The neutralizing antibody GNbAC1 abrogates HERV-W envelope protein-mediated oligodendroglial maturation blockade

2014 ◽  
Vol 21 (9) ◽  
pp. 1200-1203 ◽  
Author(s):  
David Kremer ◽  
Moritz Förster ◽  
Tanja Schichel ◽  
Peter Göttle ◽  
Hans-Peter Hartung ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Envelope Protein ◽  
Nitrosative Stress ◽  
Immune Cell ◽  
Neutralizing Antibody ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Stress Reactions ◽  
Induce Stress ◽  
Inflammatory Reactions

Background: The envelope protein (ENV) of the human endogenous retrovirus type W is implicated in inflammatory reactions in multiple sclerosis (MS) but also interferes with oligodendroglial maturation. A neutralizing antibody GNbAC1 has been developed and successfully been tested in clinical trials. Objectives and methods: We stimulated primary oligodendroglial cells with ENV upon preincubation with GNbAC1 and assessed for nitrosative stress and myelin expression. Results: Neutralization of ENV by GNbAC1 reduces its ability to induce stress reactions resulting in a rescue of myelin expression. Conclusions: Beyond immune cell modulation, this monoclonal antibody may therefore help to overcome the oligodendroglial differentiation blockade in MS.

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

2019 ◽  
Vol 116 (30) ◽  
pp. 15216-15225 ◽  
Author(s):  
David Kremer ◽  
Joel Gruchot ◽  
Vivien Weyers ◽  
Lisa Oldemeier ◽  
Peter Göttle ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Envelope Protein ◽  
Spatial Association ◽  
Myeloid Cells ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Myelinated Axons ◽  
Neuroprotective Effects ◽  
Microglial Polarization ◽  
Underlying Mechanisms

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.

scholarly journals Human Endogenous Retrovirus Type W Envelope from Multiple Sclerosis Demyelinating Lesions Shows Unique Solubility and Antigenic Characteristics

2021 ◽  
Author(s):  
Benjamin Charvet ◽  
Justine Pierquin ◽  
Joanna Brunel ◽  
Rianne Gorter ◽  
Christophe Quétard ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Envelope Protein ◽  
Endogenous Retrovirus ◽  
Brain Lesions ◽  
Human Endogenous Retrovirus ◽  
Soluble Antigen ◽  
Physico Chemical ◽  
Demyelinating Lesions ◽  
Ms Pathogenesis

AbstractIn multiple sclerosis (MS), human endogenous retrovirus W family (HERV-W) envelope protein, pHERV-W ENV, limits remyelination and induces microglia-mediated neurodegeneration. To better understand its role, we examined the soluble pHERV-W antigen from MS brain lesions detected by specific antibodies. Physico-chemical and antigenic characteristics confirmed differences between pHERV-W ENV and syncytin-1. pHERV-W ENV monomers and trimers remained associated with membranes, while hexamers self-assembled from monomers into a soluble macrostructure involving sulfatides in MS brain. Extracellular hexamers are stabilized by internal hydrophobic bonds and external hydrophilic moieties. HERV-W studies in MS also suggest that this diffusible antigen may correspond to a previously described high-molecular-weight neurotoxic factor secreted by MS B-cells and thus represents a major agonist in MS pathogenesis. Adapted methods are now needed to identify encoding HERV provirus(es) in affected cells DNA. The properties and origin of MS brain pHERV-W ENV soluble antigen will allow a better understanding of the role of HERVs in MS pathogenesis. The present results anyhow pave the way to an accurate detection of the different forms of pHERV-W ENV antigen with appropriate conditions that remained unseen until now.

