Role of cellular prion protein in the pathogenesis of NeuroAIDS

描述（由申请人提供）：细胞朊病毒蛋白在中枢神经系统（CNS） HIV感染的发病机制中的作用导致大量个体发生称为HIV相关神经系统疾病（HAND）的一系列神经系统并发症。HAND的基础还没有被很好地理解。尽管与中枢神经系统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HAND的一个更好的指标，而不是病毒载量，这表明粘附分子失调、血脑屏障（BBB）完整性和白细胞浸润和损伤密切相关。受感染的单核细胞穿过血脑屏障并浸润中枢神经系统实质的过程部分是由多种分子（包括粘附蛋白）的相互作用介导的。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，并对血脑屏障和中枢神经系统内的其他细胞（包括神经元）造成损害。一个这样的分子被证明介导单核细胞在全身脉管系统中的转运是PrPc。然而，PrPc在HIV的神经发病机制中的作用尚未得到研究。我们的数据表明，与未感染或没有认知损害的HIV感染个体相比，PrPc的表达和释放在患有认知障碍的HIV感染个体的大脑中发生了改变。我们还在感染SIV的猕猴脑组织中发现了PrPc。我们证明，在感染HIV的人类中，可溶性PrPc （sPrPc）释放到CSF中，而不是释放到血清中，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CD4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，可通过CCL2或hiv感染治疗显著增加。因此，我们确定了两种介质，HIV和CCL2，这取决于分析的细胞类型，导致PrPc的释放。我们还证明了sPrPc （sPrPc）是一种炎症因子，可以改变CCL2和IL-6的分泌。因此，我们的假设是，HIV感染中枢神经系统会改变PrPc的表达和释放，导致炎症和随后的认知障碍。因此，脑脊液中sPrPc的水平是HIV感染者认知能力下降/痴呆的生物标志物。为了解决这一假设，我们将扩展我们的初步数据，使用与认知状态相关的HIV感染个体的纵向研究来检查sPrPc作为HIV感染人群认知障碍的生物标志物，以及MCMD， HAD和感染但认知正常的个体的脑组织切片。我们还将研究PrPc释放的机制以及可溶性亚型对神经元存活、星形胶质细胞功能和血脑屏障完整性的影响。

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.