The Role of Viral Receptors in JCV Reactivation and Progression to PML in AIDS

描述(由申请人提供)：病毒受体是重要的宿主细胞决定因素，控制病毒的趋向性、传播和疾病发病机制。了解病毒与其同源受体之间的分子相互作用有助于深入了解病毒生物学和疾病。人类多瘤病毒JC病毒(JCV)是感染大多数人的一种重要病原体。虽然最初感染JCV被证明是相对无症状的，但该病毒会在肾脏建立持续的、终身的感染。在免疫受损的个体中，JCV可以重新激活并扩散到中枢神经系统(CMS)。在CMS中，JCV感染少突胶质细胞，即为神经元提供支持的神经胶质细胞。JCV感染会导致少突胶质细胞的细胞溶解破坏，从而导致致命的疾病-进行性多灶性白质脑病(PML)。大约5-8%的艾滋病患者会患上PML。JCV与宿主细胞受体结合并引发信号通路以启动感染循环的基本机制仍然知之甚少。利用遗传、生化和细胞生物学策略的组合方法将有助于阐明JCV-受体相互作用导致感染和PML的机制。提出了三个综合的具体目标。第一个目标将确定JCV与5-HT2AR受体结合以介导病毒附着和进入的分子机制。第二个目标将确定JCV感染后激活的信号通路，并探讨5-HT2AR在JCV诱导的信号通路中的作用。第三个目的是研究PDZ结构域蛋白在JCV感染中的作用。公共卫生相关性：综上所述，这些研究将加强我们对JCV-宿主细胞趋向性和PML发病机制的分子机制的理解。

DESCRIPTION (provided by applicant): Virus receptors are important host-cell determinants that govern viral tropism, spread, and disease pathogenesis. Understanding the molecular interactions between viruses and their cognate receptors provides significant insight into virus biology and disease. The human polyomavirus JC virus (JCV) is an important pathogen that infects the majority of the human population. While initial infection with JCV proves relatively asymptomatic, the virus establishes a persistent, life-long infection in the kidney. In immunocompromised individuals JCV can become reactivated and spread to the central nervous system (CMS). In the CMS, JCV infects oligodendrocytes, glial cells that provide support for neurons. JCV infection causes cytolytic destruction of oligodendrocytes leading to the fatal disease, Progressive Multifocal Leukoencephalopathy (PML). Approximately 5-8% of individuals with AIDS develop PML. The basic mechanisms by which JCV engages host-cell receptors and elicits signaling pathways to initiate an infectious cycle remains poorly understood. A combinatorial approach utilizing genetic, biochemical, and cell biological strategies will help to elucidate the mechanisms by which JCV-receptor interactions leads to infection and PML. Three integrated specific aims are proposed. The first aim will determine the molecular mechanisms by which JCV engages the serotonin receptor 5-HT2AR to mediate viral attachment and entry. The second aim will define the signaling pathways activated in response to JCV infection, and explore the role of 5-HT2AR in JCV-induced signaling pathways. The third aim will investigate the role of PDZ-domain proteins in JCV infection. Public Health Relevance: Taken together, these studies will enhance our understanding of JCV-host-cell tropism and the molecular mechanisms underlying the pathogenesis of PML.