Antiviral effects of HSV1‐specific meganucleases in a mouse model of relapsing herpes keratitis

Abstract

AbstractPurpose Conventional treatments of infections by Herpes simplex virus type 1 (HSV1) do not reduce the burden of latent virus and the resulting risk of viral reactivation. Specific endonucleases (such as meganucleases) could be a tool to reduce relapsing herpetic keratitis in pre‐treated tissues.Methods Three weeks after subconjunctival inoculation of rAAV (recombinant adenovirus‐associated vector) encoding either a meganuclease targeting the HSV1 genome or the Green Fluorescent Protein (GFP) as a negative control, mice were infected with HSV1 strain SC16 to induce a latent infection in the trigeminal ganglia (TGs). 28 days later, mice were subjected to a reactivation stimulus (heatshock). Corneas and TGs were analyzed for the presence of HSV‐1 genome and of several viral transcripts (LAT, TK and UL18).Results In the corneas, as in TG, meganuclease‐treated mice had fewer copies of viral genomes (viral load) and LAT, TK and UL18 transcripts (signs of viral replication) than control mice, ie treated with rAAV encoding GFP (p = 0.002 to p = 0.0008), suggesting a significant reduction of viral replication after herpes reactivation stimulus.Conclusion The production of a specific HSV1 meganuclease seems to reduce the importance of HSV1 reactivation in TGs (the site of herpetic latency) and corneas, suggesting that specific HSV1 meganuclease could be tested in therapeutic protocols with the aim of reducing herpetic corneal relapses.