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 C 分支目前占新发 HIV 感染的 50% 以上，并且是目前全球最常见传播的亚型。虽然 HIV-1 相关痴呆 (HAD) 仍然是美国和欧洲 B 分支感染者中艾滋病的主要神经病理学表现，但在印度和撒哈拉以南非洲等 C 分支感染流行的地区，HAD 的发病率似乎较低。神经艾滋病的低表观患病率是否是由于 HIV 分支发病机制的潜在差异，或者仅仅是数据采样、临床诊断或机会性感染等混杂变量的结果，目前尚不清楚。 B 型和 C 型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）介导发病机制的机制尚未得到研究。我们最近的初步数据表明，在 HIV-1 感染过程中，B 型病毒株可能比 C 型病毒株产生更多的神经毒素，例如谷氨酸。我们之前已经证明，MP 的 HIV-1 进化枝 B 感染会通过谷氨酰胺酶导致谷氨酸产量增加。在此 R21 应用中，我们假设神经毒性是通过脑部炎症和 HIV-1 感染的巨噬细胞中谷氨酰胺酶的失调介导的。与 HIV B 分支相比，我们假设 C 分支分离株将表现出感染效率降低、细胞因子/趋化因子谱改变以及受感染 MP 产生的谷氨酸减少，从而为大脑 B 分支和 C 分支感染之间的差异提供机制见解。我们将应用被一组 HIV-1 毒株（HIV-1 实验室进化枝 B 毒株、初级进化枝 B 毒株和初级进化枝 C 毒株）感染的人单核细胞源性巨噬细胞 (MDM) 应用于严重联合免疫缺陷 (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。该方法将利用模拟 HIV-1 感染和脑 MP 免疫激活的实验室检测来研究 CNS 免疫反应对炎症因子和神经毒素产生以及 HAD 期间发生的神经元损伤的影响。该应用将为详细说明病毒进化枝之间的差异以及对艾滋病毒引起的脑部炎症和痴呆症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会确定治疗 HAD 和其他神经退行性疾病的新治疗策略。 HIV-1 病毒株 C 分支目前占新发 HIV 感染的 50% 以上，并且是目前全球最常见传播的亚型。虽然 HIV-1 相关痴呆仍然是美国和欧洲 HIV-1 B 型感染者中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 C 型感染流行的地区，HIV-1 相关痴呆的发病率似乎较低。该应用将为详细说明病毒进化枝 B 和 C 之间的差异以及对 HIV 诱发的痴呆症的潜在影响奠定基础。我们希望确定 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。