Singh Vir B, Wooten Alicia K, Jackson Joseph W, Maggirwar Sanjay B, Kiebala Michelle
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 672, Rochester, NY, 14642, USA,
J Neurovirol. 2015 Apr;21(2):186-98. doi: 10.1007/s13365-015-0318-2. Epub 2015 Jan 31.
Long-term persistence of human immunodeficiency virus type-1 (HIV) in the central nervous system (CNS) results in mild to severe neurocognitive impairment in a significant proportion of the HIV-infected population. These neurological deficits are known as HIV-associated neurocognitive disorders (HAND). Microglia are CNS-resident immune cells that are directly infected by HIV and consequently secrete proinflammatory molecules that contribute to HIV-induced neuroinflammation. Indeed, the number of activated macrophage and microglia in the brain is more highly correlated with cognitive impairment than the amount of neuronal apoptosis. Ankyrin-rich membrane spanning protein (ARMS/Kidins220) is a multidomain transmembrane protein that is involved with neurotrophin signaling in the CNS. We have previously established the role of ARMS in mediating neuronal survival via a neurotrophin-dependent mechanism. Recent reports also have suggested that ARMS is involved with cell signaling in multiple immune cell types. In this study, we aim to investigate the role of ARMS in HIV Tat-mediated microglial cell activation by employing in vitro methods. Following ARMS depletion by a lentivirus encoding ARMS-specific short hairpin RNA (shRNA), we observed a marked reduction in the HIV Tat-induced proinflammatory response, associated with loss of tumor necrosis factor alpha production and nuclear factor-kappa B (NF-κB) activation. Furthermore, co-immunoprecipitation studies suggested that ARMS physically interacts with inhibitory kappa B kinase subunits in order to facilitate NF-κB activation. Our results establish the role of ARMS in microglial activation by HIV Tat and warrant additional studies to better understand these molecular mechanisms, which may uncover novel therapeutic targets for the treatment of HAND.
1型人类免疫缺陷病毒（HIV）在中枢神经系统（CNS）中的长期持续存在，导致相当一部分HIV感染人群出现轻度至重度的神经认知障碍。这些神经功能缺陷被称为HIV相关神经认知障碍（HAND）。小胶质细胞是驻留在中枢神经系统的免疫细胞，可被HIV直接感染，进而分泌促炎分子，导致HIV诱导的神经炎症。事实上，大脑中活化的巨噬细胞和小胶质细胞数量与认知障碍的相关性，比神经元凋亡数量的相关性更高。富含锚蛋白的跨膜蛋白（ARMS/Kidins220）是一种多结构域跨膜蛋白，参与中枢神经系统中的神经营养因子信号传导。我们之前已经确定了ARMS在通过神经营养因子依赖性机制介导神经元存活中的作用。最近的报道还表明，ARMS参与多种免疫细胞类型的细胞信号传导。在本研究中，我们旨在通过体外方法研究ARMS在HIV反式激活转录蛋白（Tat）介导的小胶质细胞激活中的作用。在用编码ARMS特异性短发夹RNA（shRNA）的慢病毒耗尽ARMS后，我们观察到HIV Tat诱导的促炎反应显著降低，这与肿瘤坏死因子α产生的丧失和核因子κB（NF-κB）激活有关。此外，免疫共沉淀研究表明，ARMS与抑制性κB激酶亚基发生物理相互作用，以促进NF-κB激活。我们的结果确定了ARMS在HIV Tat介导的小胶质细胞激活中的作用，有必要进行更多研究以更好地理解这些分子机制，这可能会揭示治疗HAND的新治疗靶点。
