Monocyte/macrophage traffic and peripheral nerve pathogenesis

描述（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%。越来越多来自人类的报道强调了巨噬细胞激活和背根神经节（DRG）炎症对周围神经病变病理性疼痛持续的贡献，但巨噬细胞运输和DRG巨噬细胞作为病毒库的证明尚不清楚。周围神经病变的发病机制尚不完全清楚，但可能是巨噬细胞介导的。在本应用程序中，我们将使用SIV艾滋病恒河猴模型来确定是否：1)持续的单核细胞运输到DRG驱动周围神经病变的发病机制，有效的抗逆转录病毒治疗（ART）将减少这种影响，2)M1/M2调节比预测早期和慢性周围神经病变，有效的ART将改变这一比例，3)临床相关的生物标志物（sCD163, BrdU， IENF）与DRG病理有关，4)DRG巨噬细胞是有或没有ART的病毒储存库。成功完成本应用程序的研究将使我们能够定义：1)DRG病理的单核细胞/巨噬细胞机制，2)PNS疾病期间单核细胞/巨噬细胞免疫调节，3)周围神经疾病的临床标志物，4)DRG巨噬细胞作为病毒复制的活性位点和病毒储存库。的总体假设

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.