Maraviroc and NeuroAIDS Pathogenesis

马拉韦罗和神经艾滋病发病机制

• 批准号: 8667965
• 负责人: Cecilia M. Shikuma
• 金额: $ 67.99万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8667965
• 关键词: AIDS neuropathy; Autopsy; Biological Assay; Biology; Blood - brain barrier anatomy; Blood Cells; Blood Circulation; Brain; Brain imaging; Brain region; CD14 gene; CD4 Lymphocyte Count; CD8B1 gene; Cells; Characteristics; Chemokine (C-C Motif) Receptor 5; 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; Impairment; Inflammation; Inflammatory; Lead; Leukocytes; Literature; Lymphocyte; Magnetic Resonance Spectroscopy; Mediating; Mediator of activation protein; Neopterin; Neurocognitive; 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; neuroimaging; neuropsychological; neurotoxic; prevent; psychologic; public health relevance; 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(r)), 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（由申请人提供）：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。我们最近对接受 Maraviroc（MVC，Selzentry(r)）（一种 CCR5 受体负变构抑制剂）进行稳定抗逆转录病毒治疗 (ART) 的受试者进行了一项为期 24 周的小型单组试点研究。我们在一项初步研究中发现，MVC 强化导致 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 子集频率降低）； CD8+ T 细胞活化减少（CD38+HLA-DR+ CD8+ T 细胞百分比降低）；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。我们现在提出一项随机、安慰剂对照、为期 48 周的研究，对 42 名患有轻度至中度 NCI 且接受 ART 治疗的 HIV 感染受试者进行 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，并将检查对 HIV NCI 发病机制重要的一系列事件。我们将评估 MO 表型、HIV DNA 负担和功能的变化；通过多体素磁共振波谱成像 (MRSI) 观察神经元和炎症性脑代谢物的变化。我们将这项提案的重点放在 MO 的作用上，该文献基于已发表的文献，假设这些细胞在 HIV NCI 中发挥关键作用，并且基于我们的初步数据结果，即 MVC 似乎会导致 MO 免疫激活和 HIV 感染 MO 数量的减少（CD14+ 细胞内的 HIV DNA）在血液中。我们假设使用 MVC 后会观察到激活的 MO 子集的减少。我们将通过评估整个 MO（CD14+ 细胞）中的 HIV DNA 水平来扩展我们的数据，正如我们在初步数据中所做的那样，而且还评估每个子集中的 HIV DNA 水平。最后，在探索性目标中，我们建议使用 MRSI（一种能够评估整个大脑二维图像中的代谢物的 MRS 神经成像技术）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。