Interferon Alpha Regulation of Murine Gammaherpesvirus Latency

描述（由申请人提供）：I型干扰素（IFN）细胞因子家族包括抗病毒感染的第一道先天防御。缺乏IFN受体（IFNAR 1-/-）的小鼠显示高水平的病毒复制和增加的死亡率，表明IFN在宿主对病毒感染的反应中起关键作用。然而，IFN功能的流行模型假设这些细胞因子仅在急性感染期间起作用，并且一旦适应性免疫应答使病毒复制沉默，这些细胞因子就被抑制。关于IFN在慢性或潜伏感染中的潜在功能知之甚少。我们意外地发现IFN在体内潜伏期期间阻止鼠疱疹病毒68（MHV 68）的再活化。MHV 68是小鼠的天然病原体，与人类的遗传和病理相似。疱疹病毒Epstein-Barr病毒和卡波西肉瘤疱疹病毒。IFN在MHV 68潜伏期的作用并不需要最充分表征的IFN刺激的抗病毒基因，这促使我们考虑一种新的机制。事实上，我们的初步数据表明，IFN直接调节MHV 68潜伏基因的表达，通过结合细胞干扰素调节因子（IRF）的病毒启动子在潜伏感染的B细胞。这表明了一个有趣的假设，疱疹病毒已经进化到整合其基因表达电路与IFN信号通路，从而选择宿主抗病毒系统，以促进免疫妥协期间的战略时机的重新激活。拟议的研究使用易处理的MHV 68系统，以确定IFN在体内调节病毒潜伏基因表达和再激活的生理作用。提出了三个特定目的：（i）检验IFN通过在潜伏期直接作用于感染细胞来调节MHV 68感染的假设;（ii）鉴定控制复制、基因表达和再活化的干扰素调节的病毒启动子元件;（iii）定义IRF调节潜伏病毒基因表达和再活化的机制。这项研究对于了解IFN在慢性感染中的功能具有广泛的意义，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肿瘤相关。疱疹病毒

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.