A stress-activated cellular mechanism is likely involved in allowing herpes simplex virus to reactivate, according to findings published in the journal Cell Host and Microbe. 

This research was conducted using primary neurons from mice. But the researchers from the University of North Carolina School of Medicine said the cellular pathways involved are found in human neurons.

The researchers focused on a protein called JNK, which had been linked to stress. In a dish of mouse neurons, they added chemicals to mimic the loss of nerve growth factor, which neurons need to remain healthy. They also used a corticosteroid – a natural stress hormone – that previously had been shown to activate the JNK pathway and trigger neuron death.


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As they studied the cells, the researchers noted that the JNK protein pathway – which includes proteins called DLK and JIP3 – was activated just before the virus began to leave neurons. They then inhibited the JNK pathway and noted that the virus was no longer able to reactivate.

When the researchers took a closer look, they found that the herpes virus can be reactivated even though the viral DNA in neurons was still in a repressed state. That is, the histones associated with viral DNA did not undergo demethylation – a process that allows tightly packaged DNA to become more open so that gene expression can occur, including HSV gene expression, which was precisely what the virus needed in order to be reactivated.

If the JNK pathway is crucial for viral reactivation in humans, then it could be possible to develop treatments for the diseases that are linked to HSV, as well as its closely-related viruses, according to the study conclusions.

Reference

1. Cliffe AR, Arbuckle JH, Vogel JL, et al. Neuronal Stress Pathway Mediating a Histone Methyl/Phospho Switch Is Required for Herpes Simplex Virus ReactivationCell Host Microbe. 2015;649-658.