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

巨噬细胞靶向治疗艾滋病毒和艾滋病毒；

• 批准号: 8358005
• 负责人: Susan V. Westmoreland
• 金额: $ 6.84万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358005
• 关键词: AIDS neuropathy; Acquired Immunodeficiency Syndrome; Acute; Animals; Blood; CD14 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Central Nervous System Diseases; Development; Disease; FCGR3B gene; Flushing; Funding; Grant; Guanidines; HIV; Infection; Lymphocyte Depletion; Lymphoid; Macaca mulatta; Modeling; National Center for Research Resources; New England; Pathogenesis; Polyamines; Population; Primates; Principal Investigator; Research; Research Infrastructure; Resources; SIV; Source; Target Populations; Testing; Tissues; United States National Institutes of Health; Viral; analog; base; cost; inhibitor/antagonist; killings; macrophage; monocyte; simian human immunodeficiency virus

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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 PPG 的这个项目将利用 SIV 和 SHIV 感染恒河猴，研究多胺合成抑制剂 (PBI) 对 AIDS 发病机制和神经艾滋病后遗症的影响。 为此，我们最初建议研究多胺类似物 CG-047、合成胍化合物 PA-OO1 和本申请中称为 PA-OO2 的 CNI-1493。 我们假设 PBI 将灭活和/或选择性地靶向 CD14 和 CD16 单核细胞/巨噬细胞群，其中一些被感染。 我们建议使用 a) SIV 感染的 CD8+ 淋巴细胞耗竭模型，导致快速、持续和严重的 CNS 疾病，b) SHIV 感染模型，快速耗竭 CD4+ T 淋巴细胞，导致单核细胞/巨噬细胞中 SIV 高度复制，以进行研究PBI 延迟和/逆转中枢神经系统疾病冲洗单核细胞/巨噬细胞病毒库的作用。我们提出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）是否会失活和/或杀死选定的 CD14 CD16 单核细胞群，导致在急性感染和 AIDS 发展过程中清除 SIV 的单核细胞/巨噬细胞库。 目标 2 中的研究检验了以下假设：PBI 失活和/或杀死特定的 CD14 CD16 单核细胞群，从而抑制和/或逆转 SIVE。 目标 3 中的研究检验了以下假设：对 SHIV 感染动物施用 PBI，这些动物消耗了单核细胞/巨噬细胞 SIV 复制量高的 CD4+ T 细胞，可清除或减少血液、淋巴和中枢神经系统组织中的病毒库。