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活化的炎性单核细胞（MO）通过血脑屏障（BBB）迁移到大脑中。我们最近对接受稳定抗逆转录病毒治疗（ART）的受试者进行了一项小型、24周、单臂、初步研究，该研究使用马拉韦罗（MVC，Selzentry®），一种CCR 5受体的负变构抑制剂。我们在一项初步研究中发现，MVC强化导致HIV感染MO减少，（CD 14+细胞中细胞内HIV DNA减少）; MO活化减少（表达CD 16的MO亚群的频率较低）; CD 8 + T细胞活化减少（较低的CD 38 +HLA-DR+ CD 8 + T细胞%）;并且至关重要的是，在患有轻度/中度NCI的受试者中神经心理学（NP）表现的改善。我们现在提出了一项随机、安慰剂对照、48周的研究，在42名接受ART治疗的轻度至中度NCI的HIV感染受试者中进行MVC强化，包括神经影像学和免疫学检测。我们将评估NP性能的48周变化作为主要终点，并将检查对HIV NCI发病机制重要的事件级联。我们将通过多体素磁共振波谱成像（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物的变化。我们将这一建议集中在MO的作用上，这是基于已发表的文献，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，即MVC似乎诱导MO免疫活化减少和血流中HIV感染MO（CD 14+细胞内的HIV DNA）数量减少。我们假设在MVC使用后将观察到激活的MO亚群减少。我们将通过评估HIV DNA水平来扩展我们的数据，不仅在MO（CD 14+细胞）作为一个整体，正如我们的初步数据所做的那样，而且在每个子集内。最后，在探索性目的中，我们提出使用MRSI非侵入性地评估MVC是否影响炎症和神经元健康的脑标志物，MRSI是一种能够在整个大脑的二维图像上评估代谢物的MRS神经成像技术。

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.