Monocyte/macrophage traffic and peripheral nerve pathogenesis

描述（由申请人提供）：周围神经病变是HIV感染最常见的神经系统并发症，在HIV感染患者中神经病变的患病率高达69.4%。越来越多的人类报告强调了巨噬细胞活化和背根神经节（DRG）炎症对周围神经病变中病理性疼痛持续性的贡献，但巨噬细胞运输和DRG巨噬细胞作为病毒储库的证明尚不清楚。周围神经病变的发病机制尚不完全清楚，但它可能是巨噬细胞介导的。在本申请中，我们将使用艾滋病的SIV恒河猴模型来确定是否：1）持续的单核细胞运输至DRG驱动周围神经病变发病机制，并且有效的抗逆转录病毒疗法（ART）将最小化该效应，2）M1/M2的比率调节性预测早期与慢性周围神经病变，并且有效的ART将改变该比率，3）临床相关的生物标志物（sCD 163，BrdU，IENF）与DRG病理学有关，4）DRG巨噬细胞是病毒储库，有和没有ART。成功完成本申请的研究将使我们能够确定：1）DRG病理的单核细胞/巨噬细胞机制，2）PNS疾病期间的单核细胞/巨噬细胞免疫调节，3）周围神经疾病的临床标志物和4）DRG巨噬细胞作为病毒复制的活性位点和作为病毒储库。总体假设 应用是持续的单核细胞/巨噬细胞运输驱动DRG发病机制，临床相关的生物标志物和IENF有效地预测有和没有ART的外周神经病理学。目的1的研究将确定单核细胞运输和巨噬细胞周转驱动PNS发病机制的作用，并建立DRG损伤和IENF损失之间的相关性，假设单核细胞向DRG的运输介导损伤并与PNS病理学相关。子目标将解决以下假设： 的M1/M2巨噬细胞预测早期与慢性PNS病变。此外，DRG巨噬细胞作为病毒复制的活性位点和/或作为潜伏的病毒储库将在该目的中被定义。目标2中的研究将定义全身性病毒抑制的作用：1）停止或减缓PNS疾病; 2）停止或减缓巨噬细胞向DRG募集; 3）清除DRG病毒储库。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的运输和潜在清除DRG病毒储库来减缓PNS疾病进展。本申请中描述的研究提供了一个令人兴奋的机会来定义单核细胞/巨噬细胞运输和巨噬细胞活化在PNS疾病和神经元损伤中的作用以及全身性病毒免疫抑制的作用。本文提出的研究将为开发针对HIV周围神经病变中单核细胞/巨噬细胞的治疗方法提供新的研究途径。

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.