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Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):15216-15225. doi: 10.1073/pnas.1901283116. Epub 2019 Jun 18.

pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis.

Author information

Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
Montreal Neurological Institute & Hospital, McGill University, Montreal, QC H4A 3K9, Canada.
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
GeNeuro, CH-1228 Geneva, Switzerland.
Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany;


Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.


axonal degeneration; demyelination; endogenous retrovirus; multiple sclerosis; myeloid cells

[Available on 2019-12-18]

Conflict of interest statement

Conflict of interest statement: J.G., V.W., L.O., L.H., J.H.J., Y.K.T.X., C.V., and R.D. have no competing interests. D.K. received compensation for speaking from Grifols SA. B.D.T. received consultant and speaking fees from Biogen, Genentech, and Sanofi Genzyme. He receives advisory board fees from Disarm Therapeutics and Sanofi Genzyme. He is founder, chair of the Scientific Advisory Board, and chief scientific officer of Renovo Neural. P.G. and P.K. performed consultancy work for GeNeuro. P.K. received compensation for speaking from Sanofi Genzyme. H.P. receives compensation for his work by GeNeuro and is inventor on patents owned by BioMérieux, INSERM, or GeNeuro, but has transferred all his rights to BioMérieux or to GeNeuro under applicable laws for employed inventors. H.-P.H. received compensation for consulting, speaking, and serving on steering committees from Bayer Healthcare, Biogen, GeNeuro, MedImmune, Merck, Novartis, Opexa, Receptos Celgene, Roche, Sanofi Genzyme, and Teva with approval by the rector of Heinrich Heine University.

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