Immune control of latent gammaherpesvirus infection

描述(申请人提供)：伽马疱疹病毒，如爱泼斯坦巴尔病毒(EBV)和卡波西肉瘤相关疱疹病毒是重要的人类病原体，与淋巴增生性疾病和各种恶性肿瘤有关，包括伯基特淋巴瘤、霍奇金病、鼻咽癌和卡波西肉瘤。最初的裂解感染被有效清除，但病毒建立了终身潜伏，有效地躲避了免疫系统。周期性的病毒重新激活是零星发生的，但通过免疫控制的宿主机制进行控制。CD8+T细胞已被证明对EBV的控制很重要，但其机制尚不清楚。在目前的方案中，我们将利用一种新的小鼠模型，小鼠伽马疱疹病毒-68，MHV-68，来研究这类重要病毒的免疫控制的基本机制。我们实验室和其他实验室积累的数据表明，MHV-68潜伏期存在于多种细胞类型和解剖部位。因此，确定免疫控制的关键第一步是确定潜伏期储存库的特征，并确定维持潜在负荷的机制，这将在本提案的目标1和2中解决。考虑到这些信息，我们将在目标3中检查控制潜伏期和防止病毒复发的免疫机制。这对人类健康很重要，因为艾滋病或移植后免疫抑制导致的免疫控制丧失与潜伏期增加和疾病发生有关。一种易于操作的实验小鼠模型的出现是该领域的一大进步，并使基本机制得以解决。预计这项建议中收集的基本信息将为临床相关的人类伽马疱疹病毒的免疫控制机制提供洞察力。

DESCRIPTION (provided by applicant): Gammaherpesviruses, such as Epstein Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus are important human pathogens, associated with lymphoproliferative disorders and various maligancies, including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and Kaposi's sarcoma. The initial lytic infection is efficiently cleared, but the virus establishes life-long latency, effectively hiding from the immune system. Periodic viral reactivation occurs sporadically, but is kept in check by host mechanisms of immune control. CD8+ T cells have been shown to be important for control of EBV, but the mechanisms are poorly understood. In the current proposal, we will exploit a new mouse model, murine gammaherpesvirus-68, MHV-68, to study basic mechanisms of immune control of this important class of viruses. Accumulating data from our laboratory and others show that MHV-68 latency is harbored in multiple cell types and anatomical sites. Therefore, an essential first step in characterizing immune control is to characterize reservoirs of latency, and determine mechanisms for maintaining the latent load, which will be addressed in Aims 1 and 2 of the current proposal. Taking this information into account, we will then examine immune mechanisms for controlling latency and preventing viral recrudescence in Aim 3. This is important for human health, as loss of immune control as a consequence of AIDS or post-transplant immunosuppression is associated with increased latent load and the onset of disease. The availability of an easily manipulated experimental mouse model is a major advance in the field, and allows fundamental mechanisms to be addressed. It is anticipated that the basic information gathered in this proposal will provide insight into the mechanisms of immune control of the clinically-relevant human gammaherpesviruses.