NeuroAIDS Therapy in the EcoHIV Mouse Model

EcoHIV 小鼠模型中的神经艾滋病治疗

基本信息

批准号：
7495847
负责人：
DAVID J VOLSKY
金额：
$ 20.33万
依托单位：
ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS
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：
2008-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7495847
关键词：
AIDS Dementia Complex AIDS neuropathy Acute Adult Animal Model Animals Anti-Retroviral Agents Antiviral Agents Bone Marrow Bone Marrow Cells Brain Brain Diseases Cells Cellular Assay Central Nervous System Infections Confusion Development Disease Disease Marker Experimental Models Functional disorder Future Gene Expression HIV Envelope Protein gp120 HIV-1 Highly Active Antiretroviral Therapy Human Immunocompetent Immunologic Deficiency Syndromes Infection Intravenous Life Lymphocyte Memory Methods Modeling Monitor Movement Mus Nervous system structure Neuraxis Neuropathogenesis Nevirapine New Agents Numbers Pathogenesis Patients Penetration Peripheral Pharmaceutical Preparations Polymerase Chain Reaction Prevention Prophylactic treatment Protease Inhibitor Proteins Public Health Reporting Saquinavir Spleen Testing Time Tissues Transcript Viral Viral Load result Virus Virus Diseases Virus Replication Week Zalcitabine abacavir brain cell brain tissue design drug efficacy drug testing immune function immunocytochemistry improved in vivo macrophage mouse model nervous system disorder prevent programs pup translational study young adult

项目摘要

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy (HAART) for HIV-1 infection effectively reduces systemic virus burden and improves immune function in most compliant patients. Nevertheless, HIV-1-associated dementia and other nervous system disorders persist. Viral reservoirs in long-lived macrophages and brain cells are not sensitive to HAART and the brain is inaccessible to certain drugs. This application is designed to investigate the effects of antiviral drugs on HIV-1 replication and pathogenesis in the brain experimentally using a new model of HIV-1 infection of immunocompetent mice by the chimeric virus, EcoHIV/NDK. This virus encodes all the proteins of HIV-1, except gp120, and thus preserves sensitivity to HAART agents. We recently reported that zalcitabine and abacavir block EcoHIV/NDK infection of mice and show in this application that nevirapine and the protease inhibitor saquinavir significantly reduce virus spread in mice. Access to a large number of infected animals and monitoring of virus in multiple tissues using real-time PCR permit quantitative test of drug efficacy, and through assay of cellular transcripts, brain cell dysfunction in our model. In this developmental program we propose to 1) test the efficacy of antiretroviral drugs for prophylaxis of acute peripheral and central nervous system infection of adult and young mice by EcoHIV/NDK and 2) test the efficacy of antiretroviral drugs for reduction of established EcoHIV/NDK infection in peripheral tissues and brain and consequential neuropathogenesis in young mice. Virus burden in lymphocytes, macrophages, and the brain and activation of brain cell gene expression will be determined by real-time PCR and microglial activation will be assessed by immunocytochemistry. This program directly investigates whether drugs with poor access to the brain can prevent establishment of a nervous system reservoir of HIV-1 and brain disease, whether virus resident in the brain is sensitive to HAART agents, and to what extent inhibition of ongoing virus replication depletes viral reservoirs in brain cells, macrophages, and bone marrow and ameliorates brain disease. This developmental program is proposed to guide future translational studies in this animal model to screen or develop new agents for their ability to prevent HIV-1-associated neuropathogenesis. PUBLIC HEALTH RELEVANCE HIV-1 infection causes immunodeficiency and often nervous system disorders resulting in memory lapses, confusion, and poorly controlled movements. This application proposes to use mice experimentally infected by HIV-1 and antiviral drugs now used in human beings to determine whether they block infection and disease in the mouse brain. In addition, the application will test if drugs given to mice after infection actually eliminate virus from the brain, giving promise for the ability of antiviral drugs to control the nervous system disease seen in infected human beings.

描述（由申请人提供）：HIV-1感染的高度活性抗逆转录病毒疗法（HAART）有效地减轻了全身病毒负担，并改善了大多数兼容的患者的免疫功能。然而，HIV-1相关的痴呆症和其他神经系统疾病持续存在。长寿命巨噬细胞中的病毒储量和脑细胞对HAART不敏感，大脑对某些药物无法接近。该应用旨在研究抗病毒药物对脑在脑中使用嵌合病毒EcoHIV/NDK的HIV-1感染的新型HIV-1感染模型对HIV-1的复制和发病机理的影响。该病毒编码除GP120以外的所有HIV-1的蛋白质，因此可以保留对HAART剂的敏感性。我们最近报道说，Zalcitabine和Abacavir阻滞了小鼠的Ecohiv/NDK感染，并在此应用中表明Nevirapine和蛋白酶抑制剂Saquinavir显着降低了小鼠中病毒的扩散。使用实时PCR允许对药物疗效的定量测试，并通过分析细胞转录本，我们的模型中的脑细胞功能障碍，从而获得大量感染动物并在多个组织中监测病毒。在此发展计划中，我们建议1）测试抗逆转录病毒药物对成年和年轻小鼠的急性外周和中枢神经系统感染的预防，并通过Ecohiv/NDK和2）测试抗逆转录病毒药物的抗逆转录病毒药物的功效，以减少Ecohiv/NDK感染在年轻人中和脑料中的降低。淋巴细胞，巨噬细胞以及脑细胞基因表达的大脑和激活中的病毒负担将由实时PCR确定，小胶质细胞激活将通过免疫细胞化学评估。该计划直接调查了无法吸引大脑的药物是否可以防止建立HIV-1和脑部疾病的神经系统储量，是否驻留在大脑中的病毒对HAART剂敏感，以及在多大程度上抑制了持续的病毒复制耗尽病毒病毒储存，脑细胞中的脑细胞，巨噬细胞，巨噬细胞，骨气和骨气和脑膜病。提出了该开发计划，以指导该动物模型中的未来翻译研究，以筛选或开发新的药物，以防止与HIV-1相关的神经病发生能力。公共卫生相关性HIV-1感染会引起免疫缺陷，并经常导致神经系统疾病导致记忆失误，混乱和控制不良的运动。该应用建议使用人类现在使用的HIV-1和抗病毒药物实验感染的小鼠来确定它们是否阻断了小鼠大脑中的感染和疾病。此外，该应用将测试感染后给小鼠服用的药物是否实际上消除了大脑病毒，从而有望抗病药物控制感染人类中神经系统疾病的能力。