BREAKING! SARS-CoV-2 Infection Induces Human Endogenous Retrovirus Type W Envelope Protein Expression In Blood Lymphocytes And Tissues!

HERV-W-COVD-19: A new international study involving researchers from various institutions in France, Spain, Germany, Mexico and Switzerland has alarmingly found that SARS-CoV-2 infection induces Human Endogenous Retrovirus Type W (HERV-W) Envelope (ENV) Protein Expression in blood lymphocytes and tissues and can trigger a variety of clinical conditions, some of which are associated with Long COVID!
 


In a simple language, we could say that the conditions arising COVID-19 disease could actually be due to two pathogens ie the SARS-CoV-2 coronavirus and the human endogenous retrovirus type W (HERV-W) envelope (ENV) protein which also acts as an antigen that triggers both the innate and adaptive immunity!
 
Human endogenous retroviruses (HERVs) are a family of viruses within our genome with similarities to present day exogenous retroviruses. HERVs have been inherited by successive generations and it is possible that some have conferred biological benefits.
 
Human Endogenous Retrovirus-W (HERV-W) is the coding for a protein that would normally be part of the envelope of one family of Human Endogenous Retro-Viruses, or HERVs.
 
Typically, patients with COVID-19 may develop abnormal inflammatory response and lymphopenia, followed in some cases by delayed-onset syndromes, often long-lasting after the initial SARS-CoV-2 infection.
 
As most viral infections may also activate human endogenous retroviral elements (HERV), the study team 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.
 
The study findings shockingly showed that the exposure to SARS-CoV-2 virus activates early HERV-W and K transcription but only HERV-W ENV protein expression, during an infection and in an ACE2-independent way within peripheral blood mononuclear cell cultures from one-third of healthy donors.
 
Furthermore, the study findings showed that HERV-W ENV protein was significantly increased in serum and plasma of COVID-19 patients, correlating with its expression in CD3+ lymphocytes and with disease severity.
 
Finally, the HERV-W-COVD-19 study also found that HERV-W ENV was found expressed in post-mortem tissues of lungs, heart, brain olfactory bulb and nasal mucosa from acute COVID-19 patients in cell-types relevant for COVID-19-associated pathogenesis within affected organs, but different from those expressing of SARS-CoV-2 antigens.
 
The study findings collectively revealed that SARS-CoV-2 can induce HERV-W ENV expression in cells from individuals with symptomatic and severe COVID-19.
 
The study findings suggest that HERV-W ENV is likely to be involved in pathogenic features underlying symptoms of acute and post-acute COVID. It highlights the importance to further understand patients’ genetic susceptibility to HERV-W activation and the relevance of this pathogenic element as a prognostic marker and a therapeutic target in COVID-19 associated syndromes.
 
The study finds were published on a preprint server and are currently being peer reviewed.
 
Past studies have shown that certain infectious agents have been shown to activate pathological processes via receptor-coupled signaling pathways, by impairing the epigenetic control and/or by directly activating endogenous retroviral elements (HERVs) present in the human genome.
 
In particular, the resulting production of endogenous proteins of retroviral origin with pathogenic effects may generate clinical symptoms corresponding to the organ, tissue or cells in which they are expressed, according to the specific tropism of the triggering infectious agent.
 
HERVs represent about 8% of human chromosomal sequences and comprise about 22 families independently acquired during evolution from exogenous retroviruses via an infection of germ line cells.
 
Abnormal expression may then become self-sustained, thus creating lifelong chronic expression from host‘s genome copies in affected tissues, e.g., with cytokine-mediated feedback loops  or, possibly, mediated by their own envelope proteins.
 
Such a sustained expression has been shown to be involved in brain lesions with lifelong expansion in patients with multiple sclerosis (MS). https://pubmed.ncbi.nlm.nih.gov/27456869/
 
https://www.pnas.org/content/116/30/15216
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080128
 
https://pubmed.ncbi.nlm.nih.gov/23836485/
 
Different HERV envelope proteins were shown to exert major immunopathogenic and/or neuropathogenic effects in vitro and in vivo, associated with pathognomonic features of human diseases.
 
The study team therefore studied whether SARS-CoV-2 could activate HERV copies considered as ‘dormant enemies within’.
 
The study team only focused on HERV families already shown to be involved in the pathogenesis of human diseases such as HERV-W and HERV-K, to evaluate their potential association with COVID-19 and associated syndromes.
 
This question became critical after a recent study has revealed the significant expression of HERV-W envelope protein (ENV) in lymphoid cells from COVID-19 patients, correlating with disease outcome and markers of lymphocyte exhaustion or senescence. https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00134-1/fulltext
 
The study team initially addressed the potential role of SARS-CoV-2 in directly triggering the activation of a pathogenic HERV protein expression as reported with other viruses in, e.g., MS and in type 1 diabetes.
 
They further analyzed its expression in white blood cells and its possible detection in plasma of patients with COVID-19 presenting various clinical forms at early and late time-points.
 
