Targeting the DNA Damage Response for the Treatment of Oral Mucosal HSV-1 Infection

Abstract

Herpes simplex virus type 1 (HSV-1) is a highly prevalent pathogen that infects 67% of the world’s population. HSV-1 most commonly infects the oral mucosal epithelium and manifests as herpes simplex labialis (cold sore) or herpetic gingivostomatitis. Patients who have a compromised immune system are at serious risk for developing drug-resistant HSV-1 disease that can become life-threatening through dissemination to internal organs. Treatment options for drug-resistant HSV-1 infection are nonspecific and fraught with toxicity concerns. Thus, there is a critical need for the development of new therapeutics. HSV-1 engages the cellular DNA damage response (DDR) by activating Ataxia Telangiectasia Mutated (ATM) and its major downstream target, Checkpoint Kinase 2 (Chk2). We demonstrate that targeting ATM or Chk2 with small molecule inhibitors suppresses both wild type and acyclovir-resistant HSV-1 replication in normal human oral keratinocyte cells. Furthermore, topical application of ATM or Chk2 inhibitors reduces the severity of herpes simplex labialis in a mouse lip model. We also demonstrate for the first time that ATM signaling is required for circularization of the HSV-1 genome. Interestingly, Chk2 is not required for HSV-1 genome circularization, which suggests that additional functions of the DDR are required for HSV-1 replication. We also elucidate that ATM can be activated in both a de novo-dependent and de novo–independent manner through ICP4. These data establish that targeting the DDR has the potential for treating oral mucosal HSV-1 disease, and furthers our understanding of how the DDR is utilized during HSV-1 infection.%%%%Ph.D., Molecular and Cell Biology and Genetics – Drexel University, 2016