Herpes Simplex Virus type 1 (HSV-1) is a human DNA virus that causes a number of diseases involving the human nervous system, including keratitis and encephalitis. The virus is characterized by its ability to form latent infections in neurons of the peripheral nervous system, from which it can reactivate to cause recurrent disease. Our long-term goal is to understand the cellular responses that contribute to establishment of HSV-1 latency specifically in neurons. The latent genome persists in an episomal chromatinized state for the lifetime of the host without detectable protein expression. Reactivation can occur spontaneously or be induced by various forms of stress. The viral immediate early protein ICP0 is a multifunctional protein important for stimulating the initiation f the lytic cycle and also efficient reactivation of latent or quiescent genomes. Exactly how ICP0 creates a favorable cellular environment during lytic replication and promotes reactivation from latency remains unclear, but dependence on the E3 ubiquitin ligase activity of the RING finger domain in ICP0 suggests that degradation of its substrates is involved. Our labs and others have shown that HSV-1 infection activates and exploits aspects of the cellular DNA damage signaling cascade. We have also shown that the DNA damage machinery can act as an intrinsic cellular defense that is inactivated through degradation of specific DNA repair proteins by ICP0. Our central hypothesis is that both the DNA damage response and the behavior of ICP0 are different in neuronal cells, and that these two factors contribute to establishment of latency specifically in neurons. The objective of this proposal is to define the role of the DNA damage response in circularization and nucleosome deposition on the incoming viral genome at the earliest stages of infection, and to determine how this impacts the decision to form lytic or laten HSV infections in neurons. We will examine how ICP0 controls these processes and will determine why the ICP0 protein does not accumulate in the nucleus of infected neurons. The approach will employ novel techniques to determine how cellular responses impact infection in human neurons in culture and in animal models. These neurovirological studies are significant because they are expected to provide insights into virus-host interactions during HSV-1 infection and the early responses that determine the outcome of infection in neurons and non-neuronal cells. Knowledge of HSV-1 neuronal latency will suggest novel targets for developing antivirals against this significant human pathogen.

Public Health Relevance

Herpes simplex virus type 1 (HSV-1) is a significant human pathogen, with recurrent infections that cause much suffering and lost work productivity in the US. Central to the problem of HSV-1 disease is the ability of the virus to establish latent infections in sensory neurons, but the molecular mechanisms that control establishment and reactivation from latency are unclear. This project will determine how early cellular responses to virus infection regulate the virus lifecycle and lead to establishment of latency specifically in neurons of the human nervous system. These studies will provide insights into neuronal-specific regulation of HSV-1 gene expression and virus-host interactions, which will suggest directions for developing novel antivirals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS082240-03
Application #
8895429
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
2013-09-15
Project End
2016-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Pancholi, Neha J; Price, Alexander M; Weitzman, Matthew D (2017) Take your PIKK: tumour viruses and DNA damage response pathways. Philos Trans R Soc Lond B Biol Sci 372:
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Kulej, Katarzyna; Avgousti, Daphne C; Sidoli, Simone et al. (2017) Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection. Mol Cell Proteomics 16:S92-S107
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Avgousti, Daphne C; Weitzman, Matthew D (2015) Stress Flips a Chromatin Switch to Wake Up Latent Virus. Cell Host Microbe 18:639-41
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Deng, Zhong; Kim, Eui Tae; Vladimirova, Olga et al. (2014) HSV-1 remodels host telomeres to facilitate viral replication. Cell Rep 9:2263-78

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