Hepatitis C Drives Neuropathogenesis in HIV/HCV Coinfection Patients

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)在HIV/丙型肝炎病毒混合感染者的神经认知结果中起有害作用。丙型肝炎病毒存在于单核/巨噬细胞(M/MF)中，这是已知的进入大脑的交通工具。在大脑中，艾滋病毒和丙型肝炎病毒都出现在星形胶质细胞和小胶质细胞中。与艾滋病毒不同，未经治疗的丙型肝炎病毒携带者可能患有慢性病毒血症，不会患上痴呆症。然而，现在有越来越多的报道表明，丙型肝炎病毒，特别是HIV/丙型肝炎病毒混合感染与认知障碍有关。我们已有初步数据显示，HIV/HCV混合感染者的M/MF在HIV感染(CCL2、SN和OSM)和HCV感染(CXCL2、CXCL3、CXCL10、IL-8、CCL20)中有许多与趋化和炎症相关的基因显著升高。我们还表明，丙型肝炎病毒感染者或HIV/丙型肝炎病毒感染者M/MF的可溶性产物会导致人脑培养中神经细胞的死亡和凋亡。我们的总体假设是，丙型肝炎病毒单独感染和HIV/丙型肝炎病毒混合感染引起的慢性病毒血症激活了M/MF，从而影响了神经发病，导致认知功能障碍。我们的具体目标是：1)建立丙型肝炎病毒和艾滋病毒/丙型肝炎患者的外周M/MF基因表达谱，目的是确定激活途径和参与的重要基因/蛋白；2)利用人脑细胞聚集体或双层培养，鉴定丙型肝炎病毒和艾滋病毒/丙型肝炎患者的M/MF培养上清液处理后神经细胞的变化，特别是鉴定与每组相关的可溶性细胞因子/趋化因子谱；3)通过神经心理测试确定丙型肝炎病毒单一感染和艾滋病毒/丙型肝炎合并感染时神经认知障碍的水平，并将其与单核细胞基因阵列图谱和培养上清液神经毒性相关联。我们结合了以丙型肝炎病毒为基础的临床肝病小组的临床专业知识和具有良好特征的患者队列，以及艾滋病毒基础神经科学小组的中枢神经系统专业知识，以研究慢性丙型肝炎病毒和艾滋病毒/丙型肝炎病毒感染对中枢神经系统的影响。公共卫生相关性：大约每4名感染艾滋病毒的美国人中就有1人感染丙型肝炎病毒。许多丙型肝炎患者或两种病毒携带者都有心理健康和神经问题，如抑郁、注意力不集中或异常运动或感觉，但他们为什么会有这些还不完全清楚。这项研究比较了这两组患者的单核/巨噬细胞，即特异性免疫细胞，目的是了解它们的活动，以及它们在细胞培养中是否会对正常脑细胞造成损害。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) plays a deleterious role in neurocognitive outcomes in HIV/HCV coinfected subjects. HCV is present in monocyte/macrophage (M/MF), which is known to traffic into the brain. In the brain, both HIV and HCV have been seen in astrocytes and microglia. Unlike HIV, individuals with untreated HCV may live with chronic viremia and not develop dementia. However, there are now increasing reports that HCV and in particular HIV/HCV coinfection are associated with cognitive impairment. We have preliminary data to show that M/MF from HIV/HCV coinfected individuals have a number of significantly elevated genes associated with chemotaxis and inflammation in HIV infection (CCL2, SN and OSM) and HCV infection (CXCL2, CXCL3, CXCL10, IL-8, CCL20). We also show that soluble products from M/MF of individuals with HCV or HIV/HCV cause neural cell death and apoptosis in human brain cultures. It is our overall hypothesis that the chronic viremia from HCV monoinfection and HIV/HCV coinfection activates the M/MF and this has an impact on neuropathogenesis leading to cognitive impairment. Our Specific Aims are: 1) To develop peripheral M/MF gene expression profiles from subjects with HCV and HIV/HCV with the goal of identifying activated pathways and significant genes/proteins involved; 2) To characterize neural cell changes after treatments with M/MF supernatants from subjects with HCV and HIV/HCV using human brain cell aggregate or bilayer cultures, and specifically to identify soluble cytokine/chemokine profiles associated with each group and 3) To determine the level of neurocognitive impairment as measured by neuropsychological testing in HCV monoinfection and HIV/HCV coinfection and to correlate this with monocyte gene array profiles and supernatant neurotoxicity. We have combined the clinical expertise and well-characterized patient cohort of an HCV-based clinical hepatology group with the CNS expertise of an HIV basic neuroscience group to study the effects of chronic HCV and HIV/HCV infection on the CNS. PUBLIC HEALTH RELEVANCE: Approximately 1 in 4 Americans who are infected with HIV are also infected with the hepatitis C virus. Many people with hepatitis C or with both viruses have mental health and neurological problems, such as depression, poor concentration, or abnormal movements or sensations, but why they have these is not completely understood. This study compares monocyte/macrophages, specific immune cells, from these two groups of patients, with the aims of understanding their activities and whether they cause damage to normal brain cells in cell culture.