Abstract
The ability to establish, and reactivate from, latent infections is central to the biology and pathogenesis of HSV-1. It also poses a strong challenge to antiviral therapy, as latent HSV-1 genomes do not replicate or express any protein to be targeted. Although the processes regulating the establishment and maintenance of, and reactivation from, latency are not fully elucidated, the current general consensus is that epigenetics play a major role. A unifying model postulates that whereas HSV-1 avoids or counteracts chromatin silencing in lytic infections, it becomes silenced during latency, silencing which is somewhat disrupted during reactivation. Many years of work by different groups using a variety of approaches have also shown that the lytic HSV-1 chromatin is distinct and has unique biophysical properties not shared with most cellular chromatin. Nonetheless, the lytic and latent viral chromatins are typically enriched in post translational modifications or histone variants characteristic of active or repressed transcription, respectively. Moreover, a variety of small molecule epigenetic modulators inhibit viral replication and reactivation from latency. Despite these successes in culture and animal models, it is not obvious how epigenetic modulation would be used in antiviral therapy if the same epigenetic mechanisms governed viral and cellular gene expression. Recent work has highlighted several important differences between the viral and cellular chromatins, which appear to be of consequence to their respective epigenetic regulations. In this review, we will discuss the distinctiveness of the viral chromatin, and explore whether it is regulated by mechanisms unique enough to be exploited in antiviral therapy.