Inflammatory Mediators of Gammaherpesvirus Reactivation

人类伽玛疱疹病毒是eb病毒（EBV）和卡波西肉瘤相关疱疹病毒（KSHV），也称为人类疱疹病毒8 （HHV-8）。每种人类伽玛疱疹病毒与许多恶性肿瘤密切相关，特别是在免疫抑制的移植受者或由于同时感染人类免疫缺陷病毒而免疫抑制的个体中。像其他疱疹病毒一样，伽玛疱疹病毒的特点是能够在宿主细胞中建立潜伏期。潜伏期的再激活和随后的裂解病毒复制是伽马疱疹病毒生命周期的重要组成部分，使病毒能够传播到宿主内的其他细胞或其他易感宿主。伽玛疱疹病毒再激活过程背后的分子机制越来越为人所知，但触发这些分子事件的特定外源刺激尚未得到很好的定义。临床和实验证据表明，与第二种病原体的共同感染可能会刺激潜伏感染伽玛疱疹病毒的宿主的再激活。使用小鼠共感染模型，该应用程序将验证第二病原体的急性感染能够诱导潜伏小鼠γ疱疹病毒68 （MHV-68）的再激活的假设。具体目的是：1)确定共感染是否诱导潜伏MHV-68的再激活；2)确定选定的趋化因子和细胞因子在潜伏MHV-68再激活中的作用。与公共卫生相关：本应用程序中概述的实验将扩展我们对伽玛疱疹病毒如何重新激活的理解，从持续感染的人的非活性状态中唤醒，以创建能够感染同一个人或其他个体内其他细胞的新病毒副本。从这些实验中获得的信息将大大有助于我们对伽玛疱疹病毒生物学和发病机制的理解，并可能影响设计治疗伽玛疱疹病毒相关疾病的策略。

DESCRIPTION (provided by applicant): The human gammaherpesviruses are Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). Each human gammaherpesvirus is closely associated with a number of malignancies, particularly in immunosuppressed transplant recipients or individuals with immunosuppression due to concurrent infection with human immunodeficiency virus. Like other herpesviruses, the gammaherpesviruses are characterized by their ability to establish latency in host cells. Reactivation from latency and subsequent lytic viral replication is an essential component of the gammaherpesvirus life cycle, allowing the virus to spread to other cells within the host or to other susceptible hosts. Molecular mechanisms underlying the process of gammaherpesvirus reactivation are increasingly understood, but specific exogenous stimuli that trigger these molecular events are not yet well defined. Clinical and experimental evidence suggests that coinfection with a second pathogen may serve as a stimulus for reactivation in a host latently infected with a gammaherpesvirus. Using a mouse model of coinfection, this application will test the hypothesis that acute infection with a second pathogen is capable of inducing reactivation of latent murine gammaherpesvirus 68 (MHV-68). The specific aims are to 1) determine whether coinfection induces reactivation of latent MHV-68, and 2) define the roles of select chemokines and cytokines in reactivation of latent MHV-68. Relevance to Public Health: The experiments outlined in this application will expand our understanding of how gammaherpesviruses reactivate, awakening from an inactive state in a persistently infected person in order to create new copies of virus capable of infecting other cells within the same person or infecting other individuals. Information gained from these experiments will contribute significantly to our understanding of gammaherpesvirus biology and pathogenesis and potentially will impact on strategies designed to treat gammaherpesvirus-related disease.