HIV-1 Clade Diversity and Macrophage Mediated Neurotoxicity in HIV-1 Dementia

HIV-1 进化枝多样性和巨噬细胞介导的 HIV-1 痴呆神经毒性

• 批准号: 7612649
• 负责人: Jialin Charles Zheng
• 金额: $ 18.39万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-11 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612649
• 关键词: AIDS Dementia Complex; AIDS neuropathy; Acquired Immunodeficiency Syndrome; Address; Affect; Africa South of the Sahara; Area; Attenuated; Basal Ganglia; Biological; Biological Assay; Brain; Categories; Cells; Central Nervous System Diseases; Coculture Techniques; Complication; Conditioned Culture Media; Confocal Microscopy; Confounding Factors (Epidemiology); Consequences of HIV; Culture Media; Data; Dementia; Encephalitis; Environment; Enzyme-Linked Immunosorbent Assay; Enzymes; Europe; Foundations; Generations; Glutamates; Glutaminase; Glutamine; HIV; HIV Infections; HIV therapy; HIV-1; Harvest; High Pressure Liquid Chromatography; Human; Immune; Immune response; In Vitro; Incidence; India; Individual; Infection; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-10; Interleukin-6; Investigation; Laboratories; Lead; Measures; Mediating; Microglia; Mitochondria; Modeling; Molecular; Monitor; Mononuclear; Morphologic artifacts; Mus; Nebraska; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurologic Manifestations; Neuronal Injury; Neurons; Neuropathogenesis; Neurotoxins; Neurovirology; Opportunistic Infections; Pathogenesis; Pathway interactions; Patients; Phagocytes; Prevalence; Process; Production; Proteins; Publishing; RNA; RNA-Directed DNA Polymerase; Regulation; Relative (related person); Reporting; Request for Applications; Research; Resources; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Series; Signal Transduction; Site; Small Interfering RNA; Spleen; Syndrome; System; Therapeutic; Thick; Time; Transcript; Transfection; United States; Variant; Viral; Virus; Virus Diseases; Western Blotting; Work; brain tissue; chemokine; clinical Diagnosis; cytokine; fight against; in vivo; in vivo Model; inhibitor/antagonist; insight; macrophage; meetings; monocyte; mouse model; neuronal survival; neurotoxic; neurotoxicity; neurovirulence; novel; novel therapeutics; research study; response; small molecule; therapeutic target; virology

DESCRIPTION (provided by applicant): HIV-1 clade C is currently responsible for more than 50% of new HIV infections and is now the most commonly transmitted subtype worldwide. While HIV-1-associated dementia (HAD) continues to be a major neuropathological manifestation of AIDS among clade B-infected individuals in the US and Europe, the incidence of HAD in regions like India and sub-Saharan Africa, where clade C infection is prevalent, appears to be lower. Whether the low apparent prevalence of neuroAIDS is due to underlying differences in HIV-clade pathogenesis or simply an artifact of confounding variables such as data sampling, clinical diagnosis or opportunistic infections is unclear. Potential differences in clade B and C neurovirulence and the mechanism by which HIV-1 infected brain mononuclear phagocytes (MP; perivascular macrophages and microglia) mediate pathogenesis have yet to be investigated. Our recent preliminary data indicates clade B viral strains may produce more neurotoxins, such as glutamate, during HIV-1 infection than clade C viral strains. We have shown previously that HIV-1 clade B infection of MP leads to enhanced glutamate production through the enzyme glutaminase. In this R21 application, we hypothesize that neurotoxicity is mediated through brain inflammation and the dysregulation of glutaminase in HIV-1-infected macrophages. In comparison to HIV clade B, we hypothesize clade C isolates will demonstrate decreased infection efficiency, altered cytokine/chemokine profiles, and decreased glutamate production by infected MP, providing mechanistic insight into differences between clade B and C infection of the brain. We will apply human monocyte-derived macrophage (MDM) infected by a panel of HIV-1 strains (HIV-1 laboratory clade B strains, primary clade B strains and primary clade C strains), to a severe combined immune deficient (SCID) HIV-1 encephalitis (HIVE) mouse model, thus modeling macrophage driven HAD in vivo. This approach will utilize laboratory assays that mimic HIV-1 infection and immune activation of brain MP to investigate the effects of the CNS immune response on production of inflammatory factors and neurotoxins as well as neuronal injury as it occurs during HAD. This application will establish a foundation of work detailing the differences between viral clades and the potential implications for HIV-induced brain inflammation and dementia. Determining the mechanisms by which HIV-1 infected MP and cytokines influence neuronal injury may identify new therapeutic strategies for treating HAD and other neurodegenerative disorders. HIV-1 viral strain clade C is currently responsible for more than 50% of new HIV infections and is now the most commonly transmitted subtype worldwide. While HIV-1-associated dementia continues to be a major neurological complication of AIDS among HIV-1 clade B-infected individuals in the US and Europe, the incidence of HIV-1-associated dementia in regions like India and sub-Saharan Africa, where clade C infection is prevalent, appears to be lower. This application will establish a foundation of work detailing the differences between viral clade B and C and the potential implications for HIV-induced dementia. It is our hope that determining the mechanisms by which HIV-1 influence neuronal injury may identify new therapeutic strategies for treating HIV-1-associated dementia and other neurodegenerative disorders.

