Plasma neuronal-derived exosomes are biomarkers of HIV cognitive impairment

慢性控制良好的艾滋病毒感染的认知障碍继续影响30%-60% 关于个人的。机制仍不清楚，但可能与持续的 神经炎。认知障碍的生物标志物一直不一致，尽管 神经成像已经成为一种可能性。不幸的是，由于有限，成像是昂贵的 进入。Exosome是在正常和病理状态下从大多数ALL细胞中脱落的小微泡 条件。包装成外切体的细胞货物可以代表亲本细胞的状态。 我们用两步分离法分离了血浆中的神经源性外切体(NDE) 和细胞表面神经元特异性抗体。我们在最近完成的R21中展示了使用 质谱学表明，NDE富含50多种神经元蛋白质。此外，使用邻近度 对于神经学生物标记物的扩展分析(PEA)，我们另外确定了28种蛋白质 都在现场。至少有7种蛋白质在HIV中有统计学意义的差异表达 单独感染，HIV+女性相对于男性的神经认知障碍，以及1种蛋白质 与年龄和损伤显著相关。几种NDE蛋白与认知相关 一些领域和几个区分艾滋病毒认知障碍和阿尔茨海默病。我们的 总体假设是，NDE可用于诊断HIV感染中的认知障碍 而男性和女性在NDE中有不同的蛋白质，这将影响诊断和 治疗。我们进一步计划将轻度认知障碍与与 阿尔茨海默病前期轻度认知障碍(MCI)诊断。为了检验这一假设，我们建议 具体目标如下：(1)筛选并验证一组预测 并诊断女性和男性的艾滋病毒认知障碍，(2)确定 神经元外切体Cargo可以区分HIV相关性认知损害和轻度认知障碍 MCI/阿尔茨海默病(3)与HIV NDE蛋白靶标和认知域相关 与损伤的神经影像标志物相关；(4)建立快速超敏检测方法 用已验证的神经元外体靶蛋白诊断HIV认知功能障碍 纵向队列。我们将利用多学科方法，包括基础研究 与认知领域相关的蛋白质靶点及神经影像临床诊断 与选定的生物标志物蛋白的相关性。这些结果将对治疗产生重大影响。 随着液体生物标记物的发现和大脑中艾滋病毒的治愈，神经元的健康可以 被“实时”评估。

Cognitive impairment in chronic well-controlled HIV infection continues to affect from 30%-60% of individuals. Mechanisms are still unknown but probably associated with continued neuroinflammation. Biomarkers for cognitive impairment have been inconsistent although neuroimaging has emerged as a possibility. Unfortunately, imaging is expensive with limited access. Exosomes are small microvesicles shed from most all cells under normal and pathologic conditions. The cellular cargo packaged into exosomes can represent the state of the parent cell. We have isolated neuron-derived exosomes (NDE) in plasma using a 2-step isolation procedure and a cell surface neuron specific antibody. We have shown in a recently completed R21 using mass spectroscopy that NDE are rich in over 50 neuronal proteins. In addition, using proximity extension analysis (PEA) for neurology biomarkers, we identified an additional 28 proteins that were present. At least 7 proteins were statistically significantly differentially expressed in HIV infection alone, neurocognitive impairment in HIV+ women versus men and 1 protein that was significantly correlated with age and impairment. Several NDE proteins correlate with cognitive domains and several differentiate HIV cognitive impairment from Alzheimer’s disease. Our overall hypothesis is that NDE can be used to diagnose cognitive impairment in HIV infection and that men and women have different proteins in NDE that will influence diagnosis and treatment. We further plan to differentiate mild cognitive impairment with that associated with a pre-Alzheimer’s mild cognitive impairment (MCI) diagnosis. To test this hypothesis, we propose the following Specific Aims: (1) Select and verify a set of neuronal exosome proteins that predict and diagnose HIV cognitive impairment with aging in women and men, (2) Determine whether neuronal exosome cargo can differentiate HIV-associated cognitive impairment from mild MCI/Alzheimer’s disease (3) Correlate HIV NDE protein targets and cognitive domains associated with neuroimaging markers of injury and (4) Establish a rapid ultrasensitive assay using verified neuronal exosome target proteins for diagnosis of HIV cognitive impairment in a longitudinal cohort. We will utilize a multidisciplinary approach that includes basic research of protein targets correlated with cognitive domains and clinical diagnosis using neuroimaging correlation with selected biomarker proteins. These results will have major impact on treatment and cure of HIV in the brain as fluid biomarkers are discovered and the health of the neuron can be assessed in “real time.”