Cold sores — those annoying blisters that occasionally appear around the mouth, causing tingling, pain and loss of touch sensation — are caused by the herpes simplex virus-1 (HSV-1). We know that this neurotropic virus infects sensory neurons and reduces their excitability, but the molecular mechanism of its action remains poorly understood. Reporting in The Journal of Cell Biology, Storey et al. show that HSV-1 infection reduces the membrane expression of sodium channels in primary sensory neurons, uncovering a new way in which neuronal excitability can be regulated.

Using voltage-clamp techniques, the authors found that the amplitude of sodium currents in dorsal root ganglion cells was markedly reduced 24 hours after HSV-1 infection. By staining infected neurons with an antibody against the sodium channels, they obtained evidence for a decrease in the amount of channel protein in the plasma membrane. Furthermore, blocking membrane internalization, which does not affect viral entry, prevented the reduction of sodium currents.

How does the virus exerts its effect? As a first step to address this issue, Storey et al. set out to determine the relevance of the different stages of viral infection to the change in current amplitude. They found that blocking viral envelopment did not stop the loss of sodium currents in the infected neurons. By contrast, blocking the synthesis of viral DNA — a manipulation that eliminates the expression of 'late' but not 'early' viral proteins — prevented the decrease in current amplitude. The authors further established that the late viral protein ICP34.5 is crucial for the effect of HSV-1 on sodium currents, as infection with viruses that lack such a protein did not result in sodium channel loss.

In addition to identifying a mechanism to account for the decrease in neuronal excitability that accompanies HSV-1 infections, the data of Storey et al. point to a new way to regulate the availability of sodium channels at the plasma membrane. What intracellular pathways does this process engage? Do neurons use this mechanism under physiological conditions? HSV-1 and, in particular, ICP34.5 will be useful tools to answer these questions.