Small Animal Model of HIV Neuropathogenesis in the HAART Era

HAART时代HIV神经发病机制的小动物模型

• 批准号: 8088734
• 负责人: PIETRO P SANNA
• 金额: $ 28.49万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8088734
• 关键词: AIDS Dementia Complex; AIDS neuropathy; Address; Affect; Alcohols; Animal Model; Apoptosis; Behavior; Behavioral; Blood - brain barrier anatomy; Body Composition; Body Temperature; Body Weight; Brain; Breeding; CD4 Lymphocyte Count; Cannabinoids; Cells; Central Nervous System Diseases; Characteristics; Chronic; Clinical; Clinical Research; Cocaine; Cognition; Comorbidity; Dementia; Development; Disease; Dose; Doxycycline; Drug abuse; Electrophysiology (science); Fibroblasts; Foundations; Future; Gagging; Generations; Genes; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Heroin; Highly Active Antiretroviral Therapy; In Vitro; Incidence; Individual; Infection; Injury; Investigation; Knockout Mice; Knowledge; Laboratory Study; Macrophage Colony-Stimulating Factor; Major Depressive Disorder; Maps; Methamphetamine; Microglia; Microtubule-Associated Protein 2; Modeling; Motivation; Motor Activity; Mus; Neuraxis; Neurocognitive; Neuronal Dysfunction; Neurons; Neuropathogenesis; Nicotine; Opiates; Pathogenesis; Patients; Pattern; Permeability; Phenotype; Plasma; Play; Prevalence; Proteins; Proviruses; Recombinants; Relative (related person); Reporter; Reverse Transcriptase Polymerase Chain Reaction; Synaptophysin; System; Testing; Tetracyclines; Therapeutic; Toxic Actions; Toxic effect; Trans-Activators; Transcript; Transgenes; Transgenic Mice; Transgenic Model; Transgenic Organisms; Viral; Viral Load result; Western Blotting; base; c-fms Proto-Oncogenes; chemokine; cytokine; design; drug of abuse; food consumption; interdisciplinary approach; macrophage; mouse model; neuropathology; neurotoxic; neurotoxicity; neurotropic; novel; novel therapeutics; postsynaptic; presynaptic; promoter; protein expression; receptor; scavenger receptor; transgene expression

DESCRIPTION (provided by applicant): HIV-associated neurocognitive disorders (HAND) continue to affect people with HIV despite the advent of highly active antiretroviral therapy (HAART). While the incidence of severe HIV-associated dementia (HAD) has decreased since the introduction of HAART, the prevalence of milder and chronic forms of HIV central nervous system (CNS) disease and HIV-associated major depressive disorder remains high. Converging evidence from clinical and laboratory studies suggest the hypothesis that the toxic actions of low-level expression of multiple HIV-1 products are key to persistent central nervous system HIV disease despite viral suppression in the context of HAART. In fact, HIV-associated neurocognitive disorders in the setting of viral suppression by HAART do not correlate with indicators of florid HIV-replication such as high plasma HIV-1 viral load and low CD4+ counts. Conversely, neurocognitive disorders in the setting of HAART correlate with markers of synaptodendritic injury, such as altered patterns of presynaptic synaptophysin and postsynaptic microtubule associated protein 2 (MAP2) that can also be induced in the absence of HIV-1 infection and replication in Tg mice of HIV-1 gp120 or Tat and in neuronal cultures treated with recombinant gp120. However, while the effects of gp120 and Tat have been mostly studied in isolation, other HIV-1 proteins including gp41, Vpr, Rev, and Vpu - although not Gag and Pol - possess neurotoxic potential. This suggests that the combined action of multiple HIV-1 products may contribute to neuronal dysfunction and its evolving phenotype in the HAART setting. To address this scientific knowledge gap, here we propose to establish and characterize a transgenic mouse model to probe the effects of concomitant low level expression of multiple HIV-1 products in disease-relevant cells of the microglia/macrophage lineage. Since strains isolated from patients with HIV-1 dementia have distinct neurotoxic activities, the proposed mouse model will be based on the neurotropic JR-CSF HIV-1 clone, while most HIV-1 Tg lines are based on the T-tropic pNL4-3. The proposed HIV-1 Tg model differs from all previously established models because it will have concomitant expression of multiple proteins of a neurotropic HIV-1 clone, it will be inducible by doxycycline and, lastly, expression of the transgene will be targeted to cells of the microglia/macrophage lineage. No existing small animal model possesses all of these characteristics. The lack of viral replication in the proposed Tg mice, while motivated by the aforementioned hypothesis, will have the added practical benefit of greatly facilitating electrophysiological and behavioral studies. Ultimately, the proposed Tg mice will allow mechanistic studies aimed at the generation of new pathogenetic hypotheses of HIV-associated neurocognitive disorders in the setting of HAART and their interaction with drugs of abuse. PUBLIC HEALTH RELEVANCE: Persistent central nervous system HIV disease despite viral suppression in the context of HAART represents a mounting clinical challenge. Evidence suggests that the toxic actions of low-level HIV-1 products are key in the neuropathogenesis of persistent central nervous system HIV disease despite viral suppression in the context of HAART. The proposed study will establish and characterize a new small animal model of neuroAIDS in the HAART era to aid in the development of novel pathogenetic hypotheses and potential therapeutic approaches with the long-term goal of generating new hypotheses on the pathogenesis of HIV-1-induced neurotoxicity and the interaction of HIV-1 infection and drug abuse on cognition and motivation as well as the investigation of novel therapeutic strategies for neuroAIDS.

