MACROPHAGE TARGETED THERAPY FOR HAD AND HIV DISEASE; PROJECT #2

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 PPG项目将利用SIV和SIV感染恒河猴，研究多胺合成抑制剂(PBI)在艾滋病发病机制和神经艾滋病后遗症中的作用。为此，我们最初建议在此应用中研究多胺类似物CG-047、合成胍化合物PA-OO1和CNI-1493称为PA-OO2。我们假设PBI将灭活和/或选择性地针对CD14和CD16单核/巨噬细胞群，其中一些已被感染。我们建议使用一种SIV感染的CD8+淋巴细胞耗竭模型和一种SIV感染模型来研究PBI延缓和/或逆转CNS疾病的作用。我们提出了三个具体目标来检验我们的假设。目标1的研究将确定PBI(PA-OO1和PA-OO2)是否会在急性感染和艾滋病发展过程中灭活和/或杀死特定的CD14 CD16单核细胞群，从而清除SIV的单核/巨噬细胞储存库。Aim 2中的研究验证了PBI灭活和/或杀死特定CD14 CD16单核细胞群，抑制和/或逆转SIVE的假设。目标3中的研究验证了这样一种假设，即PBI治疗去除了具有高单核/巨噬细胞SIV复制的CD4+T细胞的SHV感染动物，清除或减少了血液、淋巴和中枢组织中的病毒库。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This Project within the PPG will investigate, using SIV and SHIV infection rhesus macaques, the effect of polyamine synthesis inhibitors (PBI) on pathogenesis AIDS and sequela of neuroAIDS. For this, we initially propose to investigate the polyamine analogues CG-047, synthetic guanidine compound PA-OO1 and CNI-1493 termed PA-OO2 in this application. We hypothesize the PBI will deactivate and/or selectively target populations of CD14 and CD16 monocyte/macrophages some of which are infected. We proposed to use a) a CD8+ lymphocyte depletion model of SIV infection that results in rapid, consistent and severe CNS disease, and b) a SHIV infection model that rapidly depletes CD4+ T lymphocytes resulting in high SIV replication in monocyte/macrophages, to study the effects of PBI delaying and/reversing CNS disease flushing monocyte/macrophage viral reservoirs. We propose three specific aims to test our hypothesis. Studies in aim 1 will determine whether PBI (PA-OO1 andPA-OO2) deactivate and/or kill select CD14 CD16 monocyte populations resulting in clearance of monocyte/macrophage reservoir of SIV during acute infection and the development of AIDS. Studies in aim 2 test the hypothesis that PBI deactivate and/or kill select CD14 CD16 monocyte populations, inhibiting and/or reversing SIVE. Studies in aim 3 test the hypothesis that PBI administered SHIV infected animals depleted of CD4+ T cells with high monocyte/macrophage SIV replication, clears or diminishes viral reservoirs in blood, lymphoid and CNS tissues.