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.