Virus-Host Cell Interactions in AIDS-Associated PML

计划摘要-摘要 进行性多灶性白质脑病(PML)是威胁患者生命的主要并发症 艾滋病患者和正在接受免疫治疗的自身免疫性疾病患者，如多发性 硬化症、克罗恩病、严重斑块型银屑病、系统性红斑狼疮、血液病 恶性肿瘤和类风湿性关节炎。矛盾的是，这种疾病是由一个普通人引起的 在失去对中枢神经系统(CNS)的正常免疫监视后，出现多瘤病毒。 最近在我们对PML的理解上取得了重大进展，包括发现了 在PML大脑中不再识别已知病毒受体的JC病毒变体，以及我们最近的 发现正常脑或PML脑内的大胶质细胞缺乏JC病毒受体，因此 不要直接绑定病毒。相反，我们发现脉络丛上皮细胞和 软脑膜细胞是JC病毒受体阳性的，结合病毒，并可能在 在中枢神经系统传播或维持JC病毒感染。我们的研究计划将重点放在 了解JC病毒或JC病毒组分如何在细胞之间直接传播，从而导致 脑白质损害是PML的标志。

Program Summary-Abstract Progressive Multifocal Leukoencephalopathy (PML) is a major life threatening complication in patients with AIDS and in patients undergoing immunotherapy for autoimmune diseases such as multiple sclerosis, Crohn's disease, severe plaque psoriasis, systemic lupus erythematosis, hematologic malignancies, and rheumatoid arthritis. The disease is paradoxically caused by a common human polyomavirus following the loss of normal immune surveillance of the central nervous system (CNS). Significant progress has recently been made in our understanding of PML including the discovery of of JC virus variants in PML brain that no longer recognize known virus receptors, and our recent discovery that macroglial cells in normal brain or in PML brain lack receptors for JC virus and hence do not directly bind virus. In contrast we discovered that choroid plexus epithelial cells and leptomeningeal cells are JC virus receptor positive, bind virus, and are likely playing a critical role in disseminating or maintaining JC virus infection in the CNS. Our research program will focus on understanding how JC virus or JC virus components spread directly from cell to cell giving rise to white matter lesions that are the hallmark of PML.