CTL REGULATION AND JHMV PERSISTENCE IN THE CENTRAL NERVOUS SYSTEM

小鼠肝炎病毒(JHMV)的JHM株能产生急性 伴有脱髓鞘的脑炎。幸存者患有慢性 与持续性病毒RNA和抗原相关的脱髓鞘 中枢神经系统(CNS)。持久性与 传染性病毒，目前还没有数据表明一种 31kb病毒基因组的持久性。免疫力之强 在急性感染期间的反应是建立 慢性病；然而，它在坚持期间的相关性尚未得到 已经成立了。该提案涉及JHMV的两个相互关联的方面-- 诱导性慢性病：病毒进化导致 抑制复制与CD8+T细胞活化在疾病中的作用 结果和记忆。我们的数据表明基因突变与 中枢神经系统的持续性不是免疫驱动事件的结果。 因此，与持久性相关的突变将在三个方面进行测试 病毒基因组中与复制有关的区域：核衣壳(N) 和包膜(E)蛋白和前导RNA序列。N蛋白是 参与转录和翻译工作。这些缺陷中的任何一个都可能 导致复制和持久性减弱。第二个目的是审查 中枢神经系统细胞作为抗原提呈细胞在病毒清除中的作用 中枢神经系统。然而，它们无法提供无菌免疫力表明 效应器反应不佳。相对频率的表征 并发现与细胞溶解效应相相关的表型 《独家新闻》将为您深入了解 与病毒复制相关的效应器功能。第三个目标是探索 中包含的唯一内存CTL种群的特殊性 中枢神经系统。持续感染期间中枢神经系统中的CTL表现为松散 识别免疫显性基因潜在变异的能力 表位。CTL亚集的选择表现出增强的选择性 记忆群体将通过表型特征和 功能分析。这些实验将为潜在的 病毒过程中对残留抗原应答的效应器功能 坚持不懈。这项提议研究了中枢神经系统如何 受调控的CTL诱导、激活和记忆反应 导致持续感染和持续感染的实质感染 慢性脱髓鞘。

The JHM strain of mouse hepatitis virus (JHMV) produces an acute encephalitis accompanied by demyelination. Survivors have chronic demyelination associated with persistent viral RNA and antigen to the central nervous system (CNS). Persistence is not associated with infectious virus and no data is yet available to suggest a mechanism for the persistence of a 31 Kb viral genome. The strength of the immune response during acute infection is a critical determinant in establishing chronic disease; however, its relevance during persistence has not been established. This proposal addresses two interrelated aspects of JHMV- induced chronic disease: potential role of viral evolution leading to attenuated replication and the role of CD8+ T cell activation for disease outcome and memory. Our data indicate that genetic mutations associated with CNS persistence are not the result of immune-driven events. Therefore, mutations associated with persistence will be tested in three areas of the viral genome involved in replication: the nucleocapsid (N) and envelope (E) proteins and the leader RNA sequence. N protein is involved in transcription and translation. Defects in any of these could result in attenuated replication and persistence. The second aim examines the role of CNS cells as antigen-presenting cells of virus clearance from the CNS. However, their inability to provide sterile immunity indicates a suboptimal effector response. Characterization of the relative frequencies and phenotype associated with the cytolytic effector phase found exclusively in the CNS will provide insights into the development of effector function relative to viral replication. The third aim explores the specificities of unique memory CTL populations contained within the CNS. CTL represent in the CNS during persistent infection appear to loose the ability to recognize potential variations in the immunodominant epitope. The selection of CTL subsets exhibiting enhanced selectivity into the memory population will be monitored by phenotypic characterization and functional assays. These experiments will provide evidence for a potential effector function in response to residual antigen during viral persistence. This proposal examines the critical question of how the CNS regulated CTL induction, activation and memory responses during a parenchymal infection that results in persistent infection and ongoing chronic demyelination.