Human Endogenous Retrovirus as Therapeutic Targets in Neurologic Disease

Abstract

Human endogenous retroviruses (HERVs) are ancient retroviral DNA sequences established into germline. They contain regulatory elements and encoded proteins few of which may provide benefits to hosts when co-opted as cellular genes. Their tight regulation is mainly achieved by epigenetic mechanisms, which can be altered by environmental factors, e.g., viral infections, leading to HERV activation. The aberrant expression of HERVs associates with neurological diseases, such as multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS), inflammatory processes and neurodegeneration. This review summarizes the recent advances on the epigenetic mechanisms controlling HERV expression and the pathogenic effects triggered by HERV de-repression. This article ends by describing new, promising therapies, targeting HERV elements, one of which, temelimab, has completed phase II trials with encouraging results in treating MS. The information gathered here may turn helpful in the design of new strategies to unveil epigenetic failures behind HERV-triggered diseases, opening new possibilities for druggable targets and/or for extending the use of temelimab to treat other associated diseases.

Anti-Human Herpesvirus 6 A/B Antibodies Titers Correlate With Multiple Sclerosis-Associated Retrovirus Envelope Expression

“…For example, while the transmembrane domine of syncytin-1 has fusogenic properties, it is not functional in pHERV-W ENV. On the other hand, while syncytin-1 is a membrane protein, pHERV-W ENV can be both membrane-associated and soluble (forming hexamers, trimers, or monomers) ( 26 , 27 ). Therefore, the same as only syncytin-1 is involved in the syncytiotrophoblast formation, only pHERV-W ENV proteins would take a part in MS pathogeny.…”

Human Endogenous Retroviruses as Gene Expression Regulators: Insights from Animal Models into Human Diseases

“…HERVs involve in the pathology of various diseases, including cancers ( Burns, 2017 ; Fischer et al, 2016 ; Gao et al, 2021 ; Kassiotis, 2014 ; Mullins and Linnebacher, 2012 ; Yu et al, 2013 ), autoimmune diseases ( Anand et al, 2017 ; Balada et al, 2009 ; Brodziak et al, 2012 ; Nelson, 1995 ; Tugnet et al, 2013 ) and neurological diseases ( Antony et al, 2011 ; Giménez-Orenga and Oltra, 2021 ; Gröger et al, 2021 ). The important topics have been extensively reviewed elsewhere ( Garcia-Montojo et al, 2018 ; Hohn et al, 2013 ).…”

“…Many studies report that transcripts and products of HERVs are detected in various cancers; breast cancers, ovarian cancers ( Wang-Johanning et al, 2007 ), lymphoma ( Contreras-Galindo et al, 2008 ), melanoma ( Serafino et al, 2009 ), germline tumors ( Herbst et al, 1996 ), leukemia ( Depil et al, 2002 ), prostate cancer ( Goering et al, 2011 ), and colon cancer ( Dolci et al, 2020 ). HERVs are also involved in the development of autoimmune diseases such as multiple sclerosis (MS) ( Garson et al, 1998 ; Komurian-Pradel et al, 1999 ; Rasmussen et al, 1995 ), rheumatoid arthritis (RA) ( Freimanis et al, 2010 ; Mameli et al, 2017 ; Nakagawa et al, 1997 ), systemic lupus erythematosus (SLE) ( Blomberg et al, 1994 ), as well as neurological diseases such as ALS ( Li et al, 2015 ; Mayer et al, 2018 ), ASD ( Balestrieri et al, 2012 ; 2019 ), attention deficit hyperactivity disorder (ADHD) ( Anand et al, 2017 ; Cipriani et al, 2018 ; D'Agati et al, 2016 ), FM ( Ovejero et al, 2020 ; Rodriguez-Pintó et al, 2014 ), schizophrenia ( Huang et al, 2011 ; Karlsson et al, 2004 ; Perron et al, 2008 ; 2012 ), and bipolar disorder (BD) ( Fries et al, 2019 ; Giménez-Orenga and Oltra, 2021 ; Goldsmith et al, 2016 ; Perron et al, 2012 ). This is likely to a continuing and growing list of diseases in which HERVs are involved in the pathology.…”

“…HERVs harbor binding sequences for KRAB-containing zinc finger proteins (KRAB-ZFPs), and histone modifications are induced by the interaction of KRAB-ZFPs to those binding sites. KRAB-ZFPs bind to transcription factor binding site (TFBS) within HERV elements, recruiting the co-repressor KRAB-associated protein 1 (KAP1), which is also called TRIM28 ( Giménez-Orenga and Oltra, 2021 ). In another study, it is shown that HERV-K is repressed by KAP1 (TRIM28) in undifferentiated human embryonic stem cells (hESCs) and differentiated cell lines HeLa and 293T cells, adult peripheral blood mononuclear cells (PBMCs), and CD4 + T cells ( Tie et al, 2018 ).…”

Cell fusion as a link between the SARS-CoV-2 spike protein, COVID-19 complications, and vaccine side effects

“…This fusion has been detected in a patient affected by shingles, [ 36 ] confirmed in a human xenograft model of this disease, [ 37 ] and accidentally discovered in an unrelated mouse model in which cortical neurons were infected with a retrovirus pseudotyped with VSV-G, the fusogen of vesicular stomatitis virus [ 38 ]. Whether the fusogens of human endogenous retroviruses (HERV), whose expression has been associated with various neurological disorders, function as pathogens of these diseases by fusing cells, as has been suggested, [ 39 ] is yet to be determined [ 40 , 41 ]. Together, these observations mean that abnormal neuronal fusion induced by viral proteins is not restricted to a particular fusogen or to certain neurons.…”