Role of cellular prion protein in the pathogenesis of NeuroAIDS

描述(申请人提供)：细胞内的蛋白在神经艾滋病的发病机制中的作用HIV感染中枢神经系统(CNS)导致在相当数量的个体中发生一系列称为HIV相关神经疾病(HAND)的神经并发症。手的基础还没有被很好地理解。虽然激活的巨噬细胞数量与早期病毒对中枢神经系统的渗透有关，但在HIV感染者中，激活的巨噬细胞数量似乎是一个更好的手部指标，而不是病毒载量，这表明黏附分子调节失调、血脑屏障(BBB)完整性以及白细胞渗透和损害密切相关。感染的单核细胞穿过血脑屏障并渗透到中枢神经系统实质的过程，部分是由包括黏附蛋白在内的各种分子的相互作用所介导的。这一炎症过程对手的发育至关重要，因为它将感染和未感染的细胞带入大脑，在那里它们激活和感染巨噬细胞/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。PrPc就是这样一种分子，它可以调节单核细胞在全身血管中的迁移。然而，PrPc在HIV神经发病机制中的作用尚未被研究。我们的数据表明，与未感染或没有认知妥协的艾滋病毒感染者相比，有认知障碍的艾滋病毒感染者的大脑中PrPc的表达和释放发生了变化。我们还在感染SIV的猕猴脑组织中显示了PrPc。我们在感染HIV的人类身上证明，可溶性PrPc(SPrPc)释放到脑脊液中，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。我们发现巨噬细胞、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，而CCL2或HIV感染可以显著增加sPrPc的释放。因此，我们确定了两种媒介，HIV和CCL2，根据所分析的细胞类型，它们导致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水平是艾滋病毒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，我们将使用与认知状态相关的艾滋病毒感染者的纵向研究来扩展我们的初步数据，以检验sPrPc作为艾滋病毒感染者中认知障碍的生物标记物，以及来自患有mcmd、HAD和感染但认知正常的个人的脑组织切片。我们还将研究PrPc的释放机制以及可溶性异构体对神经元存活、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.