HIV-1 gp120-mediated injury in brain endothelium

描述（由申请人提供）：血脑屏障（BBB）的完整性对正常脑功能至关重要。艾滋病患者的神经病理学障碍与血管周围HIV感染的巨噬细胞、神经胶质增生和血脑屏障通透性异常有关。血脑屏障的破坏常见于患有HIV-1相关痴呆（HAD）的艾滋病患者。艾滋病毒引起这些病理变化的过程尚不清楚。该提案旨在描述脑内皮在促进HIV-1相关神经病理学中的作用。Gp 120是HIV-1包膜糖蛋白，在HIV-1感染患者的血清和脑脊液中检测到浓度为0.1 nM至1 nM，可作为可溶性介质。GP 120蛋白可以引发神经毒性物质，在艾滋病患者的大脑中检测到。本研究的总体假设是：1）Gp 120可能与脑内皮细胞相互作用并引起细胞损伤，从而促进HIV-1向中枢神经系统的转运，并参与脑内的病理过程：2）脑内皮细胞可能通过Gp 120与脑内皮细胞表面的多配体蛋白聚糖的结合而成为促进HIV-1在脑内感染的微环境;阿片类药物可能通过Gp 120和阿片类药物对脑内皮细胞的协同毒性作用加速HAD的进展。该提案将描述Gp 120对人脑微血管内皮细胞（HBMEC）的致病作用，在体内发现的病毒包膜Gp 120浓度（0.1至1 nM）。本研究的主要目的是：1）通过比较人脐静脉内皮细胞（human umbilical vein endothelial cells，HUVEC）和HBMEC中Gp 120介导脑内皮细胞损伤的信号通路，阐明Gp 120介导脑内皮细胞损伤的分子机制; 2）确定多配体蛋白聚糖作为内皮细胞上Gp 120的附着受体的作用及其在HIV介导的脑内皮损伤中的作用; 3）研究Gp 120与阿片类药物（吗啡）对HBMEC通透性的潜在协同毒性。在这些研究中，我们将使用M嗜性和T嗜性HIV毒株，因为每种毒株都可以在艾滋病过程中出现。这些研究应提供深入了解预防和/或治疗策略，以维持BBB的完整性，在HIV感染的患者，从而有助于限制CNS病理。

DESCRIPTION (provided by applicant): The integrity of the blood-brain barrier (BBB) is critical for normal brain function. Neuropathological disorders in AIDS patients have been associated with perivascular HIV-infected macrophages, gliosis and abnormalities in the permeability of the BBB. Breakdown of the BBB is commonly seen in AIDS patients with HIV-1 associated dementia (HAD). The processes by which HIV causes these pathological changes are not well understood. This proposal seeks to characterize the role of brain endothelium in contributing to HIV-1 related neurological pathology. Gp120, the HIV-1 envelope glycoprotein, has been detected in the serum and cerebrospinal fluid of HIV-1 infected patients at 0.1 nM to 1 nM concentrations and can act as a soluble mediator. Gp120 protein can elicit neurotoxic substances and is detected in the brains of patients with AIDS. The overall hypotheses of this proposal are: 1) Gp120 may interact with brain endothelium and cause cell injury, thereby facilitating transit of HIV into the CNS as well as contributing to the pathology in brain; 2) brain endothelium may serve as a microenvironment which promotes HIV-1 infection in brain via the binding of Gp120 to the syndecans on the surface of brain endothelium; and 3) opioid drugs may hasten the progression of HAD due to a synergistic toxic effect of Gp120 and opioids on brain endothelium. This proposal will characterize the pathogenic effects of Gp120 on human brain microvascular endothelial cells (HBMEC), at concentrations of the viral envelope Gp120 that are found in vivo (0.1 to 1 nM). The aims of this research are: 1) to characterize the molecular mechanisms of Gp120 mediated injury of brain endothelium by elucidating the signaling pathways that mediate the injurious effects of Gp120 in HBMEC as compared to human umbilical vein endothelial cells (HUVEC) in-vitro and in-vivo; 2) to determine the role of syndecans as attachment receptors for Gp120 on endothelial cells and their role in HIV-mediated brain endothelium injury; and 3) to examine the potential synergistic toxicity of Gp120 and opioid drugs (morphine) on HBMEC permeability. In these studies, we will work with both M- and T-tropic HIV strains, since each can be present during the course of AIDS. These studies should provide insights into preventive and/or therapeutic strategies to sustain BBB integrity in HIV-infected patients, and thereby contribute to limiting CNS pathology.