV相关性痴呆（HAD）是由HIV-1在大脑内复制引发的，未感染和感染的脑巨噬细胞/小胶质细胞（M/M）的激活是与临床疾病密切相关的关键因素。广泛的研究已经将HIV刺激的M/M的产物牵涉到发病机制中，例如TNF-α，其在HAD中升高，由脑中活化的M/M产生，并且似乎在神经元损伤和活化的持续中起重要作用。虽然我们对活化M/M释放的潜在介质&神经毒素了解很多， HAD中，HIV-1如何触发M/M激活以启动最终导致神经元损伤的事件仍然是未知的，这是我们对HAD发病机制的理解中的重要空白。 为了进入细胞，HIV结合CD 4，然后结合两种趋化因子受体之一，CCR 5或CXCR 4。趋化因子受体的正常功能是介导对细胞外刺激的活化和趋化。CD 4在T细胞中的功能和信号传导是明确的，但对巨噬细胞中的CD 4功能或信号传导知之甚少。在初步研究中，我们发现HIV-1 Env糖蛋白gp 120与M/M上的CD 4和趋化因子受体结合启动细胞内信号传导，并且通过这些受体的特定途径的激活导致细胞内信号传导。 炎症介质的激活和释放，包括TNF-α和HAD发病机制中涉及的其他产物。我们的假设是，大脑中的M/M激活部分是由于gp 120与CD 4和趋化因子受体的相互作用，引发细胞内信号，导致产生炎症和神经毒性介质，如TNF-α，这引发了炎症，激活和最终神经元损伤的级联反应。我们的目标是确定特定的分子机制，HIV-1 gp 120触发M/M激活相关的HAD发病机制的大脑。为此，我们将：（1）确定HIV-1 gp 120 调节M/M中TNF-α的产生：（2）确定原代巨噬细胞中CD 4介导的信号传导途径;（3）确定与HAD相关的病毒和宿主遗传因子对巨噬细胞TNF-α诱导的影响;（4）确定并比较体外由gp 120引起的巨噬细胞基因表达改变的模式和体内HAD。我们预计，这些研究将提供深入了解启动机制的细胞激活在HAD，以及，最终，提供了一个合理的基础，有针对性的策略，以干扰这一进程。

HIV-associated dementia (HAD) is initiated by HIV-1 replication within the brain, and activation of both uninfected & infected brain macrophage/microglia (M/M) is a critical element that is closely linked to clinical disease. Extensive research has implicated products of HIV-stimulated M/M in pathogenesis, such as TNF-a, which is elevated in HAD, produced by activated M/M in the brain, and appears to play an important role in neuronal injury & the perpetuation of activation. Although much is known about potential mediators & neurotoxins that are released by activated M/M in HAD, it remains unknown how HIV-1 triggers M/M activation to initiate the events that culminate in neuronal injury and this is an important gap in our understanding of HAD pathogenesis. To enter cells, HIV binds CD4 followed by one of two chemokine receptors, CCR5 or CXCR4. Chemokine receptors' normal function is to mediate activation & chemotaxis in response to extracellular stimuli. CD4's function and signaling are well-defined in T cells, but little is known about CD4 function or signaling in macrophages. In preliminary studies, we found that HIV-1 Env glycoprotein gp120 binding to both CD4 & chemokine receptors on M/M initiates intracellular signaling, and that activation of specific pathways through these receptors leads to cellular activation and release of inflammatory mediators including TNF-a & other products implicated in HAD pathogenesis. Our hypothesis is that M/M activation in the brain results, in part, from gp120 interaction with CD4 & chemokine receptors, eliciting intracellular signals that lead to production of inflammatory & neurotoxic mediators such as TNF-a, which initiates a cascade of inflammation, activation &, ultimately, neuronal injury. Our goal is to define specific molecular mechanisms by which HIV-1 gp120 triggers M/M activation in the brain relevant to HAD pathogenesis. To do this we will: (1) Identify mechanism & pathways by which HIV-1 gp120 regulates TNF-a production in M/M: (2) Define the pathways for CD4-mediated signaling in primary macrophages: (3) Determine the effect on macrophage TNF-a induction of viral & host genetic factors linked to HAD, and; (4) Define & compare the patterns of altered macrophage gene expression in vitro elicited by gp120 & in vivo in HAD. We anticipate that these studies will provide insight into initiating mechanisms of cellular activation in HAD, as well as, ultimately, provide a rational basis for targeted strategies to interfere with this process.