Monocyte Traffic and Neuropathogenesis of AIDS

描述(申请人提供)：尽管成功的抗逆转录病毒疗法将艾滋病毒保持在血浆中不可检测的水平，但艾滋病毒并未被根除，当患者停止治疗时，病毒可能会迅速反弹。此外，ART治疗成功的患者可发生慢性免疫激活，其中枢神经系统影响包括认知功能障碍。反弹病毒的来源和慢性感染激活的细胞包括单核/巨噬细胞。在这种竞争性更新应用中，我们建议研究：1)建立和维持SIV-DNA在中枢神经系统中持续存在的机制，2)单核/巨噬细胞从中枢神经系统中流出，可以被病毒感染。我们建议单独使用ART，并与一种名为PA300的多胺合成抑制剂的新口服形式联合使用，该药物针对单核/巨噬细胞激活、运输和感染。我们建议研究血液中运输到中枢神经系统的单核/巨噬细胞，以及建立和维持前病毒DNA储存库的巨噬细胞在中枢神经系统中的聚集，并研究ART和PA300对这个储存库的影响。接下来，我们将研究ART和PA300对CD163巨噬细胞从中枢神经系统到外周淋巴器官运输的影响。这项应用的成功完成将确定血液和作为前病毒储存库的中枢神经系统中的单核/巨噬细胞亚型，ART和PA300清除这些储存库的效果，以及它们对离开中枢神经系统的SIV感染细胞的影响。

DESCRIPTION (provided by applicant): Despite successful ART that keeps HIV at non-detectable levels in plasma, HIV is not eradicated and when patients are taken off therapy, virus can quickly rebound. In addition, it is recognized that chronic immune activation occurs in patients on successful ART and the CNS effects of this include cognitive dysfunction. The source of the rebounding virus and cells that are activated with chronic infection include monocyte/macrophages. In this competitive renewal application we propose to study: 1) mechanisms that establish and maintain persistence of SIV- DNA in the CNS, 2) monocyte/macrophages that traffic out of the CNS that can be viral infected. We propose to use ART alone and in combination with a new oral form of a polyamine synthesis inhibitor, termed PA300, that targets monocyte/macrophage activation, traffic and infection. We propose to study monocyte/macrophages in blood that traffic to the CNS, macrophage accumulation in the CNS that establishes and maintains reservoirs of proviral DNA, and study the effects of ART and PA300 on this reservoir. Next, the effects of ART and PA300 on the traffic of CD163+ macrophages out of the CNS to peripheral lymph organs will be studied. Successful completion of this application will ascertain monocyte/macrophage subtypes in blood and the CNS that are proviral reservoirs, the effects of ART and PA300 to clear these reservoirs, and their effects on SIV infected cells leaving the CNS.