Viral protein blocks myelin repair, activates inflammation in models

The expression of a viral protein known as W-Env leads to the inflammatory activation of brain cells and impairs myelin repair in mouse models of multiple sclerosis (MS), a study reports.

“Our study shows that the presence of W-Env in the brains of MS patients appears to generate a toxic environment,” Joel Gruchot, a PhD student at Heinrich-Heine-University Düsseldorf in Germany and co-author of the study, said in a press release. “It cannot be determined from this data whether this actually initiates the MS disease process, because the model we used is not suitable for this. However, it has now been clearly demonstrated for the first time that the W-Env increases the decay processes and disrupts the sensitive regeneration processes.”

The study, “Transgenic expression of the HERV-W envelope protein leads to polarized glial cell populations and a neurodegenerative environment,” was published in PNAS.

The work was a collaboration between scientists at academic institutions and GeNeuro, which is developing the experimental therapy temelimab to target W-Env. Early data from clinical trials indicate it may lower nerve damage and neurodegeneration.

The new findings provide an important theoretical basis for understanding why temelimab may be effective in MS, according to Gruchot.

“After GeNeuro’s two clinical studies with its W-Env neutralizing antibody called temelimab, we can now explain why neurodegeneration successfully decreased in MS patients treated with temelimab: the antibody appears to neutralize the “toxic” W-Env protein and thus prevents its activity in the [brain and spinal cord] as well as the neurotoxic activation of” supportive brain cells, Gruchot said.

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What is W-Env and its role in MS?

Endogenous retroviruses are chunks of the human genetic code that contain genes from viruses, which merged into the human genome during prehistoric infections. W-Env is made by one of these ancient viral genes, derived from a particular virus called human endogenous retrovirus (pHERV-W).

Normally, endogenous retrovirus genes aren’t active in people, but emerging data has indicated they may become activated in disease contexts such as MS.

In this study, the scientists wanted to better understand the biological consequences of W-Env production in MS and used a mouse model engineered to express it at levels similar to what’s been documented in human tissue.

MS is caused by inflammation in the brain that damages myelin, a fatty substance that wraps around nerve fibers to help them send electric signals. The researchers first examined the consequences of W-Env expression when mice were treated with cuprizone, a chemical that damages myelin.

They found cuprizone-related myelin damage (demyelination) was accelerated in mice producing W-Env. The repair of damaged myelin also was impaired when the viral protein was expressed.

Mice with W-Env also had less growth and maturation of oligodendrocytes, the specialized cells responsible for making myelin. Oligodendrocyte growth was only impaired in mice treated with myelin-damaging cuprizone. In healthy mice, W-Env didn’t have notable effects on oligodendrocyte activity.

The presence of W-Env also led to more inflammatory activation of astrocytes and microglia, or brain cells thought to contribute to the excess inflammation that drives MS. Like the changes in oligodendrocyte biology, these changes were generally only seen with myelin damage, not in healthy mice.

Inflammation and W-Env

In a final set of experiments, the researchers tested the effects of W-Env expression in mice with experimental autoimmune encephalitis (EAE), a mouse disease used to model MS that’s generated by vaccinating the animals to induce an anti-myelin inflammatory response.

Mice producing W-Env had a more severe course of EAE, with larger brain lesions, less growth of myelin-making oligodendrocytes, and more inflammatory activation of microglia and astrocytes, results showed.

The data offer evidence that W-Env has biological activities that could worsen or drive MS, which lends support to the idea that blocking it could be a useful treatment strategy.

“The further development of suitable neutralization strategies such as by preclinical and clinical examinations of the temelimab antibody or of unrelated pharmacological approaches is highly warranted,” wrote the researchers, who acknowledged that a limitation of these models is that the mice used were engineered to produce W-Env throughout their entire lives, making it impossible to conclude about the precise effects of W-Env expression with relation to the timing of MS.