Meganucleases: novel anti-viral approach and therapeutic strategies

The majority of current anti-viral treatments are based on the prevention of productive viral replication through the utilization of agents that inhibit essential virally encoded proteins. In the majority of cases these treatments eventually become ineffective due to the generation of viral mutations that result in drug-resistance. Many chronic viral infections are due to double-stranded DNA viruses or viruses that involve a double-stranded DNA intermediate during their replicative cyde. Thus, an attractive alternative antiviral strategy is to specifically deave and either partially excise or eliminate viral DNA from infected cells and thus render them virus free.-Meganudeases are endonucleases that recognize large deavage sites (>12bp) with a high specificity. We have shown that the expression of the meganuclease I-SceI, either before or after infection with a modified Herpes Simplex Virus (HSV) containing a meganuclease recognition site, results in a dramatic reduction of viral DNA. Meganucleases specific for viral DNA could thus represent a novel class of agents for the treatment of viral infections that could cleave and either partially excise or eliminate viral DNA from infected cells, rendering them virus free. Using a semi-rational approach, we have used a two step strategy to produce meganucleases cleaving several different viral genomes. We will present data concerning the use of virus specific meganucleases for the development of a new anti-viral approach and therapeutic strategies for certain persistent infections, particularly those caused by HSV-1 in ocular herpes infections.