Animal Model Studies

PPG的这个项目将利用SIV和SIV在恒河猴身上的感染来调查 多胺生物合成抑制剂(PBI)对神经艾滋病发病机制及后遗症的影响。为此，我们 初步建议在头两年半和一年内研究多胺生物合成抑制剂PA-001 在过去的2.5年中第二次被指定为PA-002。我们假设PBI将停用和/或选择性地 CD14+和CD16+单核/巨噬细胞的目标人群，其中一些人感染了SIV。我们 建议使用a)SIV感染的CD8+淋巴细胞耗尽模型，该模型导致快速、一致和 严重CMS病合并SIV脑炎(SIVE)，以及b)迅速耗尽CD4+的SIV病毒感染模型 T淋巴细胞导致病毒在单核/巨噬细胞中高复制，研究PBI的影响； 停用和/或杀死选定的单核/巨噬细胞亚群；延迟和/或逆转中枢神经系统 疾病；可能会冲刷单核/巨噬细胞病毒库。我们提出了三个具体目标来测试 我们的假设。 特定目标1将确定PBI(PA-001和PA-002)是否失活和/或杀死SELECT CD14+CD16+ 单核/巨噬细胞在：a)急性感染(7-21天pi)和b)随着艾滋病的发展。 特定目标2将检验PBI(PA-001和PA-002)治疗失活和/或杀死SELECT的假设 CD14+CD16+单核/巨噬细胞群，延缓和/或逆转艾滋病和 意犹未尽。 特指目标3将检验这样的假设，即PBI治疗了被SIV感染的、CD4+T细胞耗尽的动物 并在单核/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。 本项目建议的研究与人类艾滋病和神经艾滋病的研究直接相关，以及 支持PPG的项目1和项目3。这些研究：使用定义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，预测SIVE发展为艾滋病和神经艾滋病的进展； 评估持续单核细胞运输在神经发病和中枢神经系统感染中的意义；以及 研究已用于人体临床试验的精选药理制剂(PBI)的潜力， 灭活并杀死受SIV感染的单核/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及直接评估 用于人类神经艾滋病临床试验的试剂。他们将增加对拟议的临床研究的支持 项目3，并将为项目1提供血液和SIV感染组织的动态采样，定义 PBI的作用机制。最后，这些研究可能更好地确定单核/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。

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.