Monocyte Traffic and Neuropathogenesis of AIDS

描述（由申请人提供）：尽管成功的ART将HIV保持在血浆中不可检测的水平，但HIV并没有被根除，当患者停止治疗时，病毒会迅速反弹。此外，人们认识到，慢性免疫激活发生在成功接受ART的患者中，其CNS效应包括认知功能障碍。反弹病毒和慢性感染激活的细胞的来源包括单核细胞/巨噬细胞。在这种竞争性更新应用中，我们建议研究：1）在CNS中建立和维持SIV-DNA持久性的机制，2）从CNS中运输出可被病毒感染的单核细胞/巨噬细胞。我们建议单独使用ART，并结合一种新的口服形式的多胺合成抑制剂，称为PA 300，目标是单核细胞/巨噬细胞活化，交通和感染。我们建议研究血液中的单核细胞/巨噬细胞运输到CNS，巨噬细胞在CNS中的积累，建立和维持前病毒DNA的水库，并研究ART和PA 300对这个水库的影响。接下来，将研究ART和PA 300对CD 163+巨噬细胞从CNS到外周淋巴器官的运输的影响。本申请的成功完成将确定血液和CNS中作为前病毒储库的单核细胞/巨噬细胞亚型、ART和PA 300清除这些储库的作用以及它们对离开CNS的SIV感染细胞的作用。

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.