The pHERV-W Envelope Protein and the Clinical Forms of Multiple Sclerosis

The role of retroviral envelope proteins belonging to the Human Endogenous Retroviral family ‘W’ (HERV-W) as potential risk factors in multiple sclerosis (MS), has been establish. The transcripts of retroviral sequences that contain the envelope proteins from the HERV-W family, such as syncytin-1 and pHERV-W, were found in the MS patients. Studies have shown that the pathological variant of the HERV-W envelope (pHERV-W) is more strongly associated with MS compared to syncytin-1. The first aim of this study was to evaluate the serological response to pHERV-W and syncytin-1-derived peptides in different clinical forms and inflammatory phases of MS, including remission, as well as progressive forms. In addition, the analysis included populations belonging to distinct geographic areas with different MS incidence rates and genome selective pressures. Subsequently, the incidence and the levels of humoral response against other viral factors already strongly associated with MS, as Epstein-Barr virus (EBV), Human Herpesvirus (HVV-6A/B) and Cytomegalovirus (CMV), were evaluated. Finally, the inflammatory response, through evaluation of cytokine production, was study in peripheral blood mononuclear cells (PBMCs) of MS patients and healthy controls following antigenic stimulation with pHERV-W and syncytin-1-derived epitopes. The results showed significantly higher humoral response levels of anti-pHERV-W than anti-syncytin-1 in MS patients in both relapsed and progressive forms compared with HC. Individuals with acute and progressive forms of MS exhibited higher levels of antibodies to other viral infections, such as EBV and HVV-6A/B. Finally, pHERV-W exposure significantly increased the cytokine production response compared with syncytin-1 in MS PBMCs, supporting the idea of pHERV-W-involvement to the development of MS neuroinflammation. A strongly correlation was also found between the proinflammatory cytokine production from pHERV-W and other viral antibody titers in MS patients. Based on the results, both EBV, HHV and CMV could act in the pathogenesis of MS by regulating the proinflammatory action of pHERV-W. In conclusion, the evaluation of the pHERV-W envelope protein could be a useful pathogenic biomarker for monitoring the development and progression of central nervous system inflammation.