Herpes Simplex Virus 1 Manipulates Host Cell Antiviral and Proviral DNA Damage Responses

Cells activate their DNA damage response (DDR) in response to DNA virus infection, including adenoviruses, papillomaviruses, polyomaviruses, and herpesviruses. In this study, we found that the DDR kinase pathways activated in normal human fibroblasts by herpes simplex virus 1 (HSV-1) input genomic DNA, HSV-1 replicating DNA, and progeny DNA and in uninfected cells treated with etoposide are different. We also found using clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 technology that different host gene products are required for the DDR in uninfected versus infected cells. Individual DDR components can be proviral or antiviral in that ataxia-telangiectasia mutated (ATM) and p53 promote and Mre11 restricts replication of ICP0-null HSV-1, but ICP0 expression eliminates these DDR effects. Thus, in total, these results argue that HSV-1 manipulates the host cell DDR to utilize specific components for its optimal replication while inactivating the antiviral aspects of the DDR.