How the herpes virus reactivates under stress

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Cold sores caused by the herpes virus resurface under stress; now, scientists have discovered the cellular mechanism that allows this to happen, according to research published in Cell Host and Microbe.

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Stress can reactivate the herpes simplex virus.

About 90% of the US population have the herpes simplex virus (HSV), which leads to cold sores, recurrent eye infections, genital lesions, and in rare cases encephalitis, an inflammation of the brain with a 30% mortality rate – or 70-80% if left untreated.

The closely related varicella zoster virus also causes chicken pox and shingles.

Previous studies have connected a protein called JNK to stress. The team already knew that HSV lays dormant in neurons and that stress triggers viral reactivation. Corticosteroid, a natural stress hormone, has been shown to activate the JNK pathway and trigger neuron death.

New research was carried out by a team at the University of North Carolina (UNC) School of Medicine, where senior author Mohanish Deshmukh specializes in neuron survival and death.

The team started by forcing the virus to become latent in mouse primary neurons and then to become reactivated. This enabled them to study specific cellular protein pathways potentially involved in viral reactivation.

Blocking the JNK pathway prevents reactivation

To find out if the virus could sense when the neurons are under stress and activate an escape pathway, they focused on the protein JNK. To a dish of mouse neurons, first author and virologist Anna Cliffe added chemicals that mimic the loss of nerve growth factor; neurons need this factor to remain healthy.

Fast facts about HSV

  • There are two types of HSV, and both are highly infectious
  • HSV-1 is mainly transmitted by oral-to-oral contact, causing “cold sores” and sometimes genital herpes
  • HSV-2 is a sexually transmitted disease that can cause genital herpes.

Learn more about herpes

She also used a corticosteroid to mimic what happens in the body, as stress causes high levels of corticosteroids to be released.

Results showed that the JNK protein pathway was activated just before the virus began to leave neurons. When the JNK pathway was blocked, the virus could no longer reactivate.

The team also found that the virus can be reactivated even when the viral DNA in neurons is repressed.

Researchers found that the histones associated with viral DNA did not undergo the process of demethylation that allows tightly packaged DNA, known as chromatin, to become more open so that gene expression – including HSV gene expression – can occur; this is how the virus becomes reactivated.

This is surprising, because normally, the methyl marks – or epigenetic modifications – need to be removed before DNA can be opened; in this case, gene expression occurred even when the methyl marks were still there.

The experiments show that the virus is able to modify its chromatin through phosphorylation of the histone next to the methyl mark; the methyl marks act as a methyl/phospho switch or, as Deshmukh says, “brakes to refuse gene expression.”

He explains that “phosphorylation releases the brakes just enough so that a little bit of viral gene expression can occur,” and phosphorylation also depends on the activation of the JNK pathway.

The experiments link the stress-activated pathway to the very earliest changes in the viral DNA.

Once the initial brakes are eased, full viral gene expression requires removal of the repressive histone methylation in order for the virus to complete the reactivation process. This, in turn, leads to full virus formation outside the neuron.

From there, disease states such as cold sores and encephalitis are born.

Deshmukh says:

“We’re excited about the possibility that this stress-activation pathway exists in humans. All of the elements of these pathways are found in human neurons. And we know that stress reactivates herpes simplex virus in humans.”

The researchers hope to replicate the results in human neurons. If they can confirm that the JNK pathway is crucial for viral reactivation in humans, this could lead to treatments for diseases linked to both HSV and other related viruses. In Cliffe’s view, the neurons identified represent “a good therapeutic target.”

Medical News Today has previously reported that interactions between different viruses could cause the reactivation of HSV.