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.

Public Health Relevance

Herpes simplex viruses (HSV) are ubiquitous human pathogens that establish lifelong infections in nerve cells. Periodically, in response to physiological stress-related cues, the virus begins to propagate and spread from the neuron to other tissue and this can lead to a variety of diseases, ranging from the benign to life-threatening. Here, we define how HSV is able to reproduce and grow productively in the presence of physiological stress, as interfering with the virus?s capacity to overcome physiological stress will help create new therapies for combating disease caused by HSV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073898-10
Application #
9942255
Study Section
Virology - A Study Section (VIRA)
Program Officer
Beisel, Christopher E
Project Start
2008-07-08
Project End
2021-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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