Markers of HIV Brain Disease under HAART: Validation in a Mouse Model

HAART 下 HIV 脑疾病的标志物：在小鼠模型中的验证

• 批准号: 8270577
• 负责人: MARY Jane POTASH
• 金额: $ 46.97万
• 依托单位: ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270577
• 关键词: Abbreviations; Address; Affect; Animal Model; Anterior; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Area; Basal Ganglia; Bioinformatics; Biological; Biological Assay; Biological Markers; Brain; Brain Diseases; Categories; Cell physiology; Cells; Central Nervous System Diseases; Cessation of life; Characteristics; Chronic; Clinical; Cognition Disorders; Cognitive; Collaborations; Communities; DNA; Data; Data Quality; Data Set; Databases; Defect; Detection; Development; Disease; Electrospray Ionization; Elements; Encephalitis; Event; Experimental Models; Fluorescence Microscopy; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; HIV; HIV Infections; HIV-1; Health; Highly Active Antiretroviral Therapy; Hippocampus (Brain); Human; Immunocompetent; Immunodeficient Mouse; Immunohistochemistry; Impairment; Individual; Infection; Inflammation; Inflammatory; Interdisciplinary Study; Intervention; Intravenous; Lead; Life; Lipids; Macrophage Activation; Measures; Medical; Metabolic; Methods; Minor; Modeling; Modification; Molecular; Molecular Profiling; Mus; Nested PCR; Neuraxis; Neurons; Oxidative Stress; Oxidative Stress Pathway; Pathway interactions; Patient Representative; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Physiology; Production; Proteins; Proviruses; RNA; Recommendation; Recording of previous events; Refractory; Relative (related person); Research; Research Personnel; Residual state; Sampling; Science; Synapses; System; Testing; Time; Tissue Sample; Validation; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; analog; base; biological adaptation to stress; brain cell; brain tissue; cognitive function; cohort; design; effective therapy; falls; frontal lobe; functional genomics; gazer; gene discovery; genome-wide; immune function; improved; large-scale database; metabolomics; molecular phenotype; motor disorder; mouse model; neurotropic; promoter; protein expression; protein profiling; receptor; response; southern hybridization; study characteristics; success; tandem mass spectrometry; tool; viral RNA; white matter

DESCRIPTION (provided by applicant): This proposal is submitted in response to PA-07-089. Despite its overall success at restoring immune function and often cognitive function in demented HIV-1-infected persons, highly active antiretroviral therapy has limited effects upon milder CNS disease that is increasingly prevalent. Based on our findings of treatment independent, significant gene dysregulation in brains of patients with minor cognitive and motor disorder (MCMD), we hypothesize that there are core changes in brain physiology arising from long-lived infected cells that persist through existing therapies, which were not designed to arrest expression of integrated provirus. Unabated production of viral proteins by these cells can cause cumulative inflammatory, antiviral, and oxidative stress reactions that affect neuronal function. To test this hypothesis as well as one mechanism underlying the core defect we propose four Specific Aims to: 1) establish genome-wide brain gene expression profiles representative of patients with milder forms of HIV CNS disease; 2) identify biological pathways and biomarkers in the brain characteristic of continuing mild HIV CNS disease in the presence of antiretroviral treatment; 3) validate selected markers of mild HIV CNS disease in a mouse model of HIV infection in immunocompetent and immunodeficient mice; 4) test the hypothesis that mild, chronic HIV CNS disease depends upon low level virus transcription unaffected by existing antiretroviral treatment. We rely upon brain tissue from well defined patient cohorts assembled by Dr. S. Morgello, gene discovery through genome wide expression analysis and bioinformatics, confirmatory studies including pathways of oxidative stress visible in lipid metabolites with Dr. Haughey, and a robust experimental model of HIV infection in mice that reproduces many features of mild CNS disease. Using chimeric HIV that can infect mice and is amenable to genetic modification, we shall test one causal hypothesis for mild CNS disease: low-level virus transcription that persists in the brain despite effective therapy maintains dysregulation of brain cell physiology that is expressed as MCMD. If these studies demonstrate that low level HIV-1 expression impairs cellular function in the brain despite antiviral treatment, efforts should be directed toward development of new antiviral agents to block viral transcription from cellular reservoirs. PUBLIC HEALTH RELEVANCE Medical science has prolonged life and improved health of HIV-infected people through development of effective antiviral drugs. Nevertheless, some aspects of HIV disease persist despite treatment, one of these leads to functional abnormalities in the brain and central nervous system. We propose to determine the molecular bases of this mild, but significant and persistent brain disease using state-of-the-art gene discovery and lipid metabolomics tools. Once confirmed in human beings, we shall use these markers of mild brain disease to test whether a similar disease caused by HIV infection of mice persists in the presence of drug treatment, even when the virus infection begins in the brain. Finally, we shall ask questions about the origin of mild brain disease in HIV infected people with effective therapy by establishing an experimental HIV infection in the brains of mice that is silent until it is turned on. By turning on and off this brain HIV, we shall determine whether it is residual HIV expression itself that causes the mild disease in the brain that cannot be controlled by existing drugs. This research may lead to two recommendations for control of the HIV CNS impairment that persists under current HAART regimes: a) earlier antiviral intervention relative to seroconversion than it is customary today; b) a call to the scientific and pharmaceutical communities to develop anti-HIV drugs that stop HIV expression.

