Role of cellular prion protein in the pathogenesis of NeuroAIDS

细胞朊病毒蛋白在神经艾滋病发病机制中的作用

基本信息

批准号：
8073781
负责人：
Joan Weinberger Berman
金额：
$ 38.55万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-23 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8073781
关键词：
AIDS neuropathy Acquired Immunodeficiency Syndrome Address Adhesions Age Astrocytes Biological Markers Blood - brain barrier anatomy Brain CCL2 gene CD4 Lymphocyte Count Cell Adhesion Molecules Cell Death Cells Cognitive Data Dementia Development Disease Endothelial Cells Functional disorder Gender HIV HIV Infections HIV encephalitis Human Impaired cognition Impairment Individual Infiltration Inflammation Inflammatory Interleukin-6 Leukocytes Life Longitudinal Studies Macaca Mediating Mediator of activation protein Microglia Nervous System Physiology Nervous System Trauma Neuraxis Neurocognitive Neurologic Neurons Neuropathogenesis Neuropsychological Tests Pathogenesis Patients Peripheral Blood Mononuclear Cell Play Population Prevalence Principal Investigator Prions Process Protein Isoforms Proteins Resources Role SIV Sampling Serum Viral Viral Load result antiretroviral therapy base brain tissue cell type chemokine global health macrophage monocyte nervous system disorder neuronal survival novel pathogenic isoform programs research study success trafficking

项目摘要

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. PUBLIC HEALTH RELEVANCE: HIV infection and HIV neurocognitive impairment are major emerging global health problems. The prevalence of HIV associated neurocognitive disorders (HAND) is increasing as people with AIDS are living longer due to success of antiretroviral therapies. Currently, there are no studies of the role of PrPc, the cellular non pathogenic isoform of the prion protein, in the context of HIV and neurocognitive impairment. We propose that PrPc is a biomarker of cognitive impairment in individuals infected with HIV and that soluble PrPc plays a key role in the pathogenesis of HAND. Our preliminary data demonstrate that PrPc in the CSF of individuals infected with HIV may be a biomarker of cognitive impairment and that soluble PrPc is an inflammatory molecule within the CNS. We will determine whether CSF PrPc in HIV infected individuals can be used as a biomarker of cognitive decline. We will also identify the mechanism by which PrPc is shed/released from CNS cells and the additional consequences of this shed/released protein on CNS function. We propose that PrPc can be a novel target for therapies to reduce HIV CNS impairment.

描述（由申请人提供）：细胞prion蛋白在中枢神经系统（CNS）神经辅助发病机理中的作用导致大量个体中称为HIV相关的神经系统疾病（手）的神经系统并发症的发展。手的基础尚未很好地理解。尽管与中枢神经系统的早期病毒浸润有关，但激活的巨噬细胞的数量似乎是HIV而不是病毒载量的个体的更好的指标，这表明粘附分子，血脑屏障（BBB）完整性和白细胞渗透和损害的粘附分子失调与粘附分子的失调密切相关。感染单核细胞穿过BBB并浸润的过程，CNS实质部分是由包括粘附蛋白在内的多种分子的相互作用介导的。这种炎症过程对于手的发展至关重要，因为它将感染和未感染的细胞带入大脑，在那里它们激活和感染巨噬细胞/小胶质细胞，并对包括神经元在内的中枢神经系统内的BBB和其他细胞产生损害。一种这样的分子显示，可以介导整个系统脉管系统的单核细胞透射率是PRPC。但是，尚未研究PRPC在HIV神经病发生中的作用。我们的数据表明，与没有认知妥协的未感染或HIV感染的个体相比，患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。我们还显示了感染SIV的猕猴的脑组织中的PRPC。我们在感染艾滋病毒的人类中证明了可溶性PRPC（SPRPC）释放到CSF中，而不是血清，是认知能力下降的生物标志物。这些结果与病毒载荷，年龄，性别和CD4计数无关。我们证明了巨噬细胞，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，可以通过CCL2或HIV感染来显着增加，这些SPRPC可以显着增加。因此，我们确定了两个介体HIV和CCL2，这些介体取决于分析的细胞类型，从而释放了PRPC。我们还证明了SPRPC（SPRPC）是改变CCL2和IL-6分泌的炎症因素。因此，我们的假设是，中枢神经系统的艾滋病毒感染改变了PRPC的表达并释放，导致炎症和随后的认知障碍。因此，CSF的SPRPC水平是感染HIV的个体认知能力下降/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况相关的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感染人群认知障碍的生物标志物，以及来自MCMD，患有MCMD，患有和认知正常正常的人的脑组织切片，以及来自MCMD的个体。我们还将检查PRPC释放的机制以及可溶性同工型对神经元存活，星形胶质细胞功能和BBB完整性的后果。公共卫生相关性：艾滋病毒感染和艾滋病毒神经认知障碍是全球主要的健康问题。由于抗逆转录病毒疗法的成功，患有艾滋病的人的寿命更长，艾滋病毒相关的神经认知疾病的患病率正在增加。当前，在HIV和神经认知障碍的背景下，尚无研究PRPC的作用，PRPC的作用，PRPC的细胞非致病性同工型。我们建议PRPC是感染HIV的个体认知障碍的生物标志物，可溶性PRPC在手的发病机理中起关键作用。我们的初步数据表明，感染HIV的个体的CSF中的PRPC可能是认知障碍的生物标志物，并且可溶性PRPC是中枢神经系统内的炎症分子。我们将确定是否可以将CSF PRPC在艾滋病毒感染中用作认知能力下降的生物标志物。我们还将确定从中枢神经系统细胞中脱离/释放PRPC的机制，以及该棚/释放蛋白在中枢神经系统功能方面的其他后果。我们建议PRPC可能是减少HIV CNS损害的疗法的新靶标。