Hepatitis C Drives Neuropathogenesis in HIV/HCV Coinfection Patients

描述（由申请方提供）：丙型肝炎病毒（HCV）在HIV/HCV合并感染受试者的神经认知结局中起有害作用。HCV存在于单核细胞/巨噬细胞（M/MF）中，已知其可进入大脑。在大脑中，HIV和HCV都见于星形胶质细胞和小胶质细胞。与HIV不同，未经治疗的HCV患者可能患有慢性病毒血症，而不会发展为痴呆症。然而，现在有越来越多的报道，HCV，特别是HIV/HCV合并感染与认知障碍。我们有初步数据表明，来自HIV/HCV共感染个体的M/MF具有许多与HIV感染（CCL 2、SN和OSM）和HCV感染（CXCL 2、CXCL 3、CXCL 10、IL-8、CCL 20）中的趋化性和炎症相关的显著升高的基因。我们还表明，可溶性产品从M/MF的个人与HCV或HIV/HCV引起神经细胞死亡和凋亡的人脑培养。我们的总体假设是，HCV单一感染和HIV/HCV合并感染引起的慢性病毒血症激活了M/MF，这对导致认知障碍的神经发病机制产生了影响。我们的具体目标是：1）开发来自HCV和HIV/HCV受试者的外周M/MF基因表达谱，目的是鉴定激活的途径和涉及的重要基因/蛋白质; 2）使用人脑细胞聚集体或双层培养物表征用来自患有HCV和HIV/HCV的受试者的M/MF上清液处理后的神经细胞变化，并特别鉴定与各组相关的可溶性细胞因子/趋化因子谱，和3）确定通过神经心理学测试测量的HCV单一感染和HIV/AIDS患者的神经认知损害水平。HCV合并感染，并将其与单核细胞基因阵列谱和上清液神经毒性相关联。我们结合了HCV临床肝病组的临床专业知识和特征良好的患者队列与HIV基础神经科学组的CNS专业知识，研究慢性HCV和HIV/HCV感染对CNS的影响。公共卫生相关性：大约四分之一感染艾滋病毒的美国人也感染了丙型肝炎病毒。许多患有丙型肝炎或两种病毒的人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。本研究比较了这两组患者的单核细胞/巨噬细胞（特异性免疫细胞），目的是了解它们的活性以及它们是否会对细胞培养中的正常脑细胞造成损伤。

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.