Maraviroc and NeuroAIDS Pathogenesis

描述（由申请人提供）：我们目前对hiv诱导的神经认知障碍（NCI）发病机制的理解集中在激活的炎症单核细胞（MO）通过血脑屏障（BBB）进入大脑的迁移。我们最近进行了一项小型的、为期24周的单臂试点研究，受试者接受稳定抗逆转录病毒治疗（ART），使用Maraviroc （MVC, Selzentry®），一种CCR5受体的负变抗抑制剂。我们在一项初步研究中发现，MVC增强导致HIV感染MO减少（CD14+细胞中细胞内HIV DNA减少）；MO激活减少（表达cd16的MO亚群频率降低）；CD8+ T细胞活化降低（CD38+HLA-DR+ CD8+ T细胞的百分比降低）；最重要的是，轻度/中度NCI受试者的神经心理学（NP）表现有所改善。我们现在提出一项随机的、安慰剂对照的、为期48周的研究，对42名接受抗逆转录病毒治疗并伴有轻度至中度NCI的HIV感染者进行MVC强化，包括神经影像学和免疫学分析。我们将评估48周内NP表现的变化作为主要终点，并将检查与HIV NCI发病机制相关的一系列重要事件。我们将评估MO表型、HIV DNA负荷和功能的变化；通过多体素磁共振光谱成像（MRSI）检测神经元和炎症性脑代谢物的变化。基于已发表的文献假设这些细胞在HIV NCI中起关键作用，以及我们的初步数据结果，MVC似乎诱导MO免疫激活和血液中HIV感染MO （CD14+细胞内的HIV DNA）数量的减少，我们将此建议的重点放在MO的作用上。我们假设，在使用MVC后，将观察到激活的MO子集的减少。我们将扩展我们的数据，不仅在MO （CD14+细胞）中作为一个整体评估HIV DNA水平，就像我们在初步数据中所做的那样，而且在每个子集中评估HIV DNA水平。最后，为了探索目的，我们建议使用MRSI（一种能够在整个大脑二维图像中评估代谢物的MRS神经成像技术）非侵入性地评估MVC是否会影响炎症和神经元健康的大脑标志物。

DESCRIPTION (provided by applicant): Our current understanding of the pathogenesis of HIV-induced neurocognitive impairment (NCI) centers on the migration of activated inflammatory monocytes (MO) through the blood brain barrier (BBB) into the brain. We recently conducted a small, 24 week, single-arm, pilot study of subjects on stable antiretroviral therapy (ART) with Maraviroc (MVC, Selzentry®), a negative allosteric inhibitor of the CCR5 receptor. We found in a preliminary study that MVC intensification led to a reduction in HIV-infected MO (decrease in intracellular HIV DNA in CD14+ cells); a decrease in MO activation (lower frequency of CD16-expressing MO subsets); decrease in CD8+ T cell activation (lower % of CD38+HLA-DR+ CD8+ T-cells); and crucially an improvement in neuropsychological (NP) performance among subjects who had mild/moderate NCI. We now propose a randomized, placebo-controlled, 48 week study of MVC intensification in 42 HIV infected subjects on ART with mild to moderate NCI and include neuroimaging and immunology assays. We will assess 48 week change in NP performance as the primary endpoint and will examine the cascade of events important to the pathogenesis of HIV NCI. We will assess change in MO phenotype, HIV DNA burden and function; and changes in neuronal and inflammatory brain metabolites by multi-voxel Magnetic Resonance Spectroscopic Imaging (MRSI). We focus this proposal on the role of MO based on published literature hypothesizing a key role for these cells in HIV NCI and on the results of our preliminary data that MVC appears to induce a decrease in MO immune activation and in the number of HIV infected MO (HIV DNA within CD14+ cells) within the bloodstream. We hypothesize that a decrease in activated MO subsets will be observed following MVC use. We will extend our data by assessing HIV DNA levels not only in MO (CD14+ cells) as a whole, as was done in our preliminary data, but within each subset. Finally, in an exploratory aim, we propose to non- invasively assess whether MVC impacts brain markers of inflammation and neuronal health using MRSI, a MRS neuro-imaging technology capable of assessing metabolites across an entire 2-dimensional image of the brain.