More about Pathogenic HERV-W Envelope protein (formerly referred to as MSRV Env)

For over 25 years, successive and independent studies have established an association between the presence of pHERV-W Env and MS pathogenesis.

The gene encoding the pHERV-W Env protein belongs to the HERV-W family of transposable genetic elements that are widely and heterogeneously dispersed in the human genome. HERVs account for up to 8% of the human genome. HERVs are believed to have originated from retroviral infections of germline cells, resulting in viable offspring carrying retrovirus DNA insertions (termed “proviruses”), which have been passed down to the genomes of modern humans from our primate ancestors. 

In the 1990’s a pathogenic member of the HERV-W family, initially referred to the multiple sclerosis associated retrovirus (MSRV), was discovered in cell cultures isolated from leptomeningeal cells taken from the cerebrospinal fluid (CSF) of patients affected with multiple sclerosis. HERVs are normally genetically and/or epigenetically repressed in healthy individuals. However, de-repression and transcription (i.e. ”transactivation”) of pHERV-W-encoded gene products, including the env protein, was demonstrated in these cells when exposed to proinflammatory cytokines and exogenous viral infections such as Epstein Barr Virus (EBV), as well as other viruses of the herpes family, which have been epidemiologically associated with MS. Over the next 2 decades, research has begun to clarify the pathophysiological mechanisms of pHERV-W in MS. Post-mortem, neuropathological studies demonstrated the presence of pHERV-W Env in active MS lesions and preferential expression of pHERV-W genomic transcripts were found in peripheral blood mononuclear cells (PBMCs) of patients with MS versus normal controls. In CSF, the presence of pHERV-W transcription products not only correlate with the diagnosis of MS but also with disease severity and the risk of progression. More recent work performed at the Center for Neurology and Neuropsychiatry, Heinrich-Heine-Universität in Düsseldorf, Germany has shown the mechanisms by which pHERV-W Env exerts its pathological effects: by activating microglia, causing them to assume a pro-inflammatory phenotype, seeking out myelinated axons to destroy and inhibiting them from scavenging myelin debris, an important mechanism of remyelination in MS lesions. In addition, it has been shown that the pHERV-W Env protein directly inhibits oligodendrocyte precurser cell maturation, thereby directly inhibiting remyelination, another important mechanism known to play a role in the pathogenesis of progressive multiple sclerosis. Importantly, all of these pathogenic effects have been shown to be ameliorated by temelimab in preclinical models.