Key questions on the epigenetics of herpes simplex virus latency

Abstract

The human pathogen, herpes simplex virus (HSV), has established a successful mechanism to persist long term in its host by maintaining a latent infection in neurons. Latent infection is defined as long-term carriage of the viral genome but lack of detectible infectious virus and the ability to reactivate following a specific stimulus. During latency, the HSV genome exists as a nuclear, unintegrated episome. Although multiple factors regulate entry into latent infection, the epigenetic structure of the latent HSV genome in neurons differs from the configuration of the viral genome during lytic infection of nonneuronal cells and therefore appears to play a central role in regulating viral gene transcription. Since the initial discoveries of chromatinization of the HSV genome during latency, multiple new developments have been made in how the viral genome could be epigenetically silenced in a way that promotes long-term persistence while maintaining the ability to reactivate. Here, we highlight recent developments and incorporate new questions that will ultimately help understand how HSV latency occurs in neurons and how the epigenetic structure of the viral genome may ultimately impact clinical HSV-associated disease.