Retroviruses have genomes that are made of RNA, and when they enter host cells, that RNA is transcribed into DNA. That viral DNA then moves to the host nucleus, and there, it's inserted into the host genome. Millions of years ago, retroviruses interacted with our primordial ancestors and left bits of their DNA behind. That DNA is still carried in our genome; it’s thought that eight percent of the human genome comes from viruses. Researchers are now investigating whether that viral RNA is involved in the development of diseases with unclear causes, like multiple sclerosis.
The viral DNA in our genome is known as human endogenous retroviruses (HERVs), which mutations have disabled. Some evolved into early components of the immune system. In Frontiers in Generics, scientists at the University of Dusseldorf have suggested that HERVs are the unknown factor causing some neurological diseases.
"HERVs have been implicated in the onset and progression of multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and schizophrenia," said the senior author of the report Professor Patrick Kuery. "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."
It may be that HERVs act as a trigger when they are reactivated. Some work has already linked HERVs and MS.
"MS is caused by direct autoimmune attacks on myelin - the fatty coating of nerve cells - in the brain and spinal cord. But we don't yet understand how these attacks are triggered," explained Kuery. "Retroviruses were first associated with MS in 1989, but only decades later was it realized that these are in fact HERVs.
"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. 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."
The proteins made from potentially reactivated HERV DNA might cause autoimmune problems due to a kind of 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. This similarity could fool the immune system into damaging myelin when it mounts an attack on HERVs."
HERVs have also been associated with gradual neuronal loss in ALS, and the peripheral demyelinating disease CIDP. There could be some link between HERVs and schizophrenia as well.
"HERV proteins have been reported to increase expression of schizophrenia-linked genes in cultured human brain cells. However, studies on schizophrenia sufferers show inconsistent changes in HERV expression in blood, CSF and postmortem brain tissue compared to healthy controls," noted Kuery.
"Of note, in relapsing MS patients a phase 2b 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," Kuery concluded.
Sources: AAAS/Eurekalert! via Frontiers, Frontiers in Microbiology
