Scientists from the University of Dusseldorf discuss in Frontiers in Genetics (“Neural Cell Responses Upon Exposure to Human Endogenous Retroviruses”) and suggest how retroviruses wound up in our genome and how these microorganisms might be linked to unsolved neurological diseases like multiple sclerosis (MS).

Retroviruses are old and they began merging with our earliest, primordial ancestors. Over the millennia, most human endogenous retroviruses (HERVs) have been silenced by mutations. Others, which had evolved to fend off rival viruses, formed the prototypical immune system and continue to protect humans from infection.

However, HERVs might also be the missing causative link in major neurological disorders.

“…HERVs are ancient retroviral elements, which invaded the human germline several million years ago. Subsequent retrotransposition events amplified these sequences, resulting in approximately 8% of the human genome being composed of HERV sequences today. These genetic elements, normally dormant within human genomes, can be (re)-activated by environmental factors such as infections with other viruses, leading to the expression of viral proteins and, in some instances, even to viral particle production. Several studies have shown that the expression of these retroviral elements correlates with the onset and progression of neurological diseases such as multiple sclerosis and amyotrophic lateral sclerosis (ALS). Further studies provided evidence on additional roles for HERVs in schizophrenia (SCZ),” the investigators wrote.

“Since these diseases are still not well understood, HERVs might constitute a new category of pathogenic components that could significantly change our understanding of these pathologies. Moreover, knowledge about their mode of action might also help to develop novel and more powerful approaches for the treatment of these complex diseases. Therefore, the main scope of this review is a description of the current knowledge on the involvement of HERV-W and HERV-K in neurological disease specifically focusing on the effects they exert on neural cells of the central nervous system.”

According to senior author Patrick Kuery, PhD, “Dormant HERVs can be reactivated by environmental factors such as inflammation, mutations, drugs, or infection with other viruses, so could provide a mechanism for their well-established epidemiological link to these disorders.”

So far, the strongest evidence links HERVs to MS.

“MS is caused by direct autoimmune attacks on myelin in the brain and spinal cord,” explained Kuery. “But we don’t yet understand how these attacks are triggered.”

A variety of studies suggest that reactivation of HERV could be just such a trigger. Retroviruses were first associated with MS in 1989, but only decades later was it realized that these are in fact HERVs, noted Kuery.

“Subsequently, it was shown that levels of HERV RNA and protein—the ‘readouts’ from reactivated HERV DNA—are increased in the brain and spinal cord fluid [CSF] of sufferers, as well as in their brain tissue postmortem,” he continued. “Linking this HERV reactivation to autoimmune attacks in MS, it was found that HERV proteins can trigger an immune response against myelin, which triggers MS-like disease in mouse models.”

Mechanistically, HERV proteins could trigger autoimmunity through “molecular mimicry.” In addition to direct effects of HERV on myelinating cells, several groups report structural similarities between HERV and myelin oligodendrocyte glycoprotein, a molecule displayed on the surface of myelin, said Kuery, who adds that “this similarity could fool the immune system into damaging myelin, when it mounts an attack on HERVs.”

Similar experiments have linked HERVs to chronic inflammatory demyelinating polyneuropathy (CIDP), as well as more distinct disease processes like progressive loss of motor neurons in ALS (Lou Gehrig’s disease).

In schizophrenia, a complex neurodevelopmental disorder, the link to HERVs is more circumstantial.

“HERV proteins have been reported to increase expression of schizophrenia-linked genes in cultured human brain cells,” reported Kuery. “However, studies on schizophrenia sufferers show inconsistent changes in HERV expression in blood, CSF, and postmortem brain tissue compared to healthy controls.”

Whether or not HERVs contribute to these and other unexplained neurological conditions requires further investigation. An important step will be to test the effects of HERV-neutralizing antibodies in humans.

“Of note, in relapsing MS patients a Phase IIb clinical trial using HERV protein-neutralizing antibody Temelimab has been conducted. We’re now waiting to see if the treatment showed beneficial effects on remyelination or attenuated neurodegeneration,” said Kuery.

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