T-cell immunity to polyomavirus infection

描述（由申请方提供）：本次更新申请的长期目标是了解负责产生和维持抗病毒CD 8 T细胞应答的机制，这些应答是遏制持续性“阴燃”病毒感染所必需的。持续性病毒感染 可分为慢性病毒血症（例如，HIV-1）和通过从非感染性潜伏状态再激活裂解复制的重复循环来维持自身的那些（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的“病毒组”的沉默居民，持续处于低水平感染状态。然而，在免疫抑制的条件下，人PyV可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病毒诱导的进行性多灶性白质脑病（PML）是HIV/AIDS人群死亡的主要原因，最近在接受体液免疫疗法治疗自身免疫性和炎性疾病的个体中出现（例如，多发性硬化症、克罗恩病和严重银屑病）。最近还从非细菌性呼吸道感染中分离出几种新的人类PyV，并可能是侵袭性致命性皮肤恶性肿瘤的致病因子。目前还没有有效的治疗PyV感染的方法。由于多瘤病毒科严格的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还不完全了解。使用小鼠多瘤病毒（MPyV），我们发现在持续感染期间招募了幼稚病毒特异性CD 8 T细胞。上一个供资周期产生的数据显示，征聘方面的时间差异 显著调节记忆T细胞区室的质量。我们假设感染过程中的动态变化决定了MPyV特异性CD 8 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-CD 8-肽：MHC三分子相互作用上。了解控制持久抗MPyV CD 8 T细胞记忆产生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的中检验上述假设：目的1：确定调节急性与持续性感染募集的抗病毒CD 8 T细胞对记忆群体的贡献的决定因素。目标二：确定急性和持续性感染募集的MPyV特异性CD 8 T细胞之间功能差异的分子信号传导机制。目的3：确定急性和持续感染期间募集的MPyV特异性记忆T细胞之间的分子差异。

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.