NeuroAIDS Therapy in the EcoHIV Mouse Model

EcoHIV 小鼠模型中的神经艾滋病治疗

• 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
• 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

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）：用于HIV-1感染的高效抗逆转录病毒疗法（HAART）可有效降低大多数依从患者的全身病毒负荷并改善免疫功能。然而，与HIV-1相关的痴呆和其他神经系统疾病仍然存在。长寿巨噬细胞和脑细胞中的病毒库对HAART不敏感，某些药物无法进入大脑。本申请的目的是研究抗病毒药物对HIV-1复制和发病机制的影响，在大脑实验中使用HIV-1感染免疫活性小鼠的嵌合病毒，EcoHIV/NDK的新模型。该病毒编码HIV-1的所有蛋白质（除gp 120外），因此保留了对HAART试剂的敏感性。我们最近报道了扎西他滨和阿巴卡韦阻断小鼠的EcoHIV/NDK感染，并在该应用中显示奈韦拉平和蛋白酶抑制剂沙奎那韦显著降低了小鼠中的病毒传播。获得大量感染的动物和使用实时PCR监测多个组织中的病毒允许定量测试药物疗效，并通过测定细胞转录本，在我们的模型中的脑细胞功能障碍。在本开发项目中，我们建议1）检测抗逆转录病毒药物预防成年和幼龄小鼠急性外周和中枢神经系统感染EcoHIV/NDK的有效性，2）检测抗逆转录病毒药物减少幼龄小鼠外周组织和脑中已建立的EcoHIV/NDK感染以及相应神经发病机制的有效性。将通过实时PCR测定淋巴细胞、巨噬细胞和脑中的病毒负荷以及脑细胞基因表达的活化，并通过免疫细胞化学评估小胶质细胞活化。该计划直接调查药物进入大脑是否可以防止建立HIV-1和脑部疾病的神经系统储库，是否驻留在大脑中的病毒对HAART药物敏感，以及在多大程度上抑制正在进行的病毒复制耗尽脑细胞，巨噬细胞和骨髓中的病毒储库并改善脑部疾病。该开发计划旨在指导未来在该动物模型中的转化研究，以筛选或开发能够预防HIV-1相关神经发病机制的新药物。公共卫生相关性HIV-1感染会导致免疫缺陷，通常还会导致神经系统疾病，从而导致记忆丧失、意识模糊和运动控制不良。该申请提出使用实验性感染HIV-1的小鼠和现在用于人类的抗病毒药物来确定它们是否阻断小鼠大脑中的感染和疾病。此外，该应用程序将测试感染后给予小鼠的药物是否真的能将病毒从大脑中清除，从而有望使抗病毒药物能够控制受感染人类的神经系统疾病。