scholarly journals TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits

2021 ◽  
Vol 15 ◽  
Author(s):  
Peter Göttle ◽  
Kira Schichel ◽  
Laura Reiche ◽  
Luisa Werner ◽  
Annika Zink ◽  
...  
Keyword(s):  
Pharmacological Treatment ◽  
Nitrosative Stress ◽  
Surface Expression ◽  
Endogenous Retrovirus ◽  
Negative Regulator ◽  
Human Endogenous Retrovirus ◽  
Myelin Repair ◽  
Morphological Alterations ◽  
Neurodegenerative Process ◽  
Env Protein

Myelin repair in the adult central nervous system (CNS) is driven by successful differentiation of resident oligodendroglial precursor cells (OPCs) and thus constitutes a neurodegenerative process capable to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis (MS). The human endogenous retrovirus type W (HERV-W) represents an MS-specific pathogenic entity, and its envelope (ENV) protein was previously identified as a negative regulator of OPC maturation—hence, it is of relevance in the context of diminished myelin repair. We here focused on the activity of the ENV protein and investigated how it can be neutralized for improved remyelination. ENV-mediated activation of toll like receptor 4 (TLR4) increases inducible nitric oxide synthase (iNOS) expression, prompts nitrosative stress, and results in myelin-associated deficits, such as decreased levels of oligodendroglial maturation marker expression and morphological alterations. The intervention of TLR4 surface expression represents a potential means to rescue such ENV-dependent deficits. To this end, the rescue capacity of specific substances, either modulating V-ATPase activity or myeloid differentiation 2 (MD2)-mediated TLR4 glycosylation status, such as compound 20 (C20), L48H437, or folimycin, was analyzed, as these processes were demonstrated to be relevant for TLR4 surface expression. We found that pharmacological treatment can rescue the maturation arrest of oligodendroglial cells and their myelination capacity and can prevent iNOS induction in the presence of the ENV protein. In addition, downregulation of TLR4 surface expression was observed. Furthermore, mitochondrial integrity crucial for oligodendroglial cell differentiation was affected in the presence of ENV and ameliorated upon pharmacological treatment. Our study, therefore, provides novel insights into possible means to overcome myelination deficits associated with HERV-W ENV-mediated myelin deficits.

scholarly journals SARS-CoV-2 induces transcription of human endogenous retrovirus RNA followed by type W envelope protein expression in human lymphoid cells.

2021 ◽  
Author(s):  
Benjamin Charvet ◽  
Magalie Mazelier ◽  
Joanna Brunel ◽  
Justine Pierquin ◽  
Said Mougari ◽  
...  
Keyword(s):  
Protein Expression ◽  
Viral Infections ◽  
Endogenous Retrovirus ◽  
Lymphoid Cells ◽  
Human Endogenous Retrovirus ◽  
Peripheral Blood Mononuclear ◽  
Initial Exposure ◽  
Pbmc Culture ◽  
Healthy Donors ◽  
Env Protein

Abstract Patients with COVID-19 may develop abnormal inflammatory response and lymphopenia, followed in some cases by delayed-onset syndromes, often long-lasting after resolution of the initial SARS-CoV-2 infection. As viral infections may activate human endogenous retroviral elements (HERV), we studied the effect of SARS-CoV-2 on HERV-W and HERV-K envelope (ENV) expression, known to be involved in immunological and neurological pathogenesis of human diseases. We demonstrate here that an initial exposure to SARS-CoV-2 virus activates early HERV-W and K transcription in peripheral blood mononuclear cell (PBMC) cultures from healthy donors. Within a week of primary PBMC culture, only HERV-W ENV protein expression was detected in lymphoid cells of some donors, although SARS-CoV-2 infection of PBMC was not observed. HERV activation was reproduced with UV-inactivated virus and with a recombinant spike protein. Interestingly, exposure to SARS-CoV-2 protein induced a significant production of interleukin 6 in PBMC, independently from detectable HERV expression. Altogether, these results show that SARS-CoV-2 viral protein could induce HERV-W ENV expression in lymphocytes from some individuals, underlying the importance to further address the implicated molecular pathways, to understand patients‘ genetic susceptibility associated to the activation of HERV-W and its possible relevance for targeting therapeutic intervention in COVID-19 associated syndromes.

