Genomic analysis of ERVWE2 locus in patients with multiple sclerosis: absence of genetic association but potential role of human endogenous retrovirus type W elements in molecular mimicry with myelin antigen

Abstract

Human endogenous retroviruses (HERVs) arise from ancient infections of the host germline cells by exogenous retroviruses, constituting 8% of the human genome. Elevated level of envelope transcripts from HERVs-W has been detected in CSF, plasma and brain tissues from patients with Multiple Sclerosis (MS), most of them from Xq22.3, 15q21.3, and 6q21 chromosomes. However, since the locus Xq22.3 (ERVWE2) lack the 5′ LTR promoter and the putative protein should be truncated due to a stop codon, we investigated the ERVWE2 genomic loci from 84 individuals, including MS patients with active HERV-W expression detected in PBMC. In addition, an automated search for promoter sequences in 20 kb nearby region of ERVWE2 reference sequence was performed. Several putative binding sites for cellular cofactors and enhancers were found, suggesting that transcription may occur via alternative promoters. However, ERVWE2 DNA sequencing of MS and healthy individuals revealed that all of them harbor a stop codon at site 39, undermining the expression of a full-length protein. Finally, since plaque formation in central nervous system (CNS) of MS patients is attributed to immunological mechanisms triggered by autoimmune attack against myelin, we also investigated the level of similarity between envelope protein and myelin oligodendrocyte glycoprotein (MOG). Comparison of the MOG to the envelope identified five retroviral regions similar to the Ig-like domain of MOG. Interestingly, one of them includes T and B cell epitopes, capable to induce T effector functions and circulating Abs in rats. In sum, although no DNA substitutions that would link ERVWE2 to the MS pathogeny was found, the similarity between the envelope protein to MOG extends the idea that ERVEW2 may be involved on the immunopathogenesis of MS, maybe facilitating the MOG recognizing by the immune system. Although awaiting experimental evidences, the data presented here may expand the scope of the endogenous retroviruses involvement on MS pathogenesis.

Multiple sclerosis and herpesvirus interaction

“…The endogenous retroviruses of the W family was isolated in the leptomeninges, choroid plexus and cultures of monocytes/macrophages in patients with multiple sclerosis and their origin is still under investigation [11][12][13][14] . Our group has recently published the first Brazilian study about the association between MS and Endogenous retrovirus with similar results 15 . The oligodendrocytes are responsible for the myelin production of the central nervous system and can be more sensitive to the endogenous retrovirus than the astrocytes on an animal model that mimics MS 16 .…”

Do Human Endogenous Retroviruses Contribute to Multiple Sclerosis, and if So, How?

“…Expression of HERV-W Env protein has been repeatedly detected on the surface of microglia and macrophages in the brains of MS patients near or in actively demyelinating lesions [ 45 , 172 , 176 ]. Moreover, several regions of the Env protein show sequence homology with MOG and at least some of these sequences function as epitopes capable of provoking T and B cell activation [ 177 , 178 ]. This is of importance as interactions between macrophages and microglia acting as APCs and autoreactive Th1 and Th17 T cells entering the CNS from the periphery are now considered to lie at the core of neuroinflammatory processes and myelin destruction in MS [ 179 ] (reviewed [ 113 ]).…”

Human Endogenous Retrovirus and Neuroinflammation in Chronic Inflammatory Demyelinating Polyradiculoneuropathy

“…This protein and its coding nucleotide sequences can thus be differentiated from the envelope sequences obtained from genomic RNA in purified retroviral particles from MS ( Mameli et al, 2009 ). The latter define an MSRV-subtype of HERV-W elements that comprises multiple related defective fixed copies in the human genome such as, e.g., a partial HERV-W copy on chromosome X that potentially encodes a truncated envelope (ERVWE2 locus) and may interfere with MSRV expression ( Roebke et al, 2010 , do Olival et al, 2013 , Garcia-Montojo et al, 2014 ). HERVs are not infectious viruses but human DNA sequences related to retrotransposable genetic elements, few of which have the potential to be activated by various environmental triggers, including infectious viruses on a “hit-and-run” mode ( Perron and Lang, 2010 , Mameli et al, 2012 ).…”