Virus Host Interactions that Regulate Translation in Cells Infected with HSV-1

虽然单纯疱疹病毒（HSV）在病毒繁殖受到抑制的人外周神经元中建立永久性潜伏感染，但导致感染性病毒产生的生长程序响应于生理应激而周期性地启动。这种生产性生长程序需要HSV控制宿主蛋白质合成机制，以强制病毒编码的mRNA翻译。宿主翻译阻遏物4 E-BP 1的失活是该过程中的关键步骤，4 E-BP 1的活性由多亚基细胞激酶mTORC 1控制。我们已经确定，翻译阻遏物4 E-BP 1的失活需要病毒Us 3 Ser Thr激酶，其功能是激活mTORC 1。值得注意的是，mTORC 1是基本细胞合成代谢和分解代谢过程的关键调节剂，并准备维持细胞内的生理稳态。此外，各种各样的生理应激，其中许多抑制mTORC 1信号传导并破坏代谢稳态，触发潜伏感染神经元的生产性复制。我们的总体目标是了解Us 3病毒Ser Thr激酶如何通过宿主mTORC 1多亚基复合物（蛋白质合成的关键调节因子）在HSV 1感染的细胞中破坏信号传导。根据我们的初步结果，我们假设，抑制mTORC 1信号，以应对不断变化的环境条件或作为一种内在的宿主防御，可以限制病毒复制。随后的mTORC 1激活响应Us 3行动是必需的，以刺激合成代谢功能（蛋白质合成），使生产性病毒复制，从而抵消基本的先天（分解代谢）宿主防御设计，以限制病毒的生长。在此，在三个具体目标中测试该假设，i）确定HSV 1感染如何改变和操纵宿主多亚基mTORC 1酶复合物的信号传导; ii）确定Us 3介导的mTORC 1信号传导如何控制在生产性感染的细胞中的病毒和细胞mRNA翻译;以及iii）定义调节mTORC 1信号传导的生理应激如何控制HSV 1复制，以及Us 3在缓解条件下的生产性生长中的影响。应力确定宿主翻译控制途径如何调节生产性HSV 1生长以及病毒功能如何在生理应激下保持其活性将改变我们对病毒-宿主相互作用的理解，并导致干扰病毒复制的新治疗策略。

While herpes simplex virus (HSV) establishes permanent latent infections in human peripheral neurons where virus reproduction is suppressed, a growth program resulting in infectious virus production periodically initiates in response to physiological stress. This productive growth program requires that HSV seize control of the host protein synthesis machinery to enforce translation of virus-encoded mRNAs. Inactivation of a host translational repressor, 4E-BP1, whose activity is controlled by the multi-subunit cellular kinase mTORC1 represents a key step in this process. We have established that inactivation of the translation repressor 4E-BP1 requires the viral Us3 Ser Thr kinase, which functions to activate mTORC1. Significantly, mTORC1 is a critical regulator of fundamental cellular anabolic and catabolic processes and is poised to maintain physiological homeostasis within cells. Moreover, a diverse assortment of physiological stresses, many of which inhibit mTORC1 signaling and disrupt metabolic homeostasis, trigger productive replication in latently-infected neurons. Our overall objective is to understand how the Us3 viral Ser Thr kinase can subvert signaling via the host mTORC1 multi-subunit complex, a key regulator of protein synthesis, in cells productively infected with HSV1. Based on our preliminary results, we hypothesize that suppressing mTORC1 signaling, in response to changing environmental conditions or as an intrinsic host defense, can limit virus replication. Subsequent mTORC1 activation in response to Us3 action is required to stimulate anabolic functions (protein synthesis) that enable productive viral replication, thus counteracting fundamental innate (catabolic) host defenses designed to limit viral growth. Here this hypothesis is tested in three specific aims that i) determine how HSV1 infection modifies and manipulates signaling by the host multi-subunit mTORC1 enzyme complex; ii) determine how Us3-mediated mTORC1 signaling controls viral and cellular mRNA translation in productively-infected cells; and iii) define how physiological stresses that regulate mTORC1 signaling control HSV1 replication and the impact of Us3 in mitigating productive growth under stress. Identifying how host translational control pathways regulate productive HSV1 growth and how viral functions preserve their activity under physiological stress will change our understanding of virus-host interactions and lead to new therapeutic strategies that interfere with viral replication.