Herpes Simplex Virus 1 Manipulates Host Cell Antiviral and Proviral DNA Damage Responses.
Max E MertensDavid M KnipePublished in: mBio (2021)
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.IMPORTANCE We investigated the relationship between the DNA damage response, a collection of vital cellular pathways that repair potentially lethal damage to the genome, and the DNA virus herpes simplex virus 1. We found that infection by the virus triggers the DNA damage response, and key proteins that mediate this response have opposing effects on the replication and production of progeny viruses. Our work provides novel insights into the relationship between DNA virus infection and the cellular response to the viral genome. We speculate that viral gene products modulate this response, providing potentially novel targets for therapeutic intervention against the virus.
Keyphrases
- herpes simplex virus
- dna damage response
- circulating tumor
- cell free
- induced apoptosis
- dna repair
- single molecule
- dna damage
- crispr cas
- cell cycle arrest
- oxidative stress
- genome wide
- nucleic acid
- endothelial cells
- copy number
- randomized controlled trial
- sars cov
- cell therapy
- hiv infected
- circulating tumor cells
- endoplasmic reticulum stress
- signaling pathway
- mesenchymal stem cells
- mass spectrometry
- long non coding rna
- cell proliferation
- early onset
- antiretroviral therapy
- pluripotent stem cells
- genome wide identification
- high resolution