Animal Model Studies

动物模型研究

• 批准号: 8061610
• 负责人: MICHAEL Shannon MCGRATH
• 金额: $ 53.03万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061610
• 关键词: AIDS neuropathy; Acquired Immunodeficiency Syndrome; Acute; Anabolism; Animal Model; Animals; Blood; Blood specimen; CD14 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Central Nervous System Diseases; Clinical Research; Clinical Trials; Development; Disease; FCGR3B gene; Flushing; HIV; Human; Infection; Lymphocyte Depletion; Lymphoid; Macaca mulatta; Modeling; Neuropathogenesis; Pathogenesis; Polyamines; Population; Primates; Reagent; Role; SIV; SIV encephalitis; Target Populations; Testing; Tissues; Viral; Virus Replication; inhibitor/antagonist; killings; macrophage; monocyte; simian human immunodeficiency virus; trafficking

This Project within the PPG will investigate, using SIV and SHIV infection in rhesus macaques, the effect of polyamine biosynthesis inhibitors (PBI) on pathogenesis AIDS and sequela of neuroAIDS. For this, we initially propose to investigate the polyamine biosynthesis inhibitors PA-001 in the first 2.5 years and a second designated PA-002 in the last 2.5 years. We hypothesize the PBI will deactivate and/or selectively target populations of CD14+ and CD16+ monocyte/macrophages, some of which are SIV infected. We propose to use a) a CD8+ lymphocyte depletion model of SIV infection that results in rapid, consistent and severe CMS disease with SIV encephalitis (SIVE), and b) a SHIV infection model that rapidly depletes CD4+ T lymphocytes resulting in high virus replication in monocyte/macrophages, to study the effects of PBI; deactivating and/or killing select monocyte/macrophage subsets; delaying the onset and/or reversing CNS disease; potentially flushing monocyte/macrophage viral reservoirs. We propose three Specific Aims to test our hypothesis. Specific Aim 1 will determine whether PBI (PA-001 and PA-002) deactivates and/or kills select CD14+CD16+ monocyte/macrophage during: a) acute infection (7-21 days pi) and b) with the development of AIDS. Specific Aim 2 will test the hypothesis that PBI (PA-001 and PA-002) treatment deactivates and/or kills select CD14+CD16+ monocyte/macrophage populations, delaying and/or reversing the development of AIDS and SIVE. Specific Aim 3 will test the hypothesis that PBI treated, SHIV infected animals that are CD4+ T cell depleted and have high virus replication in monocyte/macrophages, clears or diminishes viral reservoirs in blood, lymphoid and CNS tissues. Studies proposed in this project have direct relevance to studies of human AIDS and neuroAIDS, and support Projects 1 and 3 of the PPG. These studies: use a well-defined primate model of neuroAIDS to better identify monocyte subsets that predict progression of AIDS and neuroAIDS with SIVE development; assess the significance of continued monocyte traffic on neuropathogenesis and CNS infection; and investigate the potential of select pharmacologic agents (PBI), which have been used in human clinical trials, to deactivate and kill SIV infected monocyte/macrophages. These studies will add to our understanding of the role of monocyte/macrophages in AIDS and AIDS neuropathogenesis and directly assess the utility of reagents for use in human clinical trials for neuroAIDS. They will adds support to proposed clinical studies in Project 3, and will provide dynamic sampling of blood and SIV infected tissues for Project 1, defining mechanisms of function of PBI. Lastly, these studies may better define the role of monocyte/macrophages contributing to AIDS and functioning as cellular reservoir of HIV.

PPG 内的这个项目将利用恒河猴中的 SIV 和 SHIV 感染来研究 多胺生物合成抑制剂（PBI）对艾滋病发病机制和神经艾滋病后遗症的影响。为此，我们 最初提出在前2.5年研究多胺生物合成抑制剂PA-001并 过去 2.5 年内第二个指定为 PA-002。我们假设 PBI 将停用和/或有选择地 CD14+和CD16+单核细胞/巨噬细胞的目标群体，其中一些是SIV感染的。我们 建议使用 a) SIV 感染的 CD8+ 淋巴细胞耗竭模型，该模型可导致快速、一致和 严重 CMS 疾病伴 SIV 脑炎 (SIVE)，以及 b) 快速耗尽 CD4+ 的 SHIV 感染模型 T淋巴细胞导致单核细胞/巨噬细胞中病毒高度复制，以研究PBI的影响； 失活和/或杀死选定的单核细胞/巨噬细胞亚群；延迟发作和/或逆转中枢神经系统 疾病;可能冲洗单核细胞/巨噬细胞病毒库。我们提出三个具体目标来测试 我们的假设。 具体目标 1 将确定 PBI（PA-001 和 PA-002）是否会停用和/或杀死所选 CD14+CD16+ 单核细胞/巨噬细胞在：a) 急性感染（感染后 7-21 天）和 b) 艾滋病发展期间。 具体目标 2 将检验 PBI（PA-001 和 PA-002）治疗使选择失活和/或杀死的假设 CD14+CD16+单核细胞/巨噬细胞群，延缓和/或逆转艾滋病的发展和 SIVE。 具体目标 3 将检验 PBI 治疗、感染 SHIV 且 CD4+ T 细胞已耗尽的动物的假设 并在单核细胞/巨噬细胞中具有高病毒复制能力，清除或减少血液中的病毒库， 淋巴组织和中枢神经系统组织。 该项目提出的研究与人类艾滋病和神经艾滋病的研究直接相关，并且 支持 PPG 的项目 1 和 3。这些研究：使用明确的神经艾滋病灵长类动物模型来 更好地识别单核细胞亚群，通过 SIVE 的发展预测 AIDS 和神经艾滋病的进展； 评估持续单核细胞运输对神经发病机制和中枢神经系统感染的重要性；和 研究已用于人体临床试验的选定药物（PBI）的潜力， 灭活并杀死 SIV 感染的单核细胞/巨噬细胞。这些研究将加深我们对 单核细胞/巨噬细胞在艾滋病和艾滋病神经发病机制中的作用并直接评估其效用 用于神经艾滋病人体临床试验的试剂。他们将为拟议的临床研究提供支持 项目 3，将为项目 1 提供血液和 SIV 感染组织的动态采样，定义 PBI 的功能机制。最后，这些研究可以更好地定义单核细胞/巨噬细胞的作用 导致艾滋病并充当艾滋病毒的细胞储存库。