The opportunities and challenges of epigenetic approaches to manage herpes simplex infections

Despite the existence of antivirals that potently and efficiently inhibit the replication of herpes simplex virus 1 and 2 (HSV-1, -2), their ability to establish and maintain, and reactivate from, latency has precluded the development of curative therapies. Several groups are exploring the opportunities of targeting epigenetic regulation to permanently silence latent HSV genomes or induce their simultaneous reactivation in the presence of antivirals to flush the latent reservoirs, as has been explored for HIV.

This review covers the basic principles of epigenetic regulation with an emphasis on those mechanisms relevant to the regulation of herpes simplex viruses, as well as the current knowledge on the regulation of lytic infections and the establishment and maintenance of, and reactivation from, latency, with an emphasis on epigenetic regulation. The differences with the epigenetic regulation of viral and cellular gene expression are highlighted as are the effects of known epigenetic regulators on herpes simplex viruses. The major limitations of current models to the development of novel antiviral strategies targeting latency are highlighted.

We provide an update on the epigenetic regulation during lytic and latent HSV-1 infection, highlighting the commonalities and differences with cellular gene expression and the potential of epigenetic drugs as antivirals, including the opportunities, challenges, and potential future directions.