描述（由申请人提供）：尽管高度活跃的抗逆转录病毒疗法（HAART）出现了与HIV相关的神经认知障碍（手）继续影响HIV患者。自从HAART引入以来，严重的HIV相关性痴呆（HAT）的发生率降低了，但HIV中枢神经系统（CNS）疾病的温和和慢性形式的流行率和与HIV相关的主要抑郁症仍然很高。 来自临床和实验室研究的融合证据表明，多个HIV-1产物低水平表达的毒性作用是持续性中枢神经系统HIV疾病的关键，尽管在HAART中抑制了病毒抑制。实际上，HAART在病毒抑制中与HIV相关的神经认知障碍与佛罗里德HIV复制的指标（例如高血浆HIV-1病毒载量和低CD4+计数）无关。相反，在HAART环境中的神经认知疾病与突触性损伤的标志物相关，例如突触前突触pros的模式改变的模式和突触后微管相关蛋白2（MAP2）也可以在HIV-1感染中不存在HIV-1 GRETIRES nIV cORTIENT of HIV-1 gpin of HIV METICERTION nIV cORTICENT或TAT型gp120或TAT Atat Atat Atat Atat Atat Atat Atat Atat and和Tat Atat cristibers haart疾病。 GP120。但是，尽管GP120和TAT的作用主要是分离的，但其他HIV -1蛋白在内，包括GP41，VPR，REV和VPU（尽管不是GAG和POL）具有神经毒性潜力。这表明多种HIV-1产物的综合作用可能导致神经元功能障碍及其在HAART环境中不断发展的表型。为了解决这一科学知识差距，我们在这里建议建立和表征转基因小鼠模型，以探测多个HIV-1产物在小胶质细胞/巨噬细胞谱系中疾病相关细胞中伴随的低水平表达的影响。由于从HIV-1痴呆患者中分离出的菌株具有独特的神经毒性活性，因此提出的小鼠模型将基于神经型JR-CSF HIV-1克隆，而大多数HIV-1 TG系基于T-热带PNL4-3。 所提出的HIV-1 TG模型与所有先前建立的模型都不同，因为它将具有神经性HIV-1克隆的多种蛋白的同时表达，它将被强力霉素诱导，最后，转基因的表达将靶向微胶质细胞/乳清细胞的细胞。没有现有的小动物模型具有所有这些特征。在拟议的TG小鼠中缺乏病毒复制，虽然是由上述假设的动机，但将具有大大促进电生理学和行为研究的额外实际好处。最终，拟议的TG小鼠将允许在HAART环境中产生与HIV相关的神经认知疾病的新致病假设以及它们与滥用药物的相互作用的机理研究。 公共卫生相关性：尽管在HAART的背景下抑制了病毒抑制，但持续性的中枢神经系统艾滋病毒疾病代表了一项越来越多的临床挑战。有证据表明，低水平HIV-1产物的毒性作用是尽管HAART的抑制病毒抑制，但持续性中枢神经系统HIV疾病的神经发病是至关重要的。拟议的研究将在HAART时代建立并表征新的小动物神经辅助动物模型，以帮助发展新型的致病假设和潜在的治疗方法，其长期目标是为HIV-1引起的HIV-1发病机制产生新的假设，以实现HIV-1诱导的神经毒性和对HIV-1感染和药物的相互作用以及对确诊的策略的相互作用以及对确保的相互作用的相互作用以及对良好的研究的相互作用的研究。神经辅助。