Can persistent gamma-herpesviruses be purged from the host?

描述(申请人提供)：人类伽玛疱疹病毒，爱泼斯坦-巴尔病毒(EBV)和卡波西肉瘤相关疱疹病毒(KSHV)，建立与各种恶性肿瘤的发展相关的持续性感染。虽然感染的裂解阶段由免疫系统控制，但病毒通过建立终身潜伏来逃避免疫，即使在具有免疫能力的宿主中也是如此。感染的病理后果主要与病毒潜伏有关，目前还没有预防性或治疗性疫苗。B细胞是潜伏病毒的主要储存库，与EBV感染相关的一个重要临床问题是移植后免疫抑制后B细胞增生性疾病和/或B细胞淋巴瘤的发展。为了测试这种方法和其他治疗方法，有必要了解维持长期潜伏期的机制，这可以在实验动物模型中得到最好的解释。Gamma HV68(又称MHV-68)是一种自然产生的啮齿动物伽马疱疹病毒，可感染实验室小鼠，为进行人类无法进行的实验提供了一种易于操作的小动物自然感染模型。目前的提案利用鼠标模型来解决潜在的延迟维护机制。重要的是，我们将测试一个假设，即潜伏的病毒可以从受感染的宿主中清除。在目标1中，我们将确定病毒的重新激活和再感染是否有助于维持B细胞、巨噬细胞和树突状细胞的长期潜伏期。在目标2中，我们将确定使用B细胞耗竭抗体来模拟利妥昔单抗治疗，无论是否使用抗病毒药物，是否可以减少或消除长期潜伏期。公共卫生相关性：伽马疱疹病毒是一种致癌病毒，在人类人群中广泛传播，与恶性肿瘤的发展有关。分析发达的伽马疱疹病毒感染小鼠模型为剖析病毒潜伏期重新激活的基本事件提供了重要工具，并作为测试概念验证治疗策略的体内模型。所产生的数据将通过加强我们对伽玛疱疹病毒潜伏期的理解来推动该领域的发展，以促进人类伽玛疱疹病毒治疗策略的发展。

DESCRIPTION (provided by applicant): The human gamma-herpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), establish persistent infections that are associated with the development of a variety of malignancies. Whereas the lytic phase of the infection is controlled by the immune system, the viruses evade immunity by establishing life-long latency, even in an immunocompetent host. Pathological consequences of infection are primarily associated with viral latency, and no prophylactic or therapeutic vaccines are available. B cells are the major reservoir of latent virus, and one important clinical problem associated with EBV infection is the development of B cell lymphoproliferative disease and/or B cell lymphomas following post-transplant immunosuppression. Promising results with the clinical use of Rituximab (anti-B cell antibody therapy) to target EBV-transformed B cells in post-transplant malignancies suggest the possibility that anti-B cell therapy could be used prophylactically to substantially lower latent load or even to purge latency from the host prior to transplantation. In order to test this and other therapeutic approaches, it is essential to understand mechanisms involved in maintenance of long-term latency, which can best be elucidated in an experimental animal model. Gamma HV68 (also referred to as MHV-68) is a naturally occurring gamma-herpesvirus of rodents that infects the laboratory mouse, providing an easily manipulated small animal natural infection model for performing experiments not possible in man. The current proposal exploits the mouse model to address mechanisms underlying the maintenance of latency. Importantly, we will test the hypothesis that latent virus can be purged from an infected host. In Aim 1, we will determine whether viral reactivation and re-infection contribute to the maintenance of long-term latency in B cells, macrophages and dendritic cells. In Aim 2 we will determine whether treatment with B cell depleting antibodies to mimic Rituximab therapy, with or without anti-viral drugs, can reduce or eliminate long-term latency. PUBLIC HEALTH RELEVANCE: The gamma-herpesviruses are oncogenic viruses that are widely disseminated in the human population and associated with the development of malignancies. Analysis of the well-developed mouse model of gamma- herpesvirus infection provides an important tool to dissect fundamental events in the reactivation of viral latency, and serves as an in vivo model for testing proof of concept therapeutic strategies. The data generated will advance the field by enhancing our understanding of gamma-herpesvirus latency to facilitate the development of therapeutic strategies for the human gamma-herpesviruses.