Monocyte/macrophage traffic and peripheral nerve pathogenesis

描述(申请人提供)：周围神经病是HIV感染最常见的神经系统并发症，在HIV感染者中神经病的患病率高达69.4%。越来越多的人类报告强调巨噬细胞激活和背根神经节(DRG)炎症在周围神经病病理性疼痛持续存在中的作用，但巨噬细胞运输和DRG巨噬细胞作为病毒库的证据尚不清楚。周围神经病的发病机制尚不完全清楚，但它可能是由巨噬细胞介导的。在这项应用中，我们将使用SIV恒河猴艾滋病模型来确定：1)单核细胞持续转运到DRG是否会导致周围神经病变发生，有效的抗逆转录病毒治疗(ART)可以将这种影响降至最低；2)M1/M2调节比率可预测早期与慢性周围神经损害，有效的ART将改变这一比率；3)临床相关生物标记物(sCD163、BrdU、IENF)与DRG病理有关；4)DRG巨噬细胞是病毒库，无论是否有ART。这一应用研究的成功完成将使我们能够确定：1)DRG病理的单核/巨噬细胞机制，2)PNS疾病期间的单核/巨噬细胞免疫调节，3)周围神经疾病的临床标志，以及4)DRG巨噬细胞作为病毒复制的活跃部位和病毒储存库。的总体假设 其应用是持续的单核/巨噬细胞运输驱动了DRG的发病机制，临床相关的生物标志物和IENF有效地预测了有无ART的周围神经病理。目标1的研究将确定单核细胞转运和巨噬细胞周转在PNS发病机制中的作用，并在单核细胞转运至DRGs介导损伤并与PNS病理相关的假设下，建立DRG损伤和IENF丢失之间的相关性。一个子目标将解决这样的假设，即M1/M2巨噬细胞的比率预测早期和慢性PNS损害。此外，DRG巨噬细胞作为病毒复制的活跃部位和/或潜在的病毒库将在这一目标中被定义。AIM 2的研究将确定全身性病毒抑制在以下方面的作用：1)阻止或减缓PNS疾病；2)阻止或减缓巨噬细胞向DRG的募集；以及3)清除DRG病毒库。驱动目标2的假设是，ART的全身性病毒抑制将通过抑制单核细胞向DRG和潜在的清除DRG病毒库的运输来减缓PNS疾病的进展。本申请中描述的研究提供了一个令人兴奋的机会，以确定单核/巨噬细胞运输和巨噬细胞激活在PNS疾病和神经元损伤中的作用，以及全身病毒免疫抑制的作用。本文提出的研究将为针对HIV周围神经病的单核/巨噬细胞治疗的发展提供新的研究途径。

DESCRIPTION (provided by applicant): Peripheral neuropathy is the most common neurological complication of HIV infection with the prevalence of neuropathy as high as 69.4% in HIV-infected patients. Increasing reports from humans highlight the contribution of macrophage activation and dorsal root ganglia (DRG) inflammation to the persistence of pathological pain in peripheral neuropathy, but the demonstration of macrophage traffic and DRG macrophages as a viral reservoir is not known. The pathogenesis of peripheral neuropathy is incompletely understood, but it is likely macrophage-mediated. In this application, we will use a SIV rhesus macaque model of AIDS to determine if: 1) continual monocyte traffic to DRGs drives peripheral neuropathy pathogenesis and effective anti-retroviral therapy (ART) will minimize this effect, 2) the ratio of M1/M2 regulatory predicts early versus chronic peripheral nerve lesions and effective ART will alter this ratio, 3) clinically relevant biomarkers (sCD163, BrdU, IENF) are linked to DRG pathology, and 4) DRG macrophages are viral reservoirs with and without ART. Successful completion of studies in this application will allow us to define: 1) monocyte/ macrophage mechanisms of DRG pathology, 2) monocyte/macrophage immune regulation during PNS disease, 3) clinical markers of peripheral nerve disease and 4) DRG macrophages as active sites of viral replication and as viral reservoirs. The overall hypothesis of the application is continual monocyte/macrophage traffic drives DRG pathogenesis and clinically relevant biomarkers and IENF effectively predict peripheral nerve pathology with and without ART. Studies in aim 1 will define the role of monocyte traffic and macrophage turnover driving PNS pathogenesis and establish a correlation between DRG damage and IENF loss with the hypothesis that monocyte traffic to DRGs mediates damage and correlates to PNS pathology. A subaim will address the hypothesis that the ratio of M1/M2 macrophages predicts early versus chronic PNS lesions. Additionally, DRG macrophages as active sites of viral replication and/or as latent viral reservoirs will be defined in this aim. Studies in aim 2 will define the role of systemic viral suppression to: 1) stop or slow PNS disease; 2) stop or slow macrophage recruitment to DRGs and 3) to clear DRG viral reservoirs. The hypothesis driving aim 2 is that systemic viral suppression by ART will slow PNS disease progression by inhibiting monocyte traffic to the DRGs and potentially clear DRG viral reservoirs. The studies described in this application provide an exciting opportunity to define the role of monocyte/macrophage traffic and macrophage activation in PNS disease and neuronal injury and the role of systemic viral immune suppression. The studies proposed here will provide new avenues of investigation into the development of therapies targeting the monocyte/macrophage in HIV peripheral neuropathy.