Immune Regulation of Viral Persistence and Clearance

病毒持续存在和清除的免疫调节

基本信息

批准号：
8462531
负责人：
DAVID G BROOKS
金额：
$ 37.91万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2014-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): T cell immunity is crucial to control viral infection and prevent persistence. However, T cell functions are rapidly aborted during persistent infection, preventing viral clearance. Mounting evidence indicates that CD4 T cell helper responses are required to sustain immune competence and that the loss of CD4 T cell function is a key event permitting viral persistence. Many of the functional characteristics of CDS T cell exhaustion (failure to sustain activity, proliferate, develop memory) can potentially be explained by the loss of CD4 help. Despite immune exhaustion some persistent viral infections are eventually resolved via unknown CD4 T cell dependent mechanisms, suggesting that CD4 T cells retain helper function during viral persistence. Recently, we discovered that upregulation of IL-21 by CD4 T cells is absolutely required to sustain antiviral immunity and resolve an established persistent viral infection. The goal of this application is to understand how CD4 T cell help is altered during viral persistence and ultimately to identify the IL-21 mediated mechanisms that sustain immunity. To achieve this goal we will use the mouse model of lymphocytic choriomeningitis virus (LCMV) infection to explore virus-specific CD4 T helper differentiation during viral persistence and how IL-21 directs this developmental program. Next, we will define the mechanism whereby IL-21 simultaneously suppresses CD4 T cell mediated immunopathology and sustains CDS T cell immunity to resolve persistent viral infection. These studies will investigate a novel mechanism of CD4 T cell help during viral persistence (at a time when CD4 T cell function was previously considered lost) and will be the first to identify the immune components that resolve an established persistent viral infection. It is important to identify the mechanisms that alternatively sustain and suppress antiviral immunity to develop therapies to restore T cell function and potentially cure persistent infection.

描述（由申请人提供）：T 细胞免疫对于控制病毒感染和防止病毒持续存在至关重要。然而，在持续感染期间，T 细胞功能会迅速中止，从而阻止病毒清除。越来越多的证据表明，维持免疫能力需要 CD4 T 细胞辅助反应，而 CD4 T 细胞功能的丧失是病毒持续存在的关键事件。 CDS T 细胞耗竭的许多功能特征（无法维持活性、增殖、形成记忆）可能可以用 CD4 帮助的丧失来解释。尽管免疫衰竭，但一些持续性病毒感染最终通过未知的 CD4 T 细胞依赖性机制得到解决，这表明 CD4 T 细胞在病毒持续存在期间保留了辅助功能。最近，我们发现 CD4 T 细胞对 IL-21 的上调对于维持抗病毒免疫和解决已确定的持续性病毒感染是绝对必需的。该应用的目标是了解 CD4 T 细胞在病毒持续存在期间如何改变，并最终确定维持免疫的 IL-21 介导机制。为了实现这一目标，我们将使用淋巴细胞性脉络膜脑膜炎病毒 (LCMV) 感染的小鼠模型来探索病毒持续存在期间病毒特异性 CD4 T 辅助细胞分化以及 IL-21 如何指导这一发育程序。接下来，我们将定义 IL-21 同时抑制 CD4 T 细胞介导的免疫病理学并维持 CDS T 细胞免疫以解决持续性病毒感染的机制。这些研究将调查 CD4 T 细胞在病毒持续存在期间（当时 CD4 T 细胞功能被认为丧失）的新机制，并将首次鉴定出解决已建立的持续病毒感染的免疫成分。重要的是要确定维持和抑制抗病毒免疫的机制，以开发恢复 T 细胞功能并有可能治愈持续性感染的疗法。