Abstract

Herpes simplex viruses (HSVs) type 1 (HSV-1) and type 2 (HSV-2) are highly prevalent in the world and infections are lifelong. Individuals with clinical symptoms elicited by HSV infection may su er, among others from occasional or recurrent herpetic lesions in the orofacial and genital areas, as well as herpetic gingivostomatitis. Herpetic skin lesions are usually treated with nucleoside analogs such as acyclovir, which selectively inhibits the viral DNA polymerase. However, this drug are somewhat ine ective in treating skin lesions, as topical formulations only reduce in 1-2 days the duration of skin lesions. Cetylpyridinium chloride (CPC) is a quaternary ammonium compound with surfactant properties that is safe in humans. It is often present in hygiene products, such as mouthwashes, deodorants, aphthae-treating formulations, and oral tablets as an anti-septic to limit bacterial growth. Previous reports indicate that CPC can also modulate host signaling pathways, namely NF-κB signaling. Because HSV infection is modulated by NF-κB, we sought to assess whether CPC has antiviral e ects against HSVs. Using wild-type, acyclovir-resistant and HSV isolates with GFP reporter genes, as well as epithelial cells (Vero cells) and primary human broblasts expanded from the oral cavity, we assessed the potential antiviral capacity of CPC and its mechanism of action. We found that when added after HSV infection, CPC signi cantly limited viral replication in both cell types by interfering with viral gene expression. Furthermore, our ndings suggest that blockade of the viral replication cycle was mediated by CPC interference with the translocation of NF-κB into the nucleus of HSV-infected cells at early times post-infection (3 hours post-infection). Consistently, we observed that the antiviral e ect of CPC was time-dependent after infection, likely related to the transcription of immediate early viral genes. Interestingly, we found that the antiviral activity of CPC can be overridden by cytokines that activate NF-κB signaling, such as IL-1b and TNF-a. Taken together, our ndings suggest that formulations containing CPC may inadvertently contribute at limiting HSV replication and reduce viral shedding with potential therapeutic properties.