描述（由申请人提供）：本提案是根据PA-07-089提交的。尽管其在恢复痴呆HIV-1感染者的免疫功能和认知功能方面取得了总体成功，但高效抗逆转录病毒疗法对日益流行的轻度CNS疾病的影响有限。基于我们在患有轻微认知和运动障碍（MCMD）的患者的大脑中的治疗独立的、显著的基因失调的发现，我们假设存在由通过现有疗法持续存在的长寿命感染细胞引起的大脑生理学的核心变化，所述现有疗法不是设计用于阻止整合的前病毒的表达。这些细胞产生的病毒蛋白质有增无减，可引起累积的炎症、抗病毒和氧化应激反应，影响神经元功能。为了验证这一假设以及核心缺陷的一种机制，我们提出了四个具体目标：1）建立代表轻度HIV CNS疾病患者的全基因组脑基因表达谱; 2）鉴定抗逆转录病毒治疗存在下持续轻度HIV CNS疾病的脑特征的生物学途径和生物标志物; 3）在免疫活性小鼠和免疫缺陷小鼠的HIV感染的小鼠模型中验证轻度HIV CNS疾病的所选标志物; 4）检验轻度、慢性HIV CNS疾病取决于不受现有抗逆转录病毒治疗影响的低水平病毒转录的假设。我们依赖于由S. Morgello，通过全基因组表达分析和生物信息学进行的基因发现，包括与Haughey博士在脂质代谢物中可见的氧化应激途径的确证性研究，以及在小鼠中复制许多轻度CNS疾病特征的HIV感染的稳健实验模型。使用可以感染小鼠并适合遗传修饰的嵌合HIV，我们将测试轻度CNS疾病的一个因果假设：尽管有效治疗，但仍存在于大脑中的低水平病毒转录维持表达为MCMD的脑细胞生理学失调。如果这些研究表明，尽管抗病毒治疗，低水平的HIV-1表达会损害脑细胞功能，那么应该努力开发新的抗病毒剂来阻断细胞库中的病毒转录。公共卫生相关性医学科学通过开发有效的抗病毒药物延长了艾滋病毒感染者的寿命并改善了他们的健康状况。尽管如此，艾滋病毒疾病的某些方面仍然存在，其中一个导致大脑和中枢神经系统的功能异常。我们建议使用最先进的基因发现和脂质代谢组学工具来确定这种轻度但显著且持续的脑部疾病的分子基础。一旦在人类中得到证实，我们将使用这些轻度脑部疾病的标志物来测试由HIV感染引起的小鼠的类似疾病是否在药物治疗的情况下持续存在，即使病毒感染开始在大脑中。最后，我们将通过在小鼠大脑中建立一种实验性HIV感染来询问HIV感染者轻度脑疾病的起源，这种感染在被激活之前是沉默的，通过激活和关闭这种大脑HIV，我们将确定是否是残留的HIV表达本身导致了大脑中的轻度疾病，而这种轻度疾病不能被现有药物控制。这项研究可能会导致两个建议，以控制艾滋病毒中枢神经系统的损害，持续在目前的HAART制度：a）早期的抗病毒干预相对于血清转换比今天的习惯; B）呼吁科学和制药界开发抗艾滋病毒药物，停止艾滋病毒的表达。