SIV Encephalitis and Disease Progression

SIV 脑炎和疾病进展

• 批准号: 7059946
• 负责人: Clayton A. Wiley
• 金额: $ 65.22万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059946
• 关键词: AIDS dementia complex; Macaca mulatta; Macaca nemestrina; behavioral /social science research tag; benzodiazepine receptor; cell migration; cerebrospinal fluid; cytotoxic T lymphocyte; disease /disorder model; helper T lymphocyte; host organism interaction; infectious encephalitis; leukocyte count; longitudinal animal study; monocyte; neuropathology; positron emission tomography; psychoneuroimmunology; radiotracer; simian immunodeficiency virus; virus cytopathogenic effect; virus load

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患者患有临床表征为HIV相关痴呆症复合物的神经退行性疾病。根据我们的经验，由于机会性感染均匀表现出HIV脑炎以外的原因，艾滋病患者的尸检。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，但是，我们认为这可能是由于HIV感染的单核细胞的运输增加所致。单核细胞离开血流并进入中枢神经系统转化为巨噬细胞，并可以引发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HIV感染和破坏突触连通性提供了敏感靶标。 我们建议将Macaca Nemestrina和Macaco Mullata的SIV感染作为HIV脑炎的模型，以测试与我们的慢病毒神经病理论有关的几种假设。尽管没有动物疾病模型是完美的，但猿猴和人类神经系统，SIV和HIV感染之间的许多相似之处以及操纵和监测中枢神经系统损害的能力，使猕猴模型最适合这些研究。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，并随着突触基质的破坏而流入中枢神经系统。对于当前提案的所有三个目标，我们将研究一组36个SIV感染的猕猴。我们将以2周的间隔进行测量；所有动物的CSF和血清中的绝对CD4和CD8 T细胞计数和病毒载荷。在特定目标1中，我们将研究周围SIV感染与SIV脑炎的发展之间的关系。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，导致脑病毒负担增加。在特定的目标2中，我们将使用正电子发射断层扫描和外围苯二氮卓受体放射线[11C] -DAA1106评估CNS巨噬细胞的激活。我们假设，当动物开始表现出疾病进展（CD4 T细胞的下降，病毒血症的增加）时，它们将显示CSF病毒增加并增加DAA1106与CNS巨噬细胞激活一致的DAA1106的结合。在特定的目标3中，我们将测量尸检脑组织中的突触和细胞外基质损伤，并将其与外围和中央病毒载荷（DAA1106结合）进行比较。总而言之，拟议的具体目标将测试一组相互联系的假设，有助于定义突触损伤的机制和治疗靶标，以阻止其发育和进展。