Hepatitis C Drives Neuropathogenesis in HIV/HCV Coinfection Patients

丙型肝炎导致 HIV/HCV 合并感染患者的神经发病机制

• 批准号: 7860629
• 负责人: Lynn PULLIAM
• 金额: $ 34.88万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860629
• 关键词: AIDS Dementia Complex; Affect; Aftercare; American; Apoptosis; Astrocytes; Brain; CCL2 gene; CCL20 gene; CXCL10 gene; CXCL2 gene; CXCL3 gene; Cell Culture Techniques; Cell Death; Cells; Chemotaxis; Chronic; Chronic Hepatitis C; Clinical; Complication; Data; Dementia; Development; Dyskinetic syndrome; Esthesia; Gene Expression; Gene Proteins; Genes; Goals; HIV; HIV Infections; HIV Seropositivity; Hepatitis C; Hepatitis C virus; Hepatology; Highly Active Antiretroviral Therapy; Human; IL8 gene; Immune; Impaired cognition; Impairment; Individual; Inflammation; Leukocytes; Life; Measures; Mental Depression; Mental Health; Microglia; Molecular Profiling; Nerve Degeneration; Neuraxis; Neurocognitive; Neurologic; Neurons; Neuropathogenesis; Neuropsychological Tests; Neurosciences; Outcome; Pathway interactions; Patients; Peripheral; Play; Property; Proteins; Reporting; Role; Uncertainty; United States; Viremia; Virus; base; brain cell; central nervous system injury; chemokine; cohort; cytokine; macrophage; monocyte; neuropathology; neurotoxic; neurotoxicity; public health relevance; response; trafficking; viral RNA

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.

描述（由申请人提供）：丙型肝炎病毒（HCV）对 HIV/HCV 共感染受试者的神经认知结果起着有害作用。 HCV 存在于单核细胞/巨噬细胞 (M/MF) 中，已知它们会进入大脑。在大脑中，星形胶质细胞和小胶质细胞中都发现了 HIV 和 HCV。与艾滋病毒不同，未经治疗的丙型肝炎病毒患者可能患有慢性病毒血症，但不会发展为痴呆。然而，现在越来越多的报道表明丙型肝炎病毒，特别是艾滋病毒/丙型肝炎病毒合并感染与认知障碍有关。我们有初步数据表明，HIV/HCV 共感染个体的 M/MF 有许多与 HIV 感染（CCL2、SN 和 OSM）和 HCV 感染（CXCL2、CXCL3、CXCL10、IL-）趋化性和炎症相关的基因显着升高。 8、CCL20）。我们还表明，来自 HCV 或 HIV/HCV 个体的 M/MF 的可溶性产物会导致人脑培养物中的神经细胞死亡和凋亡。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会激活 M/MF，这对导致认知障碍的神经发病机制产生影响。我们的具体目标是： 1) 开发 HCV 和 HIV/HCV 受试者的外周 M/MF 基因表达谱，目的是识别激活的途径和所涉及的重要基因/蛋白质； 2) 使用人脑细胞聚集体或双层培养物表征 HCV 和 HIV/HCV 受试者的 M/MF 上清液治疗后的神经细胞变化，特别是鉴定与每组相关的可溶性细胞因子/趋化因子谱，以及 3) 确定通过 HCV 单一感染和 HIV/HCV 双重感染的神经心理学测试测量神经认知障碍的水平，并将其与单核细胞基因阵列图谱和上清液神经毒性相关联。我们将基于 HCV 的临床肝病学小组的临床专业知识和特征明确的患者队列与 HIV 基础神经科学小组的 CNS 专业知识相结合，研究慢性 HCV 和 HIV/HCV 感染对 CNS 的影响。公共卫生相关性：大约四分之一的感染艾滋病毒的美国人也感染丙型肝炎病毒。许多丙型肝炎或同时感染两种病毒的人都存在心理健康和神经系统问题，例如抑郁、注意力不集中、运动或感觉异常，但他们出现这些问题的原因尚不完全清楚。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动以及它们是否对细胞培养物中的正常脑细胞造成损害。