描述（由申请人提供）：HIV-1分支C目前负责超过50%的新HIV感染，现在是世界上最常见的传播亚型。虽然hiv -1相关痴呆（HAD）仍然是美国和欧洲b支感染者艾滋病的主要神经病理表现，但在C支感染普遍的印度和撒哈拉以南非洲等地区，HAD的发病率似乎较低。目前尚不清楚，神经艾滋病的低表观患病率是由于hiv分支发病机制的潜在差异，还是仅仅是数据采样、临床诊断或机会性感染等混杂变量的产物。B支和C支神经毒力的潜在差异以及HIV-1感染的脑单核吞噬细胞（MP；血管周围巨噬细胞和小胶质细胞）介导发病机制尚待研究。我们最近的初步数据表明，在HIV-1感染期间，进化支B型病毒株可能比进化支C型病毒株产生更多的神经毒素，如谷氨酸。我们之前已经证明，MP的HIV-1进化支B感染通过谷氨酰胺酶导致谷氨酸产生增强。在这项R21应用中，我们假设神经毒性是通过hiv -1感染巨噬细胞的脑炎症和谷氨酰胺酶失调介导的。与HIV进化枝B相比，我们假设进化枝C分离株将表现出感染效率降低，细胞因子/趋化因子谱改变，受感染的MP产生谷氨酸减少，这为进化枝B和C感染脑的差异提供了机制见解。我们将利用一组HIV-1毒株（HIV-1实验室进化支B毒株、初级进化支B毒株和初级进化支C毒株）感染的人单核细胞来源的巨噬细胞（MDM），建立严重联合免疫缺陷（SCID） HIV-1脑炎（HIVE）小鼠模型，从而在体内模拟巨噬细胞驱动的HAD。这种方法将利用模拟HIV-1感染和脑MP免疫激活的实验室分析来研究CNS免疫反应对炎症因子和神经毒素的产生以及HAD期间发生的神经元损伤的影响。该应用程序将为详细研究病毒分支之间的差异以及hiv诱导的脑炎症和痴呆的潜在影响奠定基础。确定HIV-1感染的MP和细胞因子影响神经元损伤的机制可能为治疗HAD和其他神经退行性疾病找到新的治疗策略。HIV-1病毒株进化支C目前造成了50%以上的新发HIV感染，现在是全世界传播最普遍的亚型。尽管在美国和欧洲，HIV-1相关痴呆仍然是HIV-1进化支b感染者艾滋病的主要神经系统并发症，但在印度和撒哈拉以南非洲等地区，HIV-1相关痴呆的发病率似乎较低，这些地区的进化支C感染普遍存在。该应用程序将为详细研究病毒分支B和C之间的差异以及hiv诱导的痴呆的潜在影响奠定基础。我们希望通过确定HIV-1影响神经元损伤的机制，可以确定治疗HIV-1相关痴呆和其他神经退行性疾病的新治疗策略。