CD* T cell responses to gamma-herpesviral infection

描述(申请人提供)：全球大多数人持续感染潜伏病毒。这些病毒可以在任何时候从潜伏期重新激活，导致宿主终身反复患病。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重新激活，同时防止因免疫过度而导致的病理改变。这项研究计划的目的是利用一个具有良好特征的病毒感染和潜伏期的小鼠模型，确定病毒潜伏期和重新激活在调节抗病毒CDS T细胞免疫的产生和维持中的作用。我们假设，由于来自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，这项建议的第一个目的是分析小鼠伽玛-疱疹病毒68感染后不同时间的CDS T细胞谱，以评估抗病毒CDS T细胞的功能、激活状态和层次结构的变化。通过了解抗病毒免疫反应的组成，我们可能能够识别特定的病毒表位，用于靶向治疗性疫苗接种策略。潜伏感染的细胞和从潜伏状态接受病毒重新激活的细胞可以将不同的病毒抗原呈递给循环中的CDS T细胞。在这项建议的第二个目标中，我们将通过利用无法从潜伏期重新激活或建立潜伏期的重组病毒的感染，在没有病毒潜伏期或重新激活的情况下检查CDS T细胞层次。这一目标的结果将为我们在面对持续感染时免疫反应的调节提供重要的洞察力，并可能引导我们制定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，必须了解宿主免疫反应和潜伏的病毒病原体之间的相互作用。这些研究的结果将对疫苗的设计具有重要的意义，这种疫苗可以诱导宿主CDS T细胞反应，以防止病毒在潜伏期重新激活。

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.