Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
Institute of Veterinary Pharmacology and Toxicology, University of Zürich-Vetsuisse, CH-8057 Zürich, Switzerland.
Proc Natl Acad Sci U S A. 2023 Sep 19;120(38):e2308187120. doi: 10.1073/pnas.2308187120. Epub 2023 Sep 11.
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.
人类内源性逆转录病毒 W 型（HERV-W）已被确定，并被反复证实为影响多发性硬化症（MS）中多种细胞类型的人类特异性致病实体。我们最近的研究结果表明，编码的包膜（ENV）蛋白通过干扰少突胶质前体细胞分化和使小胶质细胞向轴突损伤表型极化，干扰髓鞘修复。最近在使用中和抗 ENV 治疗性抗体的临床试验中收集了间接证据，证明了 ENV 的抗再生和退行性活性。然而，只有基于在小鼠中表达转基因 ENV，才能在此处提供其作用模式的直接证据。脱髓鞘后，我们观察到髓鞘修复缺陷、神经毒性小胶质细胞和星形胶质细胞以及轴突退化增加。突变小鼠的实验性自身免疫性脑脊髓炎活性进展更快，同时伴有激活的神经胶质细胞。因此，这项研究提供了直接证据，证明 HERV-W ENV 有助于该激活病毒实体在 MS 中的总体负面影响。
