Virus Host Cell Interactions in AIDS Associated PML

病毒生命周期的最初事件是它与存在于细胞表面的受体的相互作用。了解这些相互作用对于我们理解病毒的趋向性、传播和发病机制很重要。人乳头瘤病毒是致命性中枢神经系统(CNS)脱髓鞘疾病的病原体。进行性多灶性白质脑病(PML)。JCV还与几种人类肿瘤有关，包括寡星形细胞瘤和髓母细胞瘤。在原发感染之后，JCV在肾脏和淋巴组织中建立了终身持续感染。在少数个体中，病毒传播到中枢神经系统，感染少突胶质细胞和星形胶质细胞。限制JCV对这些细胞和组织的趋向性的机制，以及允许JCV从外周扩散到中枢神经系统的机制尚不清楚。免疫抑制疾病，包括艾滋病，是PML发生的主要危险因素，PML在这些患者中仍然是一种重要的威胁生命的疾病。我们的实验室一直在研究JCV生命周期的早期事件。我们已经确定，含有末端α(2-6)连接唾液酸的N-连接糖蛋白是JCV受体的关键组件；该受体的这一组件以组织特异性的方式表达；JCV选择性地与体内与感染相关的细胞结合。一些非允许细胞的感染被阻止在早期病毒基因表达之前的一步；而且，JCV不同于SV40，通过网状蛋白依赖受体介导的内吞进入细胞。我们研究的长期目标是确定病毒受体在介导细胞感染和确定病毒在受感染宿主中的趋向性、传播和致病中的作用。我们的工作假设基于我们以前的工作，即JCV受体相互作用是病毒进入、趋向性和在宿主内传播的关键决定因素。我们将通过以下问题来解决这一假说：1.JCV受体的特性是什么？2.JCV受体的细胞和组织分布是什么？JCV是如何穿透质膜并将其基因组定位于细胞核的？这些研究产生的数据将对其发病机制产生新的见解，并将其基因组定位于细胞核？这些研究的数据将对JCV引起的疾病的发病机制产生新的见解，并可能导致预防或治疗这些疾病的新疗法。

The initial event of the life cycle of a virus is its interaction with receptors present on the surface of a cell. Understanding these interactions is important to our understanding of viral tropism, spread, and pathogenesis. The human papillomavirus, JCV, is the etiological agent of the fatal central nervous system (CNS) demyelinating disease. progressive multi-focal leukoencephalopathy (PML). JCV has also been associated with several human tumors, including oligoastrocytoma and medullablastoma. Following primary infection, JCV establishes a lifelong persistent infection in kidney and lymphoid tissues. In a minority of individuals, the virus spreads to the CNS, infecting both oligodendrocytes and astrocytes. The mechanisms that restrict JCV tropism for these cells and tissues and the mechanisms that allow for t6he spread of JCV from the periphery to the CNS are not understood. Immunosuppressive illness, including AIDS, is a major risk factor for the development of PML and PML remains an important and life threatening disease in these patients. Our laboratory has been studying early events in the life cycle of JCV. We have determined that an N- linked glycoprotein containing terminal alpha (2-6) linked sialic acids is a critical component of the JCV receptor; that this component of the receptor is expressed in a tissue specific manner; that JCV binds selectively to cells in vivo that are associated with infection. that infection of some non-permissive cells is blocked at a step preceding early viral gene expression; and, that JCV, unlike SV40 enters cells by clathrin dependent receptor mediated endocytosis. The long term goals of our research are to define the role of virus receptors in mediating infection of cells and in determining viral tropism, spread, and pathogenesis in the infected host. Our working hypothesis, which is based on our previous work, is that JCV receptor interactions are critical determinants of viral entry, tropism, and spread within the host. We will address this hypothesis by asking the following questions: 1. What is the identity of the JCV receptor? 2. What are the cell and tissue distributions of JCV receptors? and 3. How does JCV penetrate the plasma membrane and target its genome to the nucleus? The data resulting from these studies will yield novel insights into the pathogenesis and target its genome to the nucleus? The data resulting from these studies will yield noel insights into the pathogenesis of JCV induced disease and may lead to novel therapies to prevent or treat these diseases.