When ancient viruses embedded in the human genome awaken from their epigenetically enforced slumber, they may trigger multiple sclerosis (MS). But what triggers the awakening? One possibility, suggested by several recent studies, is that human endogenous retroviruses (HERVs) are activated by infectious phenomena. Another possibility is that HERVs become active when cellular stress causes inflammatory responses to become dysregulated.

This second possibility has just been proposed by scientists based at the Institut Pasteur. HERV‐driven enhancers, they reported, “constitute a reservoir of auxiliary enhancers transiently induced by stress while chronically active in diseases like MS.”

The Institute Pasteur researchers observed that HERV‐driven enhancers are mostly active in embryonic cells but silenced in mature adult tissues. They also noticed that the counter-selection is ordinarily strongest in brain tissues.

Ancient viral sequences were neutralized during evolution. They no longer represent a source of infection. But these sequences are a source of external DNA containing information about virus behavior. Cells have been able to control these sequences to detect infections as quickly as possible and turn on their defense genes during an attack.

The ancient viral sequences known as HERV‐driven enhancers are, above all, used to control defense genes in stem cells. They lie dormant in adult cells, and it is the more traditional sequences that become active. By examining samples from patients with MS, the scientists observed that regulatory sequences of viral origin emerged from their dormant state and were responsible for abnormal expression of several proinflammatory genes.

“Our study shows that reactivation of ancient viruses does not correspond to an infectious phenomenon, but to a defense response of the body when faced with an acute inflammatory phenomenon,” explained Christian Muchardt, head of the Institut Pasteur’s epigenetic regulation unit.

Detailed findings appeared May 8 in the EMBO Journal, in an article titled, “Expression of endogenous retroviruses reflects increased usage of atypical enhancers in T cells.” This article argues that extensive stress can cause transient reactivation of HERV transcription. Also, it indicates that in multiple sclerosis, some HERV‐driven regulatory regions become chronically active.

“By exposing T cells to the pesticide dieldrin, we found that a series of HERV‐driven enhancers otherwise active only at stem cell stages can be reactivated by stress,” the article’s authors wrote. “This in part relies on peptidylarginine deiminase activity, possibly participating in the reawakening of silenced enhancers. Likewise, usage of HERV‐driven enhancers was increased in myelin‐reactive T cells from patients with MS, correlating with activation of nearby genes at several sites.”

Essentially, in multiple sclerosis, activation of viral sequences does not correspond to an infectious phenomenon but to the unexpected use of regulatory sequences, leading to chronic excessive inflammation.

“The discovery of this mechanism, linked to epigenetic phenomena, may one day pave the way for management of MS using small molecules that inhibit chromatin modification enzymes,” noted Muchardt.

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