T-cell immunity to polyomavirus infection

描述(由申请人提供)：此次续签申请的长期目标是了解负责产生和维持抗病毒CD8 T细胞反应的机制，所需的抗病毒CD8 T细胞反应需要遏制持续的“阴燃”病毒感染。持续性病毒感染 可分为慢性病毒型(例如HIV-1)和那些通过从非传染性潜伏状态重新激活裂解复制的重复循环而维持自身的病毒(例如疱疹病毒)。多瘤病毒(PYV)是包括人类在内的许多脊椎动物“病毒体”的沉默居民，持续处于低水平感染状态。然而，在免疫抑制的情况下，人类PYV可能会引发危及生命的疾病。BK病毒是肾移植功能障碍和损失的重要原因。JC病毒引起的进行性多灶性白质脑病(PML)是HIV/AIDS人群死亡的主要原因之一，最近在接受自身免疫和炎症性疾病(如多发性硬化症、克罗恩病和严重牛皮癣)体液免疫治疗的患者中出现。最近还从非细菌性呼吸道感染中分离出了几种新的人类PYV，可能是一种侵袭性致命皮肤恶性肿瘤的病原体。目前还没有有效的治疗PYV感染的方法。由于多核病毒科的紧密物种特异性限制了对自然动物宿主的感染，我们对控制这些阴燃感染所需的免疫机制尚不完全了解。利用小鼠多瘤病毒(MPyV)，我们发现在持续感染过程中，新病毒特异性CD8T细胞被招募。上一个供资周期产生的数据表明，征聘方面的时间差异 戏剧性地调节记忆T细胞隔间的质量。我们假设感染过程中的动态变化决定了MPyV特异性CD8 T细胞是否分化为有能力的记忆细胞，这反过来将反映在它们的基因表达水平和TCR-CD8-肽：MHC三分子相互作用上。了解控制产生持久的抗MPyV CD8 T细胞记忆的机制可能有助于开发干预措施，以增强对人类PYV感染的免疫力。我们将在以下三个具体目标中检验上述假设：目标1：确定调节急性与持续感染招募的抗病毒CD8 T细胞对记忆群体的贡献的决定因素。目的：研究急性感染和持续感染引起的MPyV特异性CD8T细胞功能差异的分子信号机制。目的：研究MPyV特异性记忆T细胞在急性感染和持续感染过程中的分子差异。

DESCRIPTION (provided by applicant): The long-term goal of this renewal application is to understand the mechanisms responsible for generating and maintaining antiviral CD8 T cell responses required to contain persistent "smoldering" viral infections. Persistent virus infections may be categorized into those that are chronically viremic (e.g., HIV-1) and those that maintain themselves by repetitive cycles of reactivation of lytic replication from a noninfectious latent state (e.g., herpesviruses). Polyomaviruses (PyV), silent residents of the "virome" of many vertebrates including humans, persist in a low-level infectious state. However, under conditions of immunosuppression human PyVs can incur life-threatening disease. BK virus is a significant cause of kidney transplant dysfunction and loss. A major cause of mortality in the HIV/AIDS population, JC virus-induced Progressive Multifocal Leukoencephalopathy (PML) has recently emerged in individuals receiving humoral immunotherapies for autoimmune and inflammatory diseases (e.g., multiple sclerosis, Crohn's disease, and severe psoriasis). Several new human PyVs have also recently been isolated from nonbacterial respiratory infections and as a likely causative agent for an aggressive fatal cutaneous malignancy. No effective therapies for PyV infection are available. Due to the tight species specificity of Polyomaviridae that restricts infection to natural animal reservoirs, we have an incomplete understanding of the immune mechanisms needed to keep these smoldering infections in check. Using mouse polyomavirus (MPyV), we discovered that na¿ve virus-specific CD8 T cells are recruited during persistent infection. Data generated in the last funding cycle reveal that temporal differences in recruitment dramatically modulate the quality of the memory T cell compartment. We hypothesize that dynamic changes over the course of infection govern whether MPyV-specific CD8 T cells differentiate into competent memory cells, which, in turn, will be reflected at their levels of gen expression and the TCR-CD8-peptide:MHC tri-molecular interaction. Understanding the mechanisms that control the generation of durable anti-MPyV CD8 T cell memory may help in the development of interventions to enhance immunity to human PyV infections. We will test the above hypothesis in the following three Specific Aims: Aim 1: To define determinants regulating the contribution of acute vs. persistent infection-recruited antiviral CD8 T cells to the memory population. Aim 2: To determine molecular signaling mechanisms underlying the functional differences between acute and persistent infection-recruited MPyV-specific CD8 T cells. Aim 3: To define molecular differences between MPyV-specific memory T cells recruited during acute and persistent infection.