Why does the herpes virus reactivate

A study published in the journal Nature details the mechanism used by the herpes virus to reawaken. Discovery could also be important for long-term Covid research.

Chickenpox is a clear example: the cause of the itchy skin blisters is varicella-zoster, one of nine known herpes viruses that can infect and make people sick. It is widespread throughout the world and is best known as a childhood disease. Most of the time, children react well to the infection, and as a reminder some scars are left, because it’s hard to resist the itch. The virus also does not disappear, which remains latent in the body.

The varicella-zoster variant of the herpes virus lodges in the nerve ganglia. It can reactivate years or decades later and come back in the form of shingles.

In addition to the varicella-zoster virus, the herpes virus family also includes herpes simplex viruses types 1 and 2. They are known worldwide to be responsible for painful cold sores and genital herpes. Cytomegalovirus (CMV), also from the same family, is widespread in the world and can lead to serious complications and organ damage, especially in immunosuppressed people.

The Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus can cause tumors. Human herpesviruses 6 (often divided into A and B) and 7 are also disseminated and trigger, for example, the childhood disease roseola, known as exanthema subitum.

“The most important thing about herpesviruses is that they remain dormant in the body for life after the primary infection,” explains Lars Dölken, a virologist at the University of Würzburg, Germany.

Together with research colleagues, he wanted to understand the mechanism behind the sudden awakening of pathogens. To do this, he closely examined human herpesvirus 6A (HHV-6A). The research team published the results of the study in the journal Nature. They discovered a previously unknown cellular mechanism that the virus uses to awaken from the dormant state.

From latent to active

People who catch a herpesvirus for the first time often don’t even realize it. The problem is the repeated reactivation of the virus. For this, it often takes advantage of a phase when the host’s immune system is already fighting on other fronts. This can be a cold, as well as strong physical and psychological stress. People with HIV or transplant patients are particularly susceptible.

HHV-6A installs itself in the genome of the human cell and survives there in the latency phase until a good opportunity presents itself for it to attack again and thus multiply. For this, a particular microRNA (or microRNA, in Portuguese) enters the scene and reactivates the virus.

“Almost all herpesviruses generate their own microRNAs, which are extremely important for viruses,” says virologist Dölken. “[No caso do HHV-6A, verificamos que] If we turn off this viral microRNA, then the virus is — to put it a little imprecisely — dead.”

And there are indications that the reactivation of other herpes viruses is triggered by the same mechanism.

A viral microRNA as a master regulator

MicroRNA, unlike messenger RNA (mRNA), for example, is not responsible for carrying coding information for specific proteins. Instead, viral microRNA intervenes in the metabolism of certain human microRNAs and inhibits their development.

As a result, the production of so-called type 1 interferons is disturbed. These are messenger substances with which the cell signals the presence of a virus to the immune system.

“But this is certainly not the only mechanism that is disturbed,” says Dölken. With his research, he says that only the surface of the topic has been touched.

Viral microRNA makes it possible for herpesviruses to escape the immune system, or, more precisely, B and T lymphocytes, which eliminate infected human cells. “These cells recognize proteins that are foreign to the body — for example, those of a virus.”

“However, herpesviruses manage, with the help of Ribonucleic Acid (RNA or RNA), to reprogram host cells and use them in their favor without our immune system, that is, B and T lymphocytes, having the chance to recognize the cell as infected”, explains Dölken.

From Covid-19 to herpes to long Covid?

The discovery of the crucial viral microRNA, the “master regulator” as Dölken calls it, not only made it possible for researchers to prevent herpesvirus reactivation in cell culture experiments.

Further discoveries and research could also help reactivate dormant cells in the body, which would then be recognized and rendered harmless by the immune system.

“Before transplanting an organ, it would be nice to be able to turn off dormant cells infected by the herpesvirus,” says Dölken.

With their research, virologists could also contribute to solving another problem: the long Covid. Because herpesviruses often attack an already weakened immune system, scientists also suspect that they are involved in the various patterns of long-term Covid.

“An obvious assumption is that herpesviruses are reactivated due to coronavirus infection, resulting in secondary damage,” says Dölken.

There are still more questions than answers about the long Covid, but at least there are already some prime suspects. The HHV-6 is one of them.