Maraviroc and NeuroAIDS Pathogenesis

马拉韦罗和神经艾滋病发病机制

• 批准号: 9096234
• 负责人: Cecilia M. Shikuma
• 金额: $ 64.5万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096234
• 关键词: Autopsy; Biological Assay; Biology; Blood - brain barrier anatomy; Blood Cells; Blood Circulation; Brain; Brain imaging; Brain region; CCR5 gene; CD14 gene; CD4 Lymphocyte Count; CD8B1 gene; Cells; Characteristics; Chronic; Clinical Trials; Controlled Clinical Trials; DNA; Data; Development; Event; FCGR3B gene; Frequencies; HIV; HIV Infections; HLA-DR Antigens; Health; Histologic; Image; Imaging technology; Immunology; Impaired cognition; Inflammation; Inflammatory; Lead; Leukocytes; Literature; Lymphocyte; Magnetic Resonance Spectroscopy; Mediating; Mediator of activation protein; Neopterin; Neurocognitive Deficit; Neurons; Neuropsychology; Pathogenesis; Patients; Performance; Phenotype; Pilot Projects; Placebo Control; Placebos; Plasma; Ploidies; Publishing; RNA; Randomized; Residual state; Role; Series; Study Subject; T-Cell Activation; T-Lymphocyte; TNF gene; Virus; antiretroviral therapy; arm; base; brain tissue; double-blind placebo controlled trial; immune activation; improved; inflammatory marker; inhibitor/antagonist; macrophage; magnetic resonance spectroscopic imaging; migration; monocyte; neuroAIDS; neuroimaging; neuropsychological; neurotoxic; prevent; psychologic; trend; two-dimensional

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.

描述（申请人提供）：我们目前对 HIV 引起的神经认知障碍（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）迁移到大脑中。一项为期 24 周的小型单组试点研究，受试者接受 Maraviroc（MVC，Selzentry®）（一种 CCR5 受体负变构抑制剂）的稳定抗逆转录病毒治疗 (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+ 细胞中 HIV DNA 的减少）；MO 激活的减少（CD8+ T 细胞中表达 CD16 的 MO 亚群的频率降低）；激活（CD38+HLA-DR+ CD8+ T 细胞百分比降低）；并且至关重要的是，轻度/中度 NCI 受试者的神经心理学 (NP) 表现得到改善。现在提出一项随机、安慰剂对照、为期 48 周的研究，对 42 名患有轻度至中度 NCI 的 HIV 感染受试者进行 ART 的 MVC 强化研究，包括神经影像学和免疫学检测，我们将评估 48 周 NP 表现的变化作为主要终点，并将进行检查。对 HIV NCI 发病机制重要的一系列事件我们将通过多体素磁性评估 MO 表型、HIV DNA 负荷和功能的变化以及神经元和炎症脑代谢物的变化；我们根据已发表的文献假设这些细胞在 HIV NCI 中发挥关键作用，并根据我们的初步数据结果（MVC 似乎会诱导 MO 免疫激活和减少），将此提案重点放在 MO 的作用上。我们发现，使用 MVC 后，我们将通过评估 MO 中的 HIV DNA 水平来扩展我们的数据。 （CD14+细胞）作为一个整体，正如我们在初步数据中所做的那样，但在每个子集中，最后，为了探索性的目的，我们建议使用 MRSI（一种 MRS）非侵入性地评估 MVC 是否影响炎症和神经元健康的大脑标志物。神经成像技术能够评估大脑整个二维图像的代谢物。