Gammaherpesvirus protein kinase: a master manipulator of the host during chronic infection.

γ疱疹病毒在全世界> 95%的成人中建立终身感染，并与B相关 细胞淋巴瘤目前不可能预防γ疱疹病毒驱动的淋巴瘤， 缺乏疫苗、治疗性抗病毒药物和明确的淋巴瘤发生风险因素。所有 γ疱疹病毒编码蛋白激酶，这是慢性感染和发病的关键决定因素。 这项拨款申请旨在确定生理学基础的分子和细胞机制， 完整宿主慢性感染期间γ疱疹病毒蛋白激酶的相关功能。基于 我们发表的和初步的发现，拟议的研究测试的工作模型，巨噬细胞- 内源性IFN信号传导被酶活性病毒蛋白激酶拮抗以促进传代 病毒从髓细胞到B细胞区室。一旦病毒进入B细胞， 支持潜伏的病毒基因表达并参与宿主机制以驱动B细胞分化， 建立慢性感染。成功完成拟议的研究将确定分子和 慢性疱疹病毒感染中保守的γ-疱疹病毒蛋白激酶功能的细胞机制 一个完整的自然宿主的感染。这种机制可能在病毒性淋巴瘤发生过程中起作用 并且可能为预防γ疱疹病毒驱动的淋巴瘤提供新的治疗靶点。

Gammaherpesviruses establish life-long infections in >95% of adults worldwide and are associated with B cell lymphomas. Prevention of gammaherpesvirus-driven lymphomas is currently impossible due to absence of vaccines, curative antivirals, and defined risk factors for lymphomagenesis. All gammaherpesviruses encode a protein kinase, a key determinant of chronic infection and pathogenesis. This grant application aims to define the molecular and cellular mechanisms underlying physiologically relevant functions of gammaherpesvirus protein kinases during chronic infection of an intact host. Based on our published and preliminary findings, the proposed studies test the working model that macrophage- intrinsic IFN signaling is antagonized by an enzymatically active viral protein kinase to promote the passage of the virus from myeloid to B cell compartment. Once viral access to B cells is gained, viral kinase supports latent viral gene expression and engages host mechanisms to drive B cell differentiation and establishment of chronic infection. Successful completion of the proposed studies will define molecular and cellular mechanisms underlying functions of the conserved gammaherpesvirus protein kinase during chronic infection of an intact natural host. Such mechanisms are likely to operate during viral lymphomagenesis and may present novel therapeutic targets for the prevention of gammaherpesvirus-driven lymphomas.