The study team finally examined this HERV expression in affected tissues from COVID-19 post-mortem samples. Also, since a major concern beyond the initial COVID-19 infectious phase is foreseen to result from the occurrence of long- lasting symptoms with more-or-less delayed onset and often involves neurological impairment, we examined SARS-CoV-2 and HERV-W expression in brain parenchyma.
 
For proper comparison with dominantly or frequently affected organs, the study team also examined these antigens expression in lung and cardiac tissues.
 
The study findings showed that :
 
-1) SARS-CoV-2 can activate the production of HERV-W ENV in cultured blood mononuclear cells from a sub-group of healthy donors.
 
-2) HERV-W ENV is expressed on T-lymphocytes from COVID-19 patients.
 
-3) HERV-W ENV antigen is detected in all tested plasma or sera samples from severe cases in intensive care unit, but only in about 20% of PCR positive cases after early diagnosis.
 
-4) the level of HERV-W ENV antigenemia increases with disease severity.
 
-5) HERV-W ENV expression is observed by immunohistochemistry in cell-types relevant for COVID-19 associated pathogenesis within affected organs and particularly in brain microglia.
 
To study HERV-W ENV expression beyond blood cells and plasma or serum, the study team analyzed slides from tissue samples obtained at autopsy from patients deceased from acute COVID-19. SARS-CoV-2 N antigen corroborating viral replication was readily detected in epithelial cells within lungs and nasal mucosa but not in studied sections from brain parenchyma, even in olfactory bulb sections neighboring nasal mucosa with noticeable ongoing infection.
 
The study findings present did not show any infection by SARS-CoV-2 of the central nervous system (CNS) nor of the cardiac tissues in the studied cases.
 
HERV-W ENV was strongly expressed in lymphoid infiltrates in tissues surrounding lung alveola and within nasal mucosa. It was clearly and frequently detected in blood vessels endothelium from all tissues including CNS, which revealed quite numerous within cardiac muscle and pericardiac fatty tissue.
 
 In the CNS, HERV-W ENV expression was found in scattered cells that were confirmed to be microglia. Finally, strong HERV-W ENV staining was often detected in aggregated cells corresponding to thrombotic structures in blood vessels from the lung sections. Globally, positive endothelial cells from blood vessels were seen in all studied tissues and all HERV-W ENV expressing cells did not correspond to phenotypes seen to be infected with SARS-CoV-2. This discrepancy is well illustrated by infected lung epithelial cells without HERV-W ENV expression and noninfected alveolar macrophages presenting strong HERV-W ENV membrane staining within the same lung section.
 
This is consistent with the study findings of HERV-W ENV protein presence on lymphocytes without infection by SARS-CoV-2 in COVID-19 patients and in PBMC, after in vitro activation with infectious SARS-CoV-2.
 
Most importantly, it shows HERV-W ENV expression in tissue-infiltrated lymphocytes and macrophages within affected organs, like in blood of COVID-19 patients.
 
Therefore, results from immunohistochemistry analyses indicate that HERV-W ENV expression is intimately associated with organs and cells involved in COVID-19 associated or superimposed pathology beyond tissue inflammation mediated by immune cells or cytokines, e.g., in vasculitis or intravascular thrombotic processes.
 
Moreover, given known HERV-W involvement in MS pathogenesis or in certain psychoses associated with inflammatory biomarkers [58, 86], the presently observed HERV-W ENV expression in microglia strongly suggests a role in neurological symptoms and cognitive impairment mostly occurring or persisting during the post-acute COVID-19 period.
 
In acute primary infection, one must also consider the pathogenic effects on immune cells resulting in an hyperactivation of the innate immunity via HERV-W ENV-mediated TLR4 activation with a possible contribution to the frequently observed lymphopenia along with an adaptive immune defect.
 
The induction of autoimmune manifestations as previously shown to be induced with HERV-W ENV (previously named MSRV) in a humanized mouse model, should also be considered. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080128
 
The study findings indicate that HERV-W ENV does not simply represent a biomarker of COVID-19 severity or evolution, but is also likely to be a pathogenic player contributing to the disease severity.
 
To date, various studies have considered many parameters in COVID-19 patients, but none has addressed HERV activation and expression of HERV proteins initiating and perpetuating pathogenic pathways underlying worsening clinical evolution and long-term pathology as seen with the now emerging post-COVID “wave”.
 
The long COVID wave represents millions of patients suffering from various and numerous symptoms, who develop long-term disabling active pathology for which no rationalized understanding nor therapeutic perspective can be proposed to date.
 
In face of this challenging situation, data from the present study altogether call for evaluating HERV-W ENV as a marker of severity but also as a potential therapeutic target in COVID-19 associated syndromes.
 
Hence, this should lead to already existing therapeutic molecules targeting HERV-W ENV in clinics. https://clinicaltrials.gov/ct2/show/NCT04480307
 
Urgent further characterization of HERV-W expression in population should help understanding of the individual differences in the response to SARS-CoV-2 infection, and may provide the critical set up for the identification of novel biomarkers specific for severe forms of COVID-19 and/or for long-term evolution of some post-COVID symptoms.
 
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