Severe COVID-19 disease and the high frequency of its long-term complications are now a major health problem worldwide. Due to the significant heterogeneity of COVID-19 disease profiles, biomarkers that allow either the identification of patients at high risk for developing severe forms of COVID-19 and its long-term complications, or guide personalized treatment options, are scarce. The HERVCOV project aims to analyze the role of human endogenous retroviruses (HERVs), known for their high pro-inflammatory potential, in the immunopathogenesis of COVID-19 and to identify and evaluate a set of biomarkers which will be important for the diagnosis, prognosis and follow-up of COVID-19 patients and their prioritization for targeted therapy. Recent data from the consortium has demonstrated that HERV-W envelope protein is highly expressed in lymphocytes of COVID-19 patients and correlates with inflammatory markers and respiratory outcome of the disease, strongly suggesting the role of HERVs in COVID-19 pathogenesis. The project aims to assess the biological pathways and functions that underlie the association of HERV expression and activation with severe COVID-19 forms and related complications. Biomarkers based on HERV pathogenic protein activation, SARS-CoV-2-specific immune responses, cytokine production and mandatory medical blood analyses for COVID-19 clinical monitoring will be studied in samples from different forms of COVID-19: acute, post- neuro- and long-COVID patients. Parameters will be determined that predict the clinical course of the disease and aggravation of SARS-CoV-2-induced symptoms and allow potential clustering of different bio-clinical profiles of COVID-19 patients. Diagnostic and prognostic panel(s) ?translated? from our fundamental research and subsequent evaluations of HERV-associated biomarkers will be assessed to define novel indicators in precision medicine-based therapeutic strategies, leading to individualized medical treatment in COVID-19.

SARS-CoV-2 infection may result in hyperimmune syndromes in certain patients often followed by fatal consequences. Similarly, an immunopathological expression of endogenous retroviral proteins has been incriminated in the pathogenesis of different diseases associated to hyperinflammatory response. Human endogenous retroviruses (HERVs) represent 8% of the human genome and have been generally silenced through diverse evolutionary mechanisms. However, peculiar HERV copies can be activated by different viruses and their activation may lead to the expression of immunopathogenic proteins (TLR4 agonist, superantigen). Our preliminary results showed highly elevated HERV-W ENV antigenemia in sera from severe COVID-19 cases from intensive care unities. We propose to study the mechanism of this SARS-CoV-2-mediated induction of HERV-W by analyzing larger number of samples from multicenter cohorts of COVID-19 patients, available from several European countries. We shall determine the cell type responsible for the production of HERV-W and search for the intracellular pathway linked to the SARS-CoV-2-induced activation of HERV-W. Possible other proteins encoded by endogenous retroviral elements will also be studied, in particular HERV-K envelope. HERV protein expression in SARS-CoV-2-infected primary human cells (e.g., leukocytes, adipocytes, lung epithelial cells) and cell lines in vitro will be analyzed. In addition, the study of HERV-W and HERV-K expression in different cell types obtained from COVID-19 patients will be performed and associated with the quantification of HERV-W and HERV-K envelope antigenemia in sera from COVID-19 patients, using WES platform (an automated capillary-based size sorting and immunolabeling system) and HERV-proteins specific monoclonal antibodies, developed by Geneuro-Innovation. This will include the murine parental antibody of temelimab, an HERV-W ENV neutralizing humanized IgG4 with already achieved and ongoing clinical phase 2 trials in multiple sclerosis. The project will be achieved in close collaboration between two groups: H. Perron’s, at Geneuro Innovation, and B. Horvat’s in International Center for Infectiology Research (CIRI) in Lyon, with complementary skills and sharing the common goal to develop new efficient anti-viral approaches, including those targeting HERV immunopathogenic effects. The partners share long-term collaboration experience in the field of induction of HERV expression by exogenous viruses. They have excellent expertise in studies of HERVs involvement in diseases (Geneuro Innovation) and in immunovirological studies (CIRI). The project is expected to provide a proof of concept for the role of HERV proteins, known for their strong proinflammatory effect, in the genesis of COVID-19 immunoinflammatory syndromes. The use of HERV-specific antibodies developed by Geneuro Innovation will include the ones further humanized to produce therapeutic antibodies. Temelimab (anti-HERV-W ENV IgG4) could be made immediately available in great quantity for a therapeutic intervention preventing the onset of immune-mediated severe forms of COVID-19. This would address the development of a new approach in the treatment of SARS-CoV-2-infected patients. The results of this proof of concept study are expected to provide the critical set up for a novel therapeutic strategy against the COVID-19 and thus open up new perspectives for preventing and treating immunopathological complications of this emergent infectious disease. This is also expected to mitigate the sanitary consequences of the current COVID-19 pandemic.