Animal Model Studies

PPG内的本项目将使用恒河猴中的SIV和SHIV感染来研究 多胺生物合成抑制剂（PBI）在艾滋病发病机制和神经艾滋病后遗症中的作用。为此我们 初步提出在前2.5年研究多胺生物合成抑制剂PA-001， 在过去的2.5年里第二次被命名为PA-002。我们假设PBI将停用和/或选择性地 靶向CD 14+和CD 16+单核细胞/巨噬细胞群体，其中一些是SIV感染的。我们 建议使用a）SIV感染的CD 8+淋巴细胞耗竭模型，其导致快速、一致和 伴有SIV脑炎的严重CMS疾病（SIVE），和B）快速消耗CD 4+的SIV感染模型 T淋巴细胞导致单核细胞/巨噬细胞中的高病毒复制，以研究PBI的影响; 灭活和/或杀死选择的单核细胞/巨噬细胞亚群;延迟CNS的发作和/或逆转CNS 疾病;可能冲洗单核细胞/巨噬细胞病毒库。我们提出了三个具体的目标来测试 我们的假设 特异性目标1将确定PBI（PA-001和PA-002）是否灭活和/或杀死选择的CD 14 + CD 16 + 单核细胞/巨噬细胞在：a）急性感染（感染后7-21天）和B）伴随AIDS的发展。 具体目标2将检验PBI（PA-001和PA-002）处理灭活和/或杀死选择的假设 CD 14 + CD 16+单核细胞/巨噬细胞群，延迟和/或逆转AIDS的发展， SIVE。 具体目标3将检验PBI处理的、CD 4 + T细胞耗尽的SHIV感染动物的假设 并且在单核细胞/巨噬细胞中具有高病毒复制，清除或减少血液中的病毒储库， 淋巴和CNS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， 支持项目编制小组的项目1和项目3。这些研究：使用一个定义明确的神经艾滋病灵长类动物模型， 更好地识别单核细胞亚群，预测艾滋病和神经艾滋病的进展与SIVE发展; 评估持续单核细胞运输对神经发病机制和CNS感染的意义;以及 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。这些研究将增加我们对 单核/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 用于人类神经艾滋病临床试验的试剂。他们将为拟议的临床研究提供支持， 将为项目1提供血液和SIV感染组织的动态采样， 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，并作为艾滋病毒的细胞库。

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.