SIV Encephalitis and Disease Progression

SIV 脑炎和疾病进展

• 批准号: 7689596
• 负责人: Clayton A. Wiley
• 金额: $ 3.65万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689596
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Address; Animal Disease Models; Animals; Autopsy; Benzodiazepine Receptor; Binding; Blood; Brain; Brain region; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Complex; DAA 1106; Development; Disease; Disease Progression; Encephalitis; Exhibits; Extracellular Matrix; HIV Infections; HIV encephalitis; Human; Immune; Individual; Infection; Infiltration; Left; Ligand Binding; Ligands; Macaca; Macaca mulatta; Macaca nemestrina; Measurement; Measures; Microglia; Modeling; Monitor; Nervous system structure; Neurodegenerative Disorders; Neuropathogenesis; Opportunistic Infections; Pathogenesis; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Population; Positron-Emission Tomography; Research Personnel; SIV; SIV encephalitis; Scanning; Serum; Stream; Synapses; Systemic disease; Systemic infection; T-Lymphocyte; Testing; Tissues; Variant; Viral; Viral Load result; Viremia; Virus; Week; brain tissue; experience; extracellular; immunosuppressed; macrophage; monocyte; neuropathology; radioligand; research study; theories; therapeutic target; trafficking

DESCRIPTION (provided by applicant): Approximately 1/4 of immunosuppressed AIDS patients develop a neurodegenerative disorder clinically characterized as HIV associated dementia complex. In our experience, autopsies of AIDS patients who had become demented for reasons other than opportunistic infection uniformly demonstrated HIV encephalitis. Why there is such an abundance of activated and infected macrophages in the CNS remains an enigma, however, we theorize that it may be due to increased trafficking of HIV-infected monocytes. Monocytes are activated upon leaving the blood stream and entering the CNS where they transform into macrophages and can initiate viral replication and a neuroinflammatory cascade. Tissue damage begins a cycle of astrocytic and microglial activation, providing susceptible targets for further HIV infection and destruction of synaptic connectivity. We propose to use SIV infection of Macaca nemestrina and Macaco mullata as models of HIV encephalitis to test several hypotheses related to our theory of lentiviral neuropathogenesis. While no animal disease model is perfect, numerous similarities between simian and human nervous systems, between SIV and HIV infection and the capacity to manipulate and monitor CNS damage, make the macaque models optimal for these studies. Our overarching hypothesis is: Progression of SIV infection leads to increased monocyte/macrophage infection and trafficking into the CNS with destruction of the synaptic matrix. For all 3 aims of the current proposal, we will study a group of 36 SIV infected macaques. At 2-week intervals we will measure; absolute CD4 and CD8 T-cell counts and viral loads in the CSF and serum of all animals. In Specific Aim 1 we will examine the relationship between peripheral SIV infection and the development of SIV encephalitis. These experiments will test the hypothesis that: with progression of immune suppression there is increased trafficking of SIV infected monocytes causing increased brain viral burden. In Specific Aim 2 we will assess activation of CNS macrophages using Positron Emission Tomography and the peripheral benzodiazepine receptor radioligand [11C]-DAA1106. We hypothesize that when animals begin to show disease progression (decline in CD4 T-cells, increase in viremia) they will show increased CSF virus and increased binding of DAA1106 consistent with activation of CNS macrophages. In Specific Aim 3 we will measure synaptic and extracellular matrix damage in autopsy brain tissues and compare them to the temporal course of peripheral and central viral loads, DAA1106 binding. In summary, the proposed specific aims will test a set of interconnected hypotheses helping define mechanisms of synaptic damage and therapeutic targets to arrest its development and progression.

描述（由申请人提供）：大约 1/4 的免疫抑制 AIDS 患者会出现神经退行性疾病，临床特征为 HIV 相关痴呆综合征。根据我们的经验，对因机会性感染以外的原因而变得精神错乱的艾滋病患者进行尸检，结果一致表明患有艾滋病毒脑炎。为什么中枢神经系统中有如此丰富的激活和感染的巨噬细胞仍然是一个谜，然而，我们推测这可能是由于感染艾滋病毒的单核细胞的运输增加所致。单核细胞在离开血流并进入中枢神经系统后被激活，在那里它们转化为巨噬细胞，并可以启动病毒复制和神经炎症级联反应。组织损伤开始了星形胶质细胞和小胶质细胞激活的循环，为进一步的艾滋病毒感染和突触连接的破坏提供了易感目标。 我们建议使用猕猴和猕猴的 SIV 感染作为 HIV 脑炎模型来测试与我们的慢病毒神经发病机制理论相关的几个假设。虽然没有完美的动物疾病模型，但猿猴和人类神经系统之间、SIV 和 HIV 感染之间以及操纵和监测中枢神经系统损伤的能力之间存在许多相似之处，使得猕猴模型成为这些研究的最佳模型。我们的总体假设是：SIV 感染的进展导致单核细胞/巨噬细胞感染增加并流入中枢神经系统，同时破坏突触基质。为了实现当前提案的所有 3 个目标，我们将研究一组 36 只感染 SIV 的猕猴。我们将每隔两周进行一次测量；所有动物脑脊液和血清中的绝对 CD4 和 CD8 T 细胞计数以及病毒载量。在具体目标 1 中，我们将研究外周 SIV 感染与 SIV 脑炎发展之间的关系。这些实验将检验以下假设：随着免疫抑制的进展，SIV 感染的单核细胞的运输增加，导致脑病毒负荷增加。在具体目标 2 中，我们将使用正电子发射断层扫描和外周苯二氮卓受体放射性配体 [11C]-DAA1106 评估 CNS 巨噬细胞的活化。我们假设，当动物开始表现出疾病进展（CD4 T 细胞减少、病毒血症增加）时，它们将表现出脑脊液病毒增加和 DAA1106 结合增加，这与中枢神经系统巨噬细胞的激活一致。在具体目标 3 中，我们将测量尸检脑组织中的突触和细胞外基质损伤，并将其与外周和中枢病毒载量、DAA1106 结合的时间过程进行比较。总之，所提出的具体目标将测试一组相互关联的假设，帮助定义突触损伤的机制和阻止其发展和进展的治疗目标。