CSIG-24. TARGETED INHIBITION OF CDK5-MEDIATED REGULATION OF HUMAN ENDOGENOUS RETROVIRUS K (HML-2) ENVELOPE PROTEIN IN ATYPICAL TERATOID RHABDOID TUMOR

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi38-vi38
Author(s):  
Tara Doucet-O'Hare ◽  
Jared Rosenblum ◽  
Brianna DiSanza ◽  
Catherine DeMarino ◽  
Abigail Atkinson ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Envelope Protein ◽  
Phosphorylation Site ◽  
Endogenous Retrovirus ◽  
Rhabdoid Tumor ◽  
Human Endogenous Retrovirus ◽  
Atypical Teratoid Rhabdoid Tumor ◽  
Atypical Teratoid ◽  
Targeted Inhibition

Abstract Atypical teratoid rhabdoid tumor (ATRT) is a pediatric brain tumor with a high mortality rate characterized by mutations in/ deletions of SWI/SNF matrix-associated actin-dependent regulator of chromatin sub-family B member 1 (SMARCB1). We previously showed that loss of SMARCB1 causes up-regulation and release of HML-2 subfamily of human endogenous retrovirus K envelope protein (HML-2 ENV), resulting in maintenance of pluripotency. Here, we investigated intracellular trafficking and release of HML-2 ENV. Further, we demonstrate two potential therapeutic strategies to decrease intracellular HML-2 ENV: 1) inhibition of calcium influx by ouabain, a cardiac glycoside toxic to neural stem cells, and 2) targeted inhibition of cyclin-dependent kinase 5 (CDK5), which is restricted to neurons by p35, its activator protein, by TP5. ATRT cell lines and tumor tissue obtained from patients were confirmed for SMARCB1 loss and increased HML-2 ENV. Cell viability and intracellular HML-2 ENV concentration were measured after treatment with ouabain and TP5 (CDK5 antagonist). We evaluated the calcium-mediated effect of ouabain on HML-2 intracellular concentration by treating the cells with ouabain, the calcium chelators calcimycin and EGTA, and calpeptin, a calpain inhibitor, which activates CDK5, and measuring HML-2 ENV and p35. We evaluated HML-2 ENV for a CDK5 consensus phosphorylation site and performed co-immunoprecipitation to evaluate direct interaction. We evaluated activity of CDK5 in ATRT cell lines by autoradiography. Both Ouabain and TP5 caused a decrease in cell viability in a dose-dependent manner. Further, ouabain treatment decreased HML-2 ENV intracellular concentration. We found that HML-2 ENV contains a consensus phosphorylation site for CDK5. We discovered that HML-2 ENV was bound to CDK5. We established that ATRT cell lines had hyperactive CDK5. Finally, we established that the effect of ouabain on HML-2 ENV was due to indirect inhibition of calcium-mediated activation of calpain and thus CDK5.

scholarly journals The HERV-K Human Endogenous Retrovirus Envelope Protein Antagonizes Tetherin Antiviral Activity

2014 ◽  
Vol 88 (23) ◽  
pp. 13626-13637 ◽  
Author(s):  
C. Lemaitre ◽  
F. Harper ◽  
G. Pierron ◽  
T. Heidmann ◽  
M. Dewannieux
Keyword(s):  
Antiviral Activity ◽  
Envelope Protein ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus

scholarly journals Human endogenous retrovirus W in brain lesions: Rationale for targeted therapy in multiple sclerosis

2016 ◽  
Vol 8 ◽  
pp. 11-18 ◽  
Author(s):  
Jack van Horssen ◽  
Susanne van der Pol ◽  
Philip Nijland ◽  
Sandra Amor ◽  
Hervé Perron
Keyword(s):  
Multiple Sclerosis ◽  
Targeted Therapy ◽  
Endogenous Retrovirus ◽  
Brain Lesions ◽  
Human Endogenous Retrovirus

scholarly journals An N-terminally truncated envelope protein encoded by a human endogenous retrovirus W locus on chromosome Xq22.3

Retrovirology ◽  
2010 ◽  
Vol 7 (1) ◽  
pp. 69 ◽  
Author(s):  
Christina Roebke ◽  
Silke Wahl ◽  
Georg Laufer ◽  
Christine Stadelmann ◽  
Marlies Sauter ◽  
...  
Keyword(s):  
Envelope Protein ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus
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