Interferon Alpha Regulation of Murine Gammaherpesvirus Latency

描述(申请人提供)：I型干扰素(干扰素)细胞因子家族是抵御病毒感染的第一道天然防线。缺乏干扰素受体(IFNAR1-/-)的小鼠表现出高水平的病毒复制和增加的死亡率，表明干扰素在宿主对病毒感染的反应中起着关键作用。然而，主流的干扰素功能模型认为，这些细胞因子只在急性感染期间发挥作用，一旦适应性免疫反应抑制了病毒复制，这些细胞因子就是可有可无的。关于干扰素在慢性或潜伏感染中的潜在功能，人们知之甚少。我们意外地发现，在体内潜伏期，干扰素可以阻止小鼠疱疹病毒68(MHV68)的重新激活。MHV68是小鼠的一种天然病原体，在遗传和病理上与人类疱疹病毒、爱泼斯坦-巴尔病毒和卡波西肉瘤疱疹病毒相似。干扰素在MHV68潜伏期的作用不需要最具特征的干扰素刺激的抗病毒基因，这促使我们考虑一种新的机制。事实上，我们的初步数据显示，在潜伏感染的B细胞中，干扰素通过细胞干扰素调节因子(IRF)与病毒启动子的结合直接调节MHV68潜伏基因的表达。这表明了一个有趣的假设，即疱疹病毒已经进化到将其基因表达电路与干扰素信号通路整合在一起，从而利用宿主抗病毒系统来促进免疫妥协期间重新激活的战略时机。建议的研究使用易处理的MHV68系统来确定干扰素在体内调节病毒潜伏基因表达和重新激活的生理作用。提出了三个特定的目标：(I)检验干扰素通过在潜伏期直接作用于受感染的细胞来调节MHV68感染的假设；(Ii)识别控制复制、基因表达和再激活的干扰素调节的病毒启动子元件；以及(Iii)确定IRFs调节潜伏的病毒基因表达和再激活的机制。这项研究将对了解干扰素在慢性感染中的作用具有广泛的意义，并将导致识别宿主抗病毒途径，这些途径可能被证明与控制致癌的人类疱疹病毒有关。 公共卫生相关性：拟议的研究将加强对I型干扰素在人类慢性感染中发挥作用的机制的理解。此外，由于MHV68与人类病原体Epstein-Barr病毒和Kaposi肉瘤相关疱疹病毒密切相关，这些研究将为治疗潜在的伽马疱疹病毒感染引起的癌症的潜在治疗靶点提供新的见解。

DESCRIPTION (provided by applicant): The type I interferon (IFN) cytokine family comprises the first line of innate defense against virus infections. Mice lacking the IFN receptor (IFNAR1-/-) display high-level virus replication and increased mortality, demonstrating a critical role for IFN in host response to virus infection. However, prevailing models of IFN function assume that these cytokines function solely during acute infection and are dispensable once the adaptive immune response has silenced viral replication. Relatively little is known about potential functions of IFN during chronic or latent infection. We found unexpectedly that IFN prevents reactivation of murine -herpesvirus 68 (MHV68) during latency in vivo. MHV68 is a natural pathogen of mice and displays genetic and pathologic similarities to the human ?-herpesviruses Epstein-Barr virus and Kaposi Sarcoma herpesvirus. The effects of IFN during MHV68 latency did not require the most well characterized IFN-stimulated antiviral genes, which prompted us to consider a novel mechanism. Indeed, our preliminary data show that IFN directly regulates MHV68 latent gene expression via the binding of cellular interferon regulatory factors (IRFs) to viral promoters in latently-infected B cells. This suggests the intriguing hypothesis that -herpesviruses have evolved to integrate their gene expression circuitry with IFN signaling pathways, thereby co-opting a host antiviral system to promote strategic timing of reactivation during periods of immunocompromise. The proposed research uses the tractable MHV68 system to identify the physiologic roles of IFN in regulating viral latent gene expression and reactivation in vivo. Three Specific Aims are proposed to: (i) test the hypothesis that IFN regulates MHV68 infection by acting directly on the infected cell during latency; (ii) identify interferon-regulated viral promoter elements that control replication, gene expression, and reactivation and (iii) define the mechanism by which IRFs regulate latent viral gene expression and reactivation. This research will have broad significance for understanding IFN function during chronic infections and will lead to the identification of host antiviral pathways that may prove relevant for control of oncogenic human??-herpesviruses. PUBLIC HEALTH RELEVANCE: The proposed studies will enhance an understanding of mechanisms by which type I interferons function in chronic infections in humans. Furthermore, as MHV68 is closely related to the human pathogens Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus, these studies will provide new insights into potential therapeutic targets for treatment of cancers arising during latent gammaherpesvirus infection.