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

在全世界95%的成年人中，伽马疱疹病毒会造成终身感染，并与乙型病毒性肝炎有关 细胞性淋巴瘤。目前还不可能预防由伽马疱疹病毒引起的淋巴瘤 缺乏疫苗、有效的抗病毒药物和确定的淋巴肿大危险因素。全 伽马疱疹病毒编码一种蛋白激酶，这是慢性感染和发病机制的关键决定因素。 这项资助申请旨在定义生理基础上的分子和细胞机制。 伽马疱疹病毒蛋白激酶在完整宿主慢性感染过程中的相关功能。基于 我们已发表的和初步的发现，拟议的研究测试了巨噬细胞- 内源性干扰素信号被一种酶活性的病毒蛋白激酶拮抗以促进其通过 病毒从髓系到B细胞室。一旦病毒获得了对B细胞的访问，病毒激酶 支持潜伏的病毒基因表达，并参与宿主机制以推动B细胞分化和 建立慢性感染。成功完成拟议的研究将定义分子和 慢性丙型肝炎过程中保守的伽马疱疹病毒蛋白激酶功能的细胞机制 感染完好的自然宿主。这种机制很可能在病毒淋巴增生症过程中起作用。 并可能为预防伽马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.