SIV Encephalitis and Disease Progression

描述（由申请人提供）：大约1/4的免疫抑制AIDS患者发展为神经退行性疾病，临床特征为HIV相关痴呆综合征。根据我们的经验，对那些并非由于机会性感染而变得痴呆的艾滋病患者进行尸检时，一致表现为HIV脑炎。为什么在中枢神经系统中有如此丰富的活化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HIV感染的单核细胞的运输增加。单核细胞在离开血流并进入CNS时被激活，在CNS中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。组织损伤开始星形胶质细胞和小胶质细胞活化的循环，为进一步的HIV感染和突触连接的破坏提供易感靶点。 我们建议使用SIV感染的猕猴nemestrina和猕猴mullata作为模型的HIV脑炎，以测试几个假设与我们的慢病毒神经发病机制的理论。虽然没有一种动物疾病模型是完美的，但猿和人类神经系统之间、SIV和HIV感染之间以及操纵和监测CNS损伤的能力之间的许多相似之处，使猕猴模型成为这些研究的最佳模型。我们的首要假设是：SIV感染的进展导致单核细胞/巨噬细胞感染增加并运输到CNS中，同时破坏突触基质。对于当前提案的所有3个目标，我们将研究一组36只SIV感染的猕猴。每隔2周，我们将测量所有动物的CSF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感染和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体[11 C]-DAA1106评估CNS巨噬细胞的活化。我们假设，当动物开始显示疾病进展（CD4 T细胞下降，病毒血症增加）时，它们将显示CSF病毒增加和DAA1106结合增加，与CNS巨噬细胞活化一致。在特定目标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的时间过程、DAA1106结合进行比较。总之，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治疗靶点，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.