Herpes Simplex Virus Latency Is Noisier the Closer We Look

Abstract

During herpes simplex virus (HSV) latency, the viral genome is harbored in peripheral neurons in the absence of infectious virus but with the potential to restart infection. Advances in epigenetics have helped explain how viral gene expression is largely inhibited during latency. Paradoxically, at the same time, the view that latency is entirely silent has been eroding. This low-level noise has implications for our understanding of HSV latency and should not be ignored.

Keywords: HSV; herpes simplex virus; latency.

FIG 1

HSV latency is maintained by multiple levels of regulation, shown here as layers of an onion. Full reactivation and shedding at the skin occur when the virus overcomes all of the layers. LATs and miRNAs are drawn as prolatency factors, but there may be RNA species or situations where expression of these predispose toward viral activity. The loops between the arrows pointing up toward silence and down toward reactivation represent cycling between viral activity and repression. These are drawn to suggest some mechanisms that drive the cycles, e.g., leaky lytic expression may drive a neuron-intrinsic and/or an adaptive immune response in the peripheral nervous system (PNS) that leads to a tightening of repression and re-enforcement of latency. A less conventional view is that the shortest of these cycles represents a program of gene expression that is a characteristic of latency itself, rather than being an aborted step toward reactivation.