Role of cellular prion protein in the pathogenesis of NeuroAIDS

描述（由申请人提供）：细胞朊病毒蛋白在神经艾滋病发病机制中的作用中枢神经系统（CNS）的HIV感染导致大量个体发生一系列神经系统并发症，称为HIV相关神经系统疾病（HAND）。HAND的基础还不太清楚。虽然与CNS的早期病毒浸润有关，但活化巨噬细胞的数量似乎是HIV患者中HAND的更好指标，而不是病毒载量，表明粘附分子的失调，血脑屏障（BBB）完整性和白细胞浸润和损伤密切相关。感染的单核细胞穿过BBB并浸润CNS实质的过程部分地由多种分子（包括粘附蛋白）的相互作用介导。这种炎症过程对HAND的发展至关重要，因为它将感染和未感染的细胞带入大脑，在那里它们激活并感染巨噬细胞/小胶质细胞，并对BBB和CNS内的其他细胞（包括神经元）造成损伤。一种这样的分子显示介导单核细胞穿过全身脉管系统的迁移是PrPc。然而，PrPc在HIV神经发病机制中的作用尚未研究。我们的数据表明，PrPc的表达和释放的改变，在大脑中的HIV感染的个人与认知障碍相比，未感染或HIV感染的个人没有认知妥协。我们还发现PrPc在感染SIV的猕猴的脑组织中。我们证明，在感染HIV的人中，可溶性PrPc（sPrPc）释放到CSF中，而不是血清中，是认知能力下降的生物标志物。这些结果与病毒载量、年龄、性别和CD 4计数无关。我们证明，巨噬细胞，PBMC，单核细胞，内皮细胞，神经元和星形胶质细胞释放低水平的sPrPc，可以显着增加与CCL 2或HIV感染的治疗。因此，我们确定了两种介质，HIV和CCL 2，这取决于分析的细胞类型，导致PrPc的释放。我们还证明sPrPc（sPrPc）是一种炎症因子，可改变CCL 2和IL-6的分泌。因此，我们的假设是，CNS的HIV感染改变了PrPc的表达和释放，导致炎症和随后的认知障碍。因此，sPrPc的CSF水平是感染HIV的个体中认知下降/痴呆的生物标志物。为了解决这一假设，我们将使用与认知状态相关的HIV感染个体的纵向研究来扩展我们的初步数据，以检查sPrPc作为HIV感染人群中认知障碍的生物标志物，以及来自MCMD、HAD和被感染但认知正常的个体的脑组织切片。我们还将研究PrPc释放的机制和可溶性同种型对神经元存活、星形胶质细胞功能和BBB完整性的影响。

DESCRIPTION (provided by applicant): Role of cellular prion protein in the pathogenesis of NeuroAIDS HIV infection of the central nervous system (CNS) results in the development of a spectrum of neurological complications known as HIV associated neurologic disorders (HAND) in a significant number of individuals. The basis of HAND is not well understood. Although associated with early viral infiltration of the CNS, the number of activated macrophages appears to be a much better indicator of HAND in individuals with HIV rather than viral load, suggesting that dysregulation of adhesion molecules, blood brain barrier (BBB) integrity and leukocyte infiltration and impairment are tightly correlated. The process by which infected monocytes cross the BBB and infiltrate the CNS parenchyma is mediated, in part, by the interactions of a variety of molecules, including adhesion proteins. This inflammatory process is critical to the development of HAND as it brings both infected and uninfected cells into the brain where they activate and infect macrophages/microglia and effect damage to the BBB and other cells within the CNS, including neurons. One such molecule shown to mediate monocyte transmigration across the systemic vasculature is PrPc. However, the role of PrPc in the context of the neuropathogenesis of HIV has not been examined. Our data demonstrate that PrPc expression and release are altered in the brains of HIV-infected individuals with cognitive impairment as compared to uninfected or HIV- infected individuals without cognitive compromise. We also showed PrPc in the brain tissue of macaques infected with SIV. We demonstrated in humans infected with HIV that release of soluble PrPc (sPrPc) into the CSF, but not to the sera, is a biomarker of cognitive decline. These results were independent of viral load, age, gender and CD4 counts. We demonstrated that macrophages, PBMC, monocytes, endothelial cells, neurons and astrocytes release low levels of sPrPc that can be significantly increased by treatment with CCL2 or HIV-infection. Thus, we identified two mediators, HIV and CCL2, that, depending on the cell type analyzed, resulted in release of PrPc. We also demonstrated that sPrPc (sPrPc) is an inflammatory factor that alters secretion of CCL2 and IL-6. It is therefore our hypothesis that HIV infection of the CNS alters PrPc expression and release, resulting in inflammation and subsequent cognitive impairment. Thus, CSF levels of sPrPc are a biomarker of cognitive decline/dementia in individuals infected with HIV. To address this hypothesis we will expand our preliminary data using longitudinal studies of HIV- infected individuals in correlation with cognitive status to examine sPrPc as a biomarker of cognitive impairment in the HIV-infected population, as well as brain tissue sections from individuals with MCMD, HAD and who are infected but cognitively normal. We will also examine the mechanisms of PrPc release and the consequences of the soluble isoform on neuronal survival, astrocyte function and BBB integrity.