Herpes Simplex Virus 1 (HSV-1) is a ubiquitous pathogen that exists worldwide, and has a seroprevalance of 57.7% in the United States. The oromucosal surface is a prominent reservoir for HSV-1 pathogeneses that manifest as herpes simplex labialis (HSL), primary herpetic gingivostomatis, and intraoral vesicles that arise in the hard palate and attached gingival. HSL refers to HSV-1 infection of the lip and mouth, and is the most common of these maladies. While current treatments are efficacious for treating symptoms in most people, drug resistant strains of HSV-1 have developed in the immunocompromised population of HSL patients. It is reported that HSV-1 resistant strains occur in 3.5%-7% of HIV-positive patients and at a rate of 4.1%-10.9% in recipients of hematopoietic stem cells. Since most of the drugs used to treat infection are derived from acyclovir and have the same mechanism of action, there are no safe and effective drugs available to treat these individuals. This presents a critical need to develop novel therapeutics to treat HSL that function through a mechanism of action distinct from that of acyclovir. HSV-1 infection occurs in the oral mucosa where the virus manipulates the DNA damage response (DDR) of the oral epithelial cell to create an optimal environment for virus production. HSV-1 activates the ataxia telangiectasia mutated (ATM) sensor kinase, and while the cause of ATM activation in response to HSV- 1 infection is unknown, the downstream signaling is required for productive infection. ATM activation is an upstream event that can result in modification of chromatin packaging and repair of DNA double strand breaks by homologous recombination. Additionally, both chromatin modification and recombination are required for the pathogenesis of HSV-1.Therefore, we hypothesize that activation of the ATM signaling pathway is necessary for replication of HSV- Here, we propose to evaluate the validity to this hypothesis by analyzing the impact of ATM activation on the chromatin packaging state of the viral genome. We will also evaluate how recombination of the viral genome is impacted by ATM activity. The long term goal of this research is to develop novel therapeutic targets that differ from the mechanism of action of acyclovir, and can be used to treat immunocompormised individuals with HSL. Within the scope of the proposed project, we expect to elucidate the function(s) of ATM activation -required for productive HSV-1 infection in an in vitro and in vivo model system that mimics HSL conditions.
The development of drug resistant HSV-1 strains in a subset of immunocompromised patients suffering from herpes simplex labialis has necessitated the need for novel drug therapies. The mission of this project is to elucidate the relationship between HSV-1infection and the DNA damage response of the cellular host, with the goal of identifying promising drug targets with a novel mechanism of action.