Autoantibodies against unmodified and citrullinated human endogenous retrovirus K envelope protein in rheumatoid arthritis patients

2021 ◽  
pp. jrheum.201492
Author(s):  
Xiaoxing Wang ◽  
Amanda Hefton ◽  
Kathryn Ni ◽  
Kennedy C. Ukadike ◽  
Michael A. Bowen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Healthy Adult ◽  
Endogenous Retrovirus ◽  
Arginine Deiminase ◽  
Human Endogenous Retrovirus ◽  
Published Data ◽  
Erosive Disease ◽  
Protein Arginine Deiminase ◽  
Env Protein ◽  
Neutrophil Cell

Objective Autoantibodies against proteins encoded by human endogenous retrovirus K (HERV-K) have been reported in patients with rheumatoid arthritis (RA), but their relevance, if any, has remained unresolved. We revisited this question and tested if such autoantibodies may react with citrullinated epitopes on the envelope (Env) protein of HERV-K. Methods Immunoblotting and ELISAs were conducted with unmodified Env protein and with Env citrullinated by protein arginine deiminase (PAD) 4. Sera from 100 RA patients, plasma from 32 juvenile idiopathic arthritis (JIA) patients, and healthy adult and pediatric controls were included. Antibody reactivity was evaluated for correlations with clinical and laboratory parameters of the patients. Results We replicated and expanded upon published data that patients with RA or JIA have autoantibodies against HERV-K Env, some with high titers. Anti-HERV-K antibodies correlated with cigarette smoking and with circulating DNA-myeloperoxidase complexes indicative of nonapoptotic neutrophil cell death. Furthermore, most of the RA patients, but not JIA patients, had autoantibodies that reacted more strongly with Env that was citrullinated by PAD4. These anticitrullinated Env autoantibodies correlated with seropositivity and tended to be higher in patients with erosive disease. Conclusion Our data suggest that anti-HERV-K immunity is elevated in RA and JIA and may have a connection with pathogenic protein citrullination in RA.

scholarly journals Detection of the human endogenous retrovirus ERV3-encoded Env-protein in human tissues using antibody-based proteomics

2013 ◽  
Vol 107 (1) ◽  
pp. 22-29 ◽  
Author(s):  
Chen Fei ◽  
Christina Atterby ◽  
Per-Henrik Edqvist ◽  
Fredrik Pontén ◽  
Wei Wei Zhang ◽  
...  
Keyword(s):  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Human Tissues ◽  
Env Protein

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 Phenotypic heterogeneity of human endogenous retrovirus particles produced by teratocarcinoma cell lines

2001 ◽  
Vol 82 (3) ◽  
pp. 591-596 ◽  
Author(s):  
Katrin Bieda ◽  
Andreas Hoffmann ◽  
Klaus Boller
Keyword(s):  
Human Genome ◽  
Cell Lines ◽  
Expression Patterns ◽  
Endogenous Retrovirus ◽  
Surface Proteins ◽  
Human Endogenous Retrovirus ◽  
Teratocarcinoma Cell ◽  
Gag Protein ◽  
Virus Particles ◽  
Env Protein

Human endogenous retrovirus (HERV) sequences represent about 0·5% of the human genome. The only HERV known to express virus particles is human teratocarcinoma-derived virus (HTDV), which is now termed HTDV/HERV-K. Between 25 and 50 different copies of HERV-K are present in the human genome, three of which contain full-length genes for viral structural proteins. To determine whether genes of different HERV-K proviruses can be expressed, the morphologies and protein expression patterns of HTDV/HERV-K produced by various human teratocarcinoma cell lines were compared. Three different types of retrovirus-like particles were observed, showing differences in the presence of viral surface proteins and the existence of free mature virions. These distinct morphological features between virion types were in accordance with the results of immunoblotting analyses that revealed differences in the cleavage of a viral Gag protein precursor and the presence of a putative Env protein. These data suggest that different HERV-K proviruses are transcribed in human teratocarcinoma cell lines.

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