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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 本项目在PPG范围内，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AIDS后遗症的影响。 为此，我们最初建议在本申请中研究多胺类似物CG-047、合成胍化合物PA-001和CNI-1493（称为PA-002）。 我们假设PBI将灭活和/或选择性靶向CD 14和CD 16单核细胞/巨噬细胞群体，其中一些被感染。 我们建议使用a）导致快速、一致和严重CNS疾病的SIV感染的CD 8+淋巴细胞耗竭模型，和B）快速耗竭CD 4 + T淋巴细胞导致单核细胞/巨噬细胞中的高SIV复制的SIV感染模型，以研究PBI延迟和/或逆转CNS疾病冲洗单核细胞/巨噬细胞病毒储库的作用。我们提出了三个具体目标来检验我们的假设。 目的1中的研究将确定PBI（PA-001和PA-002）是否灭活和/或杀死选定的CD 14 CD 16单核细胞群，从而在急性感染和AIDS发展期间清除SIV的单核细胞/巨噬细胞储库。 目的2中的研究检验了PBI灭活和/或杀死选择的CD 14-CD 16单核细胞群，抑制和/或逆转SIVE的假设。 目的3中的研究测试了以下假设：施用PBI的SIV感染的动物耗尽了具有高单核细胞/巨噬细胞SIV复制的CD 4 + T细胞，清除或减少了血液、淋巴和CNS组织中的病毒储库。