Monocyte Trafficking in the Pathogenesis of HIV Dementia

我们提出了一个多步骤模型， 伴随AIDS发作的痴呆伴全身性事件，以及 随后。我们的理论是，最初的关键步骤是增加在 血液单核细胞进入脑实质的运输，这是 通过这些细胞在离开骨之前的活化而促进 骨髓（BM）。具体来说，我们认为，与艾滋病毒有关的事件 BM内感染，和/或伴随的全身免疫激活 艾滋病，导致巨噬细胞集落刺激因子的产生增加 骨髓内的M-CSF，这反过来又导致诱导CD 16在骨髓细胞上的表达。 更多数量的单核细胞。被激活后，这些细胞 为跨内皮迁移做好准备，因此，可以更容易地穿过 血脑屏障我们认为巨噬细胞本身， 是神经病理过程的主要煽动者 导致艾滋病痴呆症，而大脑中的艾滋病感染在 作用一旦进入脑实质，单核细胞可以产生，以及 从其他细胞中引出神经毒素，如促炎细胞因子。 大量证据支持这一可能的结果。将拟议的 单核细胞进入脑内的增加与进入后事件， 痴呆症，我们建议表征（CD 14+）血管周围巨噬细胞 艾滋病患者大脑中的CD 16和HIV表达，以及 0-淀粉样前体蛋白（0-APP）-沉积，laner是 轴突损伤基于脂蛋白E4等位基因（apoE 4）， 阿尔茨海默氏症痴呆症的已知危险因素也与较高的 循环CD 16+单核细胞的水平，以及艾滋病毒痴呆，我们将检查 这种基因型与CD 16+单核细胞和HIV相关的认知功能相关， 损伤为了测试我们的模型，我们将表征血液单核细胞， 对患有和不患有痴呆症的HIV感染患者进行纵向随访， 活化、增殖、HIV感染和P-APP的表面表达。 将测定脑脊液、血清、脑和BM组织中的M-CSF水平。 测定 免疫染色将用于评价脑和骨髓切片， CD 14、CD 16和HIV表达的丰度。为了研究单核细胞从 BM至脑，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”。apo E genotyping 将包括在内。如果有效，我们的模型可能会导致新的方法， 艾滋病痴呆的预防和治疗。

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.