T Cell Vaccination Against gamma-herpesvirus Latency

描述（由申请方提供）：本提案的目的是定义负责针对γ-疱疹病毒潜伏期接种的机制。了解这些机制将有助于了解免疫的γ-疱疹病毒的基本原理。两种人类γ-疱疹病毒（Epstein-Barr病毒（EBV）和卡波西肉瘤相关疱疹病毒（KSHV，HHVS））的感染与肿瘤和淋巴组织增生性疾病相关，特别是在AIDS患者和移植受体中。对γ-疱疹病毒的免疫机制尚未完全了解，也没有针对这些病毒的有效疫苗。我们用γ-HV 68（MHV-68）感染小鼠，这是一种与感染实验室小鼠的EBV和KSHV密切相关的病毒，以确定γ-疱疹病毒致病和免疫的机制。令人惊讶的是，其他几个小组使用的亚单位疫苗接种方法有效地控制了急性γ-HV 68感染，但未能预防长期潜伏期。该建议是基于我们实验室的一项新观察，即用再活化缺陷型v-细胞周期蛋白γ-HV 68突变病毒感染可有效接种疫苗，以防止野生型潜伏期的建立。γ-HV68使用新开发的转基因小鼠模型进行的进一步研究表明，虽然接种疫苗需要B细胞，但不需要抗体。这种新的模型为我们提供了一个机会，直接评估免疫T细胞对疫苗接种对潜伏期的贡献，而没有免疫抗体的混淆效应。该提案将通过以下目标定义负责针对潜伏期接种疫苗的机制，从而扩展我们对免疫系统如何控制慢性病毒感染和疾病的基本理解。正在测试的两个潜在假设是潜伏抗原特异性T细胞：（i）是预防潜伏期建立所需的，和（ii）可以消除潜伏感染的细胞。 目的1）探讨CD 4和CD 8 T细胞在抗-HBs免疫中的作用。HV 68潜伏期目的2）鉴定T细胞识别的潜伏期相关抗原目的3）测试用潜伏期相关抗原接种的效果。

DESCRIPTION (provided by applicant): The aim of this proposal is to define the mechanisms responsible for vaccination against gamma-herpesvirus latency. Understanding these mechanisms will contribute to understanding the fundamentals of immunity to gamma-herpesviruses. Infection with two human gamma-herpesviruses, Epstein-Barr Virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV, HHVS), is associated with tumors and lymphoproliferative disease especially in AIDS patients and transplant recipients. The mechanisms of immunity to gamma-herpesviruses are incompletely understood and there are no effective vaccines against these viruses. We have used infection of mice with gamma-HV68 (MHV-68), a virus closely related to EBV and KSHV which infects laboratory mice, to define mechanisms of gamma-herpesvirus pathogenesis and immunity. Surprisingly, subunit vaccination approaches used by several other groups effectively control acute gamma-HV68 infection but fail to prevent long term latency. This proposal is based on a novel observation made in our lab that infection with a reactivation deficient v-cyclin gamma-HV68 mutant virus effectively vaccinates against establishment of latency by wildtype. gamma-HV68. Further studies using a newly developed transgenic mouse model have shown that, while B cells are required for vaccination, antibody is not required. This new model provides us an opportunity to directly evaluate the contributions of immune T cells to vaccination against latency without confounding effects of immune antibody. This proposal will define, through the following Aims, the mechanisms responsible for vaccination against latency, thereby extending our fundamental understanding of how the immune system controls chronic viral infection and disease. The two underlying hypotheses being tested are that latency antigen specific T cells are: (i) required for prevention of the establishment of latency, and (ii) can eliminate latently infected cells. Aim 1) Determine the role of CD4 and CD8 T cells in vaccination against. HV68 latencyAim 2) Identify latency associated antigens recognized by T cells Aim 3) Test the effects of vaccination with latency associated antigens.