Monocyte Trafficking in the Pathogenesis of HIV Dementia

我们提出了一个多步骤模型，将艾滋病毒的发展与 随着艾滋病的发作而发生的系统性事件的痴呆症，以及 随后。我们的理论是，最初的关键步骤是增加 血液单核细胞进入脑实质，这是 由这些细胞在离开骨骼之前的激活所促进 骨髓(BM)。具体地说，我们建议，与艾滋病毒或艾滋病毒有关的事件 BM内感染和/或伴随的全身性免疫激活 艾滋病，导致巨噬细胞集落刺激因子产生增加 (M-CSF)在骨髓内，这反过来又导致诱导CD16在 退出的单核细胞数量较多。在被激活后，这些细胞 为跨内皮细胞迁移做好准备，因此可以更容易地跨越 血脑屏障。我们认为巨噬细胞本身，也未被感染 作为艾滋病毒感染者，是神经病理过程的主要煽动者 导致艾滋病毒痴呆，而艾滋病毒在大脑中的感染起到的作用较小 角色。一旦进入脑实质，单核细胞就可以产生 从其他细胞中诱导出神经毒素，如促炎细胞因子。 相当多的证据支持这一可能的结果。要链接建议的 单核细胞转运到脑内的增加与进入后事件和 痴呆，我们建议表征(CD14+)血管周围巨噬细胞 关于CD16和艾滋病毒在艾滋病脑中的表达，以及 0-淀粉样前体蛋白(0-APP)-沉积，灯笼是 轴突损伤。据报道，脂蛋白E4等位基因(Apo E4)，a 阿尔茨海默氏症的已知危险因素，也与较高的 循环CD16+单核细胞水平，以及艾滋病毒痴呆，我们将检查 这种表型与CD16+单核细胞和HIV相关认知功能 减损。为了测试我们的模型，我们将从 患有和不患有痴呆症的艾滋病毒感染患者，纵向随访， P-APP的活化、增殖、HIV感染和表面表达。 脑脊液、血清、脑和骨髓组织中的M-CSF水平将 下定决心。 免疫染色将用于评估脑和骨髓切片是否有 CD14、CD16和HIV表达丰富。为了研究单核细胞的贩运 从BM到脑，将使用HIV GPL 60种进行系统发育分析 从未培养的组织中克隆出来，作为“示踪剂”。基于聚合酶链式反应的载脂蛋白E基因分型 将被包括在内。如果有效，我们的模型可能会带来新的方法 预防和治疗艾滋病毒痴呆。

We propose a multi-step model linking the development of HIV dementia with systemic events which occur with the onset of AIDS, and subsequently. We theorize that the Initial critical step is an increase in the trafficking of blood monocytes into the brain parenchyma, and that this is facilitated by the activation of these cells prior to their exit from bone marrow (BM). Specifically, we suggest that events related to either HIV infection within BM, and/or the generalized immune activation which accompanies AIDS, lead to increased production of macrophage colony stimulating factor (M-CSF) within BM which, in turn, leads to induction of CD16 expression on a greater number of the exiting monocytes. Being activated, these cells are primed for transendothelial migration, and hence, can more readily cross the blood-brain barrier. We propose that macrophages themselves, uninfected as well as HIV-infected, are the primary instigators of the neuropathological processes leading to HIV dementia, and that HIV infection within the brain plays a lesser role. Once within the brain parenchyma, the monocytes can produce, as well as elicit from other cells, neurotoxins such as proinflammatory cytokines. Considerable evidence supports this possible outcome. To link the proposed increase in monocyte trafficking into brain with post-entry events and dementia, we propose to characterize the (CD14+) perivascular macrophage population in AIDS brains, with respect to CD16 and HIV expression, and 0-amyloid precursor protein (0-APP)-deposition, the laner being a marker of axonal injury. Based on reports that the alipoprotein E4 allele (apo E4), a known risk factor for Alzheimer's dementia, is also associated with higher levels of circulating CD16+ monocytes, as well as HIV dementia, we will examine this enotype in conjunction with CD16+ monocytes and HIV-associated cognitive impairment. To test our model, we will characterize blood monocytes from HIV-infected patients with and without dementia, followed longitudinally, for activation, proliferation, HIV infection, and surface expression of P-APP. M-CSF levels in cerebrospinal fluid, serum and brain and BM tissues will be determined. Immunostaining will be used to evaluate brain and bone marrow sections for the abundance of CD14, CD16 and HIV expression. To study monocyte trafficking from BM to brain, phylogenetic analyses will be performed using HIV gpl 60 species cloned from uncultured tissues as "tracers." PCR-based genotyping for apo E will be included. If valid, our model could lead to new approaches for the prevention and treatment of HIV dementia.