SIV Encephalitis and Disease Progression

描述(由申请人提供)：大约四分之一的免疫抑制的艾滋病患者会发展成一种神经退行性疾病，临床特征是HIV相关性痴呆综合征。根据我们的经验，因机会性感染以外的其他原因而患上痴呆症的爱滋病患者，其身体剖检均显示为爱滋病毒脑炎。为什么中枢神经系统中有如此多的被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艾滋病毒感染的单核细胞的运输增加所致。单核细胞在离开血流进入中枢神经系统后被激活，在那里它们转化为巨噬细胞，并可启动病毒复制和神经炎性级联反应。组织损伤开始了星形胶质细胞和小胶质细胞激活的循环，为进一步感染艾滋病毒和破坏突触连接提供了易感靶点。 我们建议使用恒河猴和恒河猴的SIV感染作为HIV脑炎的模型，以检验与我们的慢病毒神经发病理论相关的几个假说。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感染之间的许多相似之处，以及操纵和监测中枢神经系统损伤的能力，使猕猴模型成为这些研究的最佳选择。我们的主要假设是：SIV感染的进展导致单核/巨噬细胞感染增加，并随着突触基质的破坏而进入中枢神经系统。对于当前提案的所有三个目标，我们将研究一组36只感染SIV的猕猴。每隔两周，我们将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，我们将探讨外周SIV感染与SIV脑炎发生发展的关系。这些实验将检验这样的假设：随着免疫抑制的进展，SIV感染的单核细胞的运输增加，导致大脑病毒负担增加。在特定目标2中，我们将使用正电子发射断层扫描和外周苯二氮卓类受体放射性配基[11C]-DAA1106来评估CNS巨噬细胞的激活。我们假设，当动物开始出现疾病进展(CD4T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。在特定的目标3中，我们将测量尸检脑组织中突触和细胞外基质的损伤，并将它们与外周和中枢病毒负载的时间进程、DAA1106结合进行比较。总之，提出的具体目标将测试一系列相互关联的假说，帮助确定突触损伤的机制和治疗目标，以阻止其发展和进展。

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.