HIV-1 Infection Increases Brain Amyloid Beta

描述（由申请人提供）：在高效抗逆转录病毒治疗（HAART）之前，HIV相关性痴呆（HAD）是一种急性神经退行性疾病。幸运的是，在HAART治疗可用的地方，HAD的发病率和严重程度有所降低。然而，具有高CD 4计数和低病毒载量的HAART患者仍然变得痴呆，并且对HIV-1感染个体的死后研究显示大脑继续受到影响。我们假设，随着HIV-1感染者寿命的延长，大脑中可能会出现一系列与年龄相关的新并发症;特别是淀粉样蛋白β（A β）的增加，这被认为是阿尔茨海默病（AD）神经炎斑块发展的起始步骤。我们有数据表明，大脑中一种主要的A β分解代谢酶被HIV-1非结构蛋白达特抑制，这可能导致A β的积累。我们的目的是进一步研究达特/NEP的相互作用，并确定其在神经退行性变中的作用。我们的具体目标是：1）确定其他HIV-1相关蛋白或HIV感染产物是否可以抑制NEP，2）鉴定神经细胞中的达特相互作用，其确定A β积累是单独的NEP抑制的结果还是涉及低密度脂蛋白受体相关蛋白（LRP），所述低密度脂蛋白受体相关蛋白（LRP）结合A β并启动其降解，和3）研究胆固醇的作用，达特和A β积累的遗传风险因子APOE; 4）确定HIV-1是否与死后脑组织中升高的A β共定位。这些研究将使用产生A β的人脑培养物，并且可以很容易地进行基因分型。我们认为，HIV-1的老年患者可能通过A β的慢性积累而有神经退行性变的风险，这与阿尔茨海默病中所见的机制相似。我们相信，这些实验的机制将对HIV-1感染的长期幸存者产生影响，并希望为我们提供新的线索，以治疗HIV相关的痴呆症。

DESCRIPTION (provided by applicant): Prior to highly active anti-retroviral therapy (HAART), HIV-associated dementia (HAD) was an acute neurodegenerative disease. Fortunately where treatment with HAART is available, there is a decrease in incidence and severity of HAD. However, patients on HAART with high CD4 counts and low viral loads still become demented and postmortem studies on HIV-l-infected individuals show the brain continues to be affected. We hypothesize that as individuals with HIV-1 infection live longer, there may be a new set of age-related complications in the brain; specifically an increase in amyloid beta (A beta), which is thought to be the initiating step in the development of neuritic plaques of Alzheimer's disease (AD). We have data to show that a major A beta catabolizing enzyme in the brain is inhibited by the HIV-1 nonstructural protein, Tat, which may result in an accumulation of A beta. It is our objective to further study the Tat/NEP interaction and determine its role in neurodegeneration. Our specific aims are: 1) To determine if other HIV-1 associated proteins or products of HIV infection can inhibit NEP, 2) To identify Tat interactions in neural cells that determine whether A beta accumulation is a consequence of NEP inhibition alone or involves the low density lipoprotein receptor-related protein (LRP), which binds A beta and initiates its degradation and 3) To investigate the role of cholesterol, Tat and the genetic risk factor APOE for A beta accumulation and 4) To determine whether HIV-1 co-localizes with elevated A beta in postmortem brain tissue. These studies will use human brain cultures that produce A beta and can easily be genotyped. We suggest that aging patients with HIV-1 may be at risk for neurodegeneration through chronic accumulation of A beta, a similar mechanism to that seen in Alzheimer's disease. We believe that mechanisms derived from these experiments will have implications for long term survivors of HIV-1 infection and hopefully give us new clues for therapeutic strategies against HIV-associated dementia.