Host Interferon: a Silent Partner in the Regulation of Herpes Simplex Virus Latency

Herpes simplex virus (HSV) establishes latent infections as a consequence of a non-cytolytic immune response that represses HSV replication, but fails to destroy neurons that harbour HSV’s genetic material. It has become increasingly evident that, in both mice and men, the host interferon system plays a critical role in tipping HSV’s latency-replication balance in favour of latency. HSV can resist interferon-induced repression provided that HSV’s two interferon antagonists, ICP0 and ICP34.5, are synthesized. Failure to synthesize either protein renders HSV interferon-sensitive and prone to establishing latent infections. Intriguingly, ICP0 and ICP34.5 are encoded within HSV’s latency-regulating RL regions. We propose that differential synthesis of ICP0 and ICP34.5 may endow HSV with the capacity to ‘choose’ between latency and replication in vivo. HSV may choose to establish a latent infection by downregulating ICP0 or ICP34.5, and render itself sensitive to the interferoninduced antiviral state. Conversely, synthesis of ICP0 and ICP34.5 may ensure that HSV resists interferon-induced repression and completes another cycle of replication.