The human endogenous retrovirus type W (HERV-W) has been identified and repeatedly confirmed as human-specific pathogenic entity affecting many cell types in multiple sclerosis (MS). Our recent contributions revealed the encoded envelope (ENV) protein to disturb myelin repair by interfering with oligodendroglial precursor differentiation and by polarizing microglial cells toward an axon-damage phenotype. Indirect proof of ENV's antiregenerative and degenerative activities has been gathered recently in clinical trials using a neutralizing anti-ENV therapeutic antibody. Yet direct proof of its mode of action can only be presented here based on transgenic ENV expression in mice. Upon demyelination, we observed myelin repair deficits, neurotoxic microglia and astroglia, and increased axon degeneration. Experimental autoimmune encephalomyelitis activity progressed faster in mutant mice equally accompanied by activated glial cells. This study therefore provides direct evidence on HERV-W ENV's contribution to the overall negative impact of this activated viral entity in MS.

Brain and Mind Center University of Sydney NSW 2050 Sydney Australia

Department of Neurology Medical Faculty Heinrich Heine University Düsseldorf 40225 Düsseldorf Germany

Department of Neurology Palacky University Olomouc 77146 Olomouc Czech Republic

Department of Neurology University of Bern CH 3010 Bern Switzerland

GeNeuro Innovation 69008 Lyon France

Institute of Veterinary Pharmacology and Toxicology University of Zürich Vetsuisse CH 8057 Zürich Switzerland

Neuroscience Center Zurich University of Zürich and ETH Zürich CH 8057 Zürich Switzerland

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