Maraviroc and NeuroAIDS Pathogenesis

描述(申请人提供)：我们目前对HIV诱导的神经认知障碍(NCI)的发病机制的理解集中在激活的炎性单核细胞(MO)通过血脑屏障(BBB)进入大脑。我们最近进行了一项为期24周的小型单臂试验性研究，受试者使用CCR5受体的阴性变构抑制剂马拉韦罗(MVC，Selzentry®)进行稳定的抗逆转录病毒治疗(ART)。我们在一项初步研究中发现，MVC强化导致HIV感染的MO减少(CD14+细胞内HIV DNA减少)；MO激活减少(CD16表达MO亚群的频率降低)；CD8+T细胞激活减少(CD38+HLA-DR+CD8+T细胞的百分比降低)；关键是，在轻度/中度NCI患者中，神经心理(NP)表现有所改善。我们现在提出了一项为期48周的随机、安慰剂对照研究，对42名患有轻中度NCI的接受ART治疗的HIV感染者进行MVC强化研究，包括神经成像和免疫学分析。我们将评估48周内NP表现的变化作为主要终点，并将检查对HIV NCI发病机制重要的一系列事件。我们将通过多体素磁共振成像(MRSI)评估MO表型、HIV DNA负荷和功能的变化，以及神经元和炎症性脑代谢产物的变化。我们根据已发表的文献，假设这些细胞在HIV NCI中起关键作用，并根据我们的初步数据结果，即MVC似乎能诱导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，从而提出这一建议。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，不仅评估整个MO(CD14+细胞)中的HIV DNA水平，就像我们在初步数据中所做的那样，而且评估每个子集内的HIV DNA水平。最后，在一个探索性的目标中，我们建议使用MRSI来非侵入性地评估MVC是否影响大脑炎症和神经元健康的标记物，MRSI是一种MRS神经成像技术，能够评估整个大脑二维图像中的代谢物。

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.