Monocyte Traffic and Neuropathogenesis of AIDS

描述（由申请人提供）：尽管成功的抗逆转录病毒疗法使血浆中的艾滋病毒保持在检测不到的水平，但艾滋病毒并没有被根除，当患者停止治疗时，病毒可能会迅速反弹。此外，人们认识到，慢性免疫激活发生在成功接受抗逆转录病毒治疗的患者身上，其对中枢神经系统的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细胞/巨噬细胞。在这一竞争性更新应用中，我们建议研究：1)SIV- DNA在中枢神经系统中建立和维持持久性的机制；2)从中枢神经系统流出的单核细胞/巨噬细胞可能被病毒感染。我们建议单独使用ART，并与一种新的口服多胺合成抑制剂PA300联合使用，该抑制剂针对单核细胞/巨噬细胞的激活、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细胞/巨噬细胞，巨噬细胞在中枢神经系统中的积累，建立和维持前病毒DNA的储库，并研究ART和PA300对该储库的影响。接下来，我们将研究ART和PA300对CD163+巨噬细胞从中枢神经系统向外周淋巴器官运输的影响。该应用程序的成功完成将确定血液和中枢神经系统中单核/巨噬细胞亚型作为前病毒储存库，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. PUBLIC HEALTH RELEVANCE: With effective antiretroviral therapy (ART), there is emerging evidence of chronic system immune activation including lymphocytes and monocyte/macrophages that continues to contribute to AIDS-related pathology and HAND (HIV-associated neurocognitive disorders). In this application, we will use a rhesus macaque SIV- infection model to define monocyte/macrophage reservoirs of SIV-DNA, and to use effective ART alone and with an adjunctive monocyte-directed therapy, to define the establishment, maintenance, and clearance of SIV- DNA in the CNS. Moreover, we propose to define the routes of egress of monocyte/macrophage, and the effect of therapy to eradicate this important HIV reservoir that can potentially reseed the periphery with virus from the CNS, even if there are non-detectable levels of virus in the plasma.