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

基本信息

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
项目类别：
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

项目摘要

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）：尽管出现了高效抗逆转录病毒疗法（HAART），但 HIV 相关神经认知障碍（HAND）继续影响着 HIV 感染者。虽然自引入HAART以来，严重的HIV相关痴呆（HAD）的发病率有所下降，但较轻微和慢性的HIV中枢神经系统（CNS）疾病和HIV相关的重度抑郁症的患病率仍然很高。来自临床和实验室研究的综合证据表明，多种 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 背景下病毒受到抑制。事实上，在HAART抑制病毒的情况下，与HIV相关的神经认知障碍与HIV大量复制的指标（例如高血浆HIV-1病毒载量和低CD4+计数）并不相关。相反，HAART 环境中的神经认知障碍与突触树突损伤的标志物相关，例如突触前突触素和突触后微管相关蛋白 2 (MAP2) 模式的改变，这些改变也可以在 Tg 小鼠中在没有 HIV-1 感染和复制的情况下诱导HIV-1 gp120 或 Tat 以及用重组 gp120 处理的神经元培养物中。然而，虽然 gp120 和 Tat 的作用大多是单独研究的，但其他 HIV-1 蛋白（包括 gp41、Vpr、Rev 和 Vpu）（尽管 Gag 和 Pol 除外）具有潜在的神经毒性。这表明多种 HIV-1 产品的联合作用可能会导致 HAART 环境中的神经元功能障碍及其不断演变的表型。为了解决这一科学知识差距，我们建议建立并表征转基因小鼠模型，以探讨多种 HIV-1 产物在小胶质细胞/巨噬细胞谱系的疾病相关细胞中同时低水平表达的影响。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，因此拟议的小鼠模型将基于神经亲性 JR-CSF HIV-1 克隆，而大多数 HIV-1 Tg 系基于 T 向性 pNL4-3 。所提出的 HIV-1 Tg 模型不同于所有先前建立的模型，因为它将同时表达嗜神经 HIV-1 克隆的多种蛋白质，它将被多西环素诱导，最后，转基因的表达将针对以下细胞：小胶质细胞/巨噬细胞谱系。现有的小动物模型不具备所有这些特征。所提出的 Tg 小鼠中缺乏病毒复制，虽然受到上述假设的推动，但将具有极大促进电生理学和行为研究的额外实际好处。最终，所提出的 Tg 小鼠将允许进行机制研究，旨在在 HAART 背景下产生 HIV 相关神经认知障碍的新发病机制及其与滥用药物的相互作用。公共卫生相关性：尽管在 HAART 背景下病毒受到抑制，但中枢神经系统 HIV 疾病仍持续存在，这是一个日益严峻的临床挑战。有证据表明，尽管在 HAART 背景下病毒受到抑制，但低水平 HIV-1 产物的毒性作用是持续性中枢神经系统 HIV 疾病的神经发病机制的关键。拟议的研究将建立并描述 HAART 时代新的神经艾滋病小动物模型，以帮助开发新的发病机制假说和潜在的治疗方法，长期目标是产生关于 HIV-1 诱导的发病机制的新假说神经毒性以及 HIV-1 感染和药物滥用对认知和动机的相互作用以及神经艾滋病新治疗策略的研究。