Antibody-mediated rescue of endogenous retrovirus-induced damage in the demyelinated central nervous system

Abstract The human endogenous retrovirus type W (HERV-W) has been identified as a human-specific neuropathological factor that preferentially affects glial cell types in multiple sclerosis (MS). Recent work using transgenic mice with expression of the HERV-W envelope (ENV) protein unveiled that this endogenous retroviral element disrupts myelin repair and polarizes microglial and astroglial cells towards axon-damaging neurotoxic phenotypes. Moreover, initial clinical trials using Temelimab, a neutralizing antibody targeting the HERV-W ENV protein, have provided circumstantial evidence that ENV exerts anti-regenerative and neurodegenerative effects in MS patients. Aligning these observations, it was therefore concluded that HERV-W represents an important factor contributing to disease progression independent of relapse activity (PIRA). Building on these findings, we here applied a neutralizing anti-ENV antibody in a non-inflammatory demyelination mouse model to directly evaluate its potential to mitigate neurodegeneration and ameliorate remyelination. In transgenic mice with human-specific expression of the HERV-W ENV protein, repetitive intraperitoneal anti-ENV antibody injections resulted in accelerated oligodendroglial differentiation, enhanced remyelination, axonal protection, and reduced neurofilament light chain leakage in the serum. Neurotoxic microglial traits were also reduced, while homeostatic parameters were stabilized. As astroglial cells underwent a similar shift, inducing regenerative traits at the expense of toxic parameters, anti-ENV application overall generated a less hostile cellular environment. This study provides direct evidence of the capacity of HERV-W neutralizing antibodies to access the central nervous system and to ameliorate damage conferred by this viral entity previously associated with smouldering disease processes. Significance Statement Although neurodegeneration is a hallmark of multiple sclerosis (MS), its underlying mechanisms are poorly understood. Clinically, it manifests as smouldering MS or progression without relapse activity (PIRA). This is the primary factor leading to the accumulation of clinical disability and is currently untreatable. This study provides the first direct evidence that antibodies directed against the HERV-W ENV protein can attenuate the activity of neurodegeneration-promoting glial cells in vivo . Our data validates neutralization of this endogenous retroviral element as a promising therapeutic approach particularly relevant to the chronic form of MS.