CD* T cell responses to gamma-herpesviral infection

描述（由申请人提供）：世界上大多数人持续感染潜伏病毒。这些病毒可以随时从潜伏中重新激活，导致宿主终生复发性疾病。目前尚不清楚宿主免疫反应如何与潜伏病毒相互作用以防止再激活，同时防止因过度活跃的免疫引起的病理。本研究计划的目标是确定病毒潜伏期和再激活在调节抗病毒CDS T细胞免疫的产生和维持中的作用，使用一个具有良好特征的病毒感染和潜伏期小鼠模型。我们假设，由于潜伏感染细胞的持续刺激信号，抗病毒CDS T细胞反应层次随着时间的推移而改变。为了验证这一假设，本提案的第一个目的是分析小鼠γ -疱疹病毒-68感染后不同时间的CDS T细胞库，以评估功能、激活状态和抗病毒CDS T细胞层次结构的变化。通过了解抗病毒免疫反应的组成，我们可能能够确定特定的病毒表位，以靶向治疗性疫苗接种策略。潜伏感染的细胞和经历潜伏期病毒再激活的细胞可以向循环的CDS T细胞呈递不同的病毒抗原。在本提案的第二个目标中，我们将通过利用重组病毒感染来研究在没有病毒潜伏期或再激活的情况下CDS T细胞的层次结构，重组病毒感染既不能从潜伏期重新激活也不能建立潜伏期。这一目标的结果将为我们提供面对持续持续感染的免疫反应调节的基本见解，并可能导致我们独特的预防性疫苗策略。公共卫生相关性：如果要开发有效的预防性或治疗性疫苗，就必须了解宿主免疫反应与潜伏性病毒病原体之间的相互作用。这些研究的结果将对设计疫苗具有重要意义，这些疫苗可引起宿主CDS T细胞反应，以防止病毒在潜伏期再激活。

DESCRIPTION (provided by applicant): The majority of people worldwide are persistently infected with latent viruses. These viruses can reactivate from latency at any time, leading to recurrent diseases for the life of the host. It is currently unknown how the host immune response interacts with latent virus to prevent reactivation while preventing pathology due to overactive immunity. The goal of this research proposal is to determine the contributions of viral latency and reactivation in regulating the generation and maintenance of antiviral CDS T cell immunity using a well-characterized mouse model of viral infection and latency. We hypothesize that the antiviral CDS T cell response hierarchy changes over time due to persistent stimulatory signals from latently-infected cells. To test this hypothesis, the first aim of this proposal will analyze the CDS T cell repertoire at various times after murine gamma-herpesvirus-68 infection to assess the functionality, activation status, and changes in the hierarchy of antiviral CDS T cells. By understanding the composition of the antiviral immune response, we may be able to identify specific viral epitopes with which to target therapeutic vaccination strategies. Latently-infected cells and cells undergoing viral reactivation from latency could present disparate viral antigens to circulating CDS T cells. In the second aim of this proposal, we will examine the CDS T cell hierarchy in the absence of viral latency or reactivation by utilizing infections with recombinant viruses that either cannot reactivate from or establish latency. The results of this aim will provide us essential insight into the regulation of the immune response in the face of an ongoing persistent infection, and may lead us to unique prophylactic vaccine strategies. PUBLIC HEALTH RELEVANCE: It is imperative to understand the interactions between the host immune response and latent viral pathogens if effective preventative or therapeutic vaccinations are to be developed. Results from these studies will have important implications in the design of vaccines that elicit the host CDS T cell response to prevent viral reactivations from latency.