Persistence of LCMV by exhaustion of antiviral T cells

描述(由申请者提供)：病毒可以使用多种策略 包括逃避免疫识别或诱导免疫抑制 避免免疫监视，从而在宿主体内持续存在。澄清 病毒持续存在并逃脱免疫监视的机制是 对我们理解病毒的发病机制和发展 控制和消除这种感染及其引起的疾病的措施。 侵袭性淋巴细胞株感染后的病毒持久性 脉络膜脑膜炎病毒(LCMV)可通过选择性下调实现 宿主中病毒特异性T细胞介导的反应(“克隆性衰竭”) 拥有成熟的免疫系统。在这种情况下，开始时的高病毒负担 感染驱动反应的细胞毒性CD8+T细胞(CTL)不同 耗竭方案，如诱导无能(功能性 无响应)和/或删除。病毒特异性CD8+T细胞的这种抑制作用 在感染的早期阶段的反应会导致持久或永久性的 持续感染。“克隆衰竭”的耐受性也会影响病毒 特异性CD4+T细胞及其功能失活可促进永久性 病毒感染的持久性。在这项提案中，我们希望延长我们的 之前的发现主要集中在分子机制上，强调 病毒特异性T细胞在成熟宿主中的“克隆性衰竭”。具体的 目标如下：(1)剖析起作用的特定病毒决定因素 在通过“克隆性衰竭”建立持续性病毒感染中的作用 病毒特异性T细胞。(2)考察抗原提呈的贡献 细胞与T细胞的相互作用导致病毒特异性T细胞的“克隆性衰竭” 持续LCMV感染的小鼠的细胞。(3)分子检测 T细胞受体信号转导机制诱导病毒特异性T细胞 小鼠慢性LCMV感染过程中的无能和/或缺失。详细的洞察 病毒与免疫系统的相互作用产生概念 更充分的疫苗和治疗策略，也将帮助我们 更好地了解免疫系统。

DESCRIPTION (provided by applicant): Viruses can use a number of strategies including escape from immune recognition or induction of immunosuppression to avoid immunological surveillance and thereby persist in the host. Elucidating the mechanisms by which viruses persist and escape immune surveillance is important to our understanding of viral pathogenesis and for the development of measures to control and eliminate such infections and the diseases they cause. Viral persistence following infection with invasive strains of lymphocytic choriomeningitis virus (LCMV) can be achieved by selective down-regulation ("clonal exhaustion") of the virus-specific T cell mediated response in a host with a mature immune system. In this scenario, high viral burden at the onset of infection drives responding cytotoxic CD8+ T cells (CTLs) into different programs of exhaustion such as induction of anergy (functional unresponsiveness) and/or deletion. This dampening of virus-specific CD8+ T cell responses in the early phase of infection results in a protracted or permanent persistence of infection. Tolerance by "clonal exhaustion" also affects virus specific CD4+ T cells and their functional inactivation can promote a permanent persistence of the viral infection. In this proposal, we wish to extend our previous findings by specifically focusing on molecular mechanisms underlining "clonal exhaustion" of virus-specific T cells in a mature host. The specific aims are the following: (1) To dissect specific viral determinants playing a role in establishment of a persistent viral infection by "clonal exhaustion" of virus-specific T cells. (2) To examine the contribution of antigen presenting cell interactions with T cells to the "clonal exhaustion" of virus-specific T cells in mice with a persistent LCMV infection. (3) To examine molecular mechanisms in T cell receptor signaling that induce virus-specific T-cell anergy and/or deletion during chronic LCMV infection of mice. Detailed insight into interaction of viruses with the immune system stands to generate concepts for more adequate vaccine and therapeutic strategies and will also help us to better understand the immune system.