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

基本信息

批准号：
7493739
负责人：
Jialin Charles Zheng
金额：
$ 23.25万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-11 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7493739
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 day fight against in vivo in vivo Model inhibitor/antagonist insight macrophage monocyte mouse model neuronal survival neurotoxic neurotoxicity neurovirulence novel novel therapeutics research study response small molecule therapeutic target virology

项目摘要

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进化枝C当前负责超过50％的新艾滋病毒感染，现在是全球最常见的亚型。尽管HIV-1相关的痴呆症（曾经）仍然是美国和欧洲进化枝B感染者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地区的发生率较低。神经辅助的明显明显流行率是否是由于HIV塑料发病机理的潜在差异，还是仅仅是诸如数据采样，临床诊断或机会性感染之类的混杂变量的伪像。进化枝B和C神经电动机的潜在差异以及HIV-1感染脑单核吞噬细胞（MP；血管周围巨噬细胞和小胶质细胞）介导的发病机理的机制尚未研究。我们最近的初步数据表明，在HIV-1感染期间，进化枝B病毒菌株可能会产生更多的神经毒素，例如谷氨酸，而不是进化枝C病毒菌株。我们先前已经证明，HIV-1进化枝B感染MP通过酶谷氨酰胺酶导致谷氨酸酶产生增强。在此R21应用中，我们假设神经毒性是通过脑炎症和HIV-1感染的巨噬细胞中谷氨酰胺酶的失调介导的。与HIV进化枝B相比，我们假设进化枝C分离株将表明感染效率降低，细胞因子/趋化因子谱的改变，并通过受感染的MP降低了谷氨酸的产生，从而提供了对大脑核B和脑部感染之间差异的机械性洞察力。我们将应用人类单核细胞衍生的巨噬细胞（MDM）感染，这些巨噬细胞（MDM）被HIV-1菌株（HIV-1实验室进化枝B菌株，原发性进化枝B菌株和原发性进化枝C菌株）感染，以严重的免疫缺陷（SCID）HIV-1 HIV-1脑炎（HIVE）脑炎（Hive）模型（HIVE）模型，从而建模了Moclophage Mocrophage Mocolaphage Mocolage ModigentiveRived Mocrophage Modiven vivo。这种方法将利用实验室测定方法，即模仿HIV-1感染和脑MP的免疫激活来研究中枢神经系统免疫反应对炎症因子和神经毒素的产生以及在HES中发生的神经元损伤的影响。该应用将建立工作的基础，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的潜在影响。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确定治疗HAT和其他神经退行性疾病的新治疗策略。 HIV-1病毒应变进化枝C目前负责超过50％的新艾滋病毒感染，现在是全球最常见的亚型。尽管HIV-1相关的痴呆症仍然是美国和欧洲HIV-1进化群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，与HIV-1相关的痴呆症的发生率似乎是较低的。该应用将建立详细介绍病毒进化枝B和C之间差异以及对HIV引起的痴呆症的潜在影响的工作的基础。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相关痴呆症和其他神经退行性疾病的新治疗策略。