The Anatomy of Viral Persistence: Lymphocyte Migration and Lymphoid Structure

描述（由申请方提供）：次级淋巴器官（SLO）的结构和微架构在免疫应答的启动和维持中起着重要作用。对结构和微结构很重要的细胞通常是病毒感染的靶点，许多病毒（包括HIV）都会发生SLO结构的破坏，但人们对病毒感染期间淋巴破坏如何发生以及这如何影响免疫反应和病毒清除知之甚少。本申请的目的是阐明病毒感染期间SLO解体所涉及的机制，并直接评估对淋巴细胞活化和病毒清除的协调和动力学的影响，假设免疫细胞相互作用的失调阻碍了对慢性感染的免疫力，并有助于慢性感染期间的免疫抑制。使用一个完善的持续性非裂解性病毒感染系统来模拟慢性感染期间SLO结构的变化，再加上该模型中的一个关键发现，即I型干扰素信号传导在脾结构破坏中很重要，我将使用分子和细胞方法来（1）剖析SLO破坏发生的机制，（2）检查异常SLO形态如何中断细胞-细胞相互作用，以及（3）操纵结构是否可以影响免疫应答和病毒结果。除了扩大我们对适应性免疫的控制和调节的知识外，这项研究还将为病毒感染期间治疗策略的发展提供信息。

DESCRIPTION (provided by applicant): The structure and microarchitecture of secondary lymphoid organs (SLO) plays a fundamental role in the initiation and maintenance of immune responses. Cells that are important to structure and microarchitecture are often targets of viral infection and disruption of SLO structure occurs in many viruses (including HIV), yet little is known about how lymphoid disruption occurs during viral infection and how this affects immune responses and viral clearance. The goal of this application is to unravel the mechanisms involved in SLO disorganization during viral infection and to directly assess the impact on the coordination and kinetics of lymphocyte activation and viral clearance with the hypothesis that deregulation of immune cell interactions impedes immunity to chronic infections and contributes to immune suppression during chronic infections. Using a well-established system of persistent non-lytic viral infection to model changes in SLO architecture during chronic infection coupled with a key discovery in this model that type I interferon signaling is important in disruption of splenic architecture, I will use molecular and cellular approaches to (1) dissect the mechanism by which SLO disruption occurs, (2) examine how abnormal SLO morphology interrupts cell-cell interactions, and (3) whether manipulation of architecture can influence immune responses and viral outcome. In addition to expanding our knowledge of control and regulation of adaptive immunity, this research will inform the development of therapeutic strategies during viral infection.