Mechanism of Action of Macrophage Targeted Drugs

HIV感染的单核细胞和巨噬细胞参与HIV相关神经系统的发病 疾病(手)。病理有限责任公司一直在系统地研究可以改变 巨噬细胞激活状态作为潜在的治疗药物。这类化合物包括多胺。 多胺合成的类似物(如CG47)和酶促抑制剂(如PA-001)。我们发现， 多胺生物合成抑制剂在调节和/或杀死CD16阳性方面特别有效 巨噬细胞。《病理》杂志的初步研究表明，多胺生物合成抑制物 PA01在降低体外单核细胞HIV DNA载量和降低SIV水平方面非常有效 猕猴血液和组织中巨噬细胞的感染。然而，通过这种机制 已取得的这些有益成果在很大程度上仍有待探索。外周血细胞的基因芯片分析 HIV感染者的血单个核细胞的mRNA水平发生了显著的变化 免疫调节蛋白，包括骨桥蛋白和腺苷脱氨酶。 这些观察结果与最近描述的天然的免疫抑制作用是一致的 单核细胞中的多胺精胺。因此，我们假设PBIs杀死了感染HIV的CD16+ 单核细胞和巨噬细胞通过诱导细胞凋亡的免疫调节机制。一个 更深入地了解PBI对HIV感染的巨噬细胞的作用机制将是 对于设计最有效的治疗手部疾病的治疗方案至关重要。因此， 本项目研究项目1的总体目标是了解PBI的作用机制 导致体外巨噬细胞内HIV前病毒载量降低。将对其进行力学研究 HIV感染者和SIV感染猕猴的单核细胞。之后提供的样本 用PBIs治疗恒河猴(项目2)和临床试验参与者(项目3)将使我们能够 证实PBI在体外的作用机制在体内也是相关的。这些研究应该 对巨噬细胞在手部发病机制中的作用提供重要的洞察力，并确定新的 未来研究的治疗靶点。

HIV infected monocytes and macrophages are involved in the pathogenesis of HIV associated neurological disease (HAND). Pathologica LLC has been systematically investigating compounds that can alter macrophage activation states as potential therapeutics. This class of compounds includes polyamine analogs (e.g. CG47) and enzymatic inhibitors of polyamine synthesis (e.g. PA-001). We have found that polyamine biosynthesis inhibitors (PBIs) are particularly effective at modulating and / or killing CD16 positive macrophages. Preliminary studies at Pathologica have established that the polyamine biosynthesis inhibitor PA01 is very efficient at reducing HIV DNA loads in mononcytes in vitro and at reducing the level of SIV infection of macrophages in the blood and tissues of rhesus macaques. However, the mechanism by which these beneficial outcomes were achieved remains largely unexplored. Microarray analyses of peripheral blood mononuclear cells from HIV infected individuals noted significant changes in the mRNA levels of immomodulatory proteins, including osteopontin and adenosine deaminase after in vitro PBI treatment. These observations are consistent with the recently described immunosuppressive role of the native polyamine spermine in monocytes. Accordingly, we hypothesize that PBIs kill HIV infected CD16+ monocytes and macrophages via an immunomodulatory mechanism involving induction of apoptosis. A more thorough understanding of the mechanism of action of PBIs against HIV infected macrophages will be critical to designing the most efficacious therapeutic regimens for the treatment of HAND. Accordingly, the overall goal of Research Project 1 of this program project is to understand the mechanism by which PBIs lead to reduced HIV proviral load in macrophages in vitro. Mechanistic studies will be performed on monocytes from HIV infected individuals and SIV infected rhesus macaques. Samples provided after treatment of rhesus macaques (Project 2) and clinical trial participants (project 3) with PBIs will allow us to confirm that the mechanism of action of PBIs seen in vitro also is relevant in vivo. These studies should provide significant insight into the role of macrophages in the pathogenesis of HAND and identify novel therapeutic targets for future studies.