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）：我们目前对艾滋病毒诱导的神经认知障碍（NCI）的发病机理（NCI）的发病机理，该中心是激活的炎症单核细胞（MO）通过血脑屏障（BBB）迁移到大脑的中心。最近，我们对CCR5受体的负性变构抑制剂（Maraviroc（MVC，Selzentry（R）），对稳定的抗逆转录病毒疗法（ART）的受试者进行了一项小型，24周的单臂试点研究。我们在一项初步研究中发现，MVC强化导致HIV感染的MO降低（CD14+细胞中细胞内HIV DNA的降低）； MO激活的降低（表达CD16的MO子集的频率较低）； CD8+ T细胞激活的减少（CD38+ HLA-DR+ CD8+ T细胞的降低）；至关重要的是NCI轻度/中度NCI受试者的神经心理学（NP）表现。现在，我们提出了一项随机的，安慰剂对照的，48周的MVC增强研究，对42名HIV感染的受试者具有轻度至中度NCI的ART受试者，并包括神经影像学和免疫学测定法。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发病机理重要的事件级联。我们将评估MO表型，HIV DNA负担和功能的变化；多素磁共振光谱成像（MRSI）通过多素磁共振成像的神经元和炎症性脑代谢产物的变化。我们将此提案重点放在MO的作用上，基于公开的文献，假设这些细胞在HIV NCI中的关键作用以及我们的初步数据的结果，即MVC似乎在血液流中诱导了MO免疫激活和HIV感染的MO（CD14+ CD14+细胞中的HIV DNA）的降低。我们假设在使用MVC后，将观察到活化的MO子集的减少。我们将通过评估HIV DNA水平不仅在MO（CD14+细胞）中的整体中评估HIV DNA水平，就像我们的初步数据一样，而且在每个子集中。最后，在探索性目标中，我们建议非侵入性评估MVC是否使用MRSI会影响炎症和神经元健康的大脑标记，MRSI是一种能够评估整个大脑二维图像的代谢物的MRS神经成像技术。