Human endogenous retroviruses and multiple sclerosis: innocent bystanders or disease determinants?

Abstract

Human endogenous retroviruses (HERVs) constitute 5-8% of human genomic DNA and are replication incompetent despite expression of individual HERV genes from different chromosomal loci depending on the specific tissue. Several HERV genes have been detected as transcripts and proteins in the central nervous system, frequently in the context of neuroinflammation. The HERV-W family has received substantial attention in large part because of associations with diverse syndromes including multiple sclerosis (MS) and several psychiatric disorders. A HERV-W-related retroelement, multiple sclerosis retrovirus (MSRV), has been reported in MS patients to be both a biomarker as well as an effector of aberrant immune responses. HERV-H and HERV-K have also been implicated in MS and other neurological diseases but await delineation of their contributions to disease. The HERV-W envelope-encoded glycosylated protein, syncytin-1, is encoded by chromosome 7q21 and exhibits increased glial expression within MS lesions. Overexpression of syncytin-1 in glia induces endoplasmic reticulum stress leading to neuroinflammation and the induction of free radicals, which damage proximate cells. Syncytin-1's receptor, ASCT1 is a neutral amino acid transporter expressed on glia and is suppressed in white matter of MS patients. Of interest, antioxidants ameliorate syncytin-1's neuropathogenic effects raising the possibility of using these agents as therapeutics for neuroinflammatory diseases. Given the multiple insertion sites of HERV genes as complete and incomplete open reading frames, together with their differing capacity to be expressed and the complexities of individual HERVs as both disease markers and bioactive effectors, HERV biology is a compelling area for understanding neuropathogenic mechanisms and developing new therapeutic strategies.

Fig. 1

Retrovirus envelope phylogeny. Phylogenetic analysis of endogenous and exogenous retrovirus env sequences from 36 different clones. The sequences were aligned in Clustal X and evolutionary distances were computed using the Poisson correction method. All positions containing gaps and missing data were eliminated from the data set. The evolutionary history was inferred using neighbor-joining method. Sequences are represented by accession numbers and the group to which they belong.

Fig. 2

Diversity within syncytin-1. (A) Multiple sites of syncytin-1 integration (indicated by arrowheads) located throughout the human genome were identified by performing a BLAT search with the syncytin-1 ORF from GenBank accession no. NM_014590 using the Ensembl human genome browser (www.ensembl.org). The genomic location of the original syncytin-1 locus on chromosome 7 is indicated by a box. (B) Phylogenetic rooted tree showing sequence diversity within syncytin-1 depending the chromosomal locus (chr# positions). Original syncytin-1 sequence (ERVWE1) is designated as syncytin-ORF chr7 NM 014590. The 10 homologous genomic regions with the highest BLAT scores over the entire length of the syncytin-1 ORF were extracted and aligned using Clustal W, including sequences from syncytin-1 and the HERV-K envelope ORF, as an outgroup (GenBank accession no. X82272). (C) Sequence heterogeneity within syncytin-1 in the vicinity of position 1099; a representative portion of an alignment of the 15 homologous genomic regions with the highest BLAT scores, including sequences truncated relative to the syncytin-1 ORF. A high level of sequence similarity in several regions allows the design of cDNA synthesis primers (red box) that will hybridize with syncytin-1-related mRNA sequences. Sequence divergence nearby will allow unambiguous identification of individual transcripts in order to determine the extent to which other syncytin-1-like transcripts are expressed.

Fig. 3

Syncytin-1-mediated neuropathogenesis in multiple sclerosis. Inflammation induces expression of syncytin-1 in astrocytes (and microglia), resulting in the release of cytokines and free radicals together with altered transport of amino acids implicated in neuropathogenesis including L- and D-serine, cysteine due to altered ASCT1 expression on astrocytes, which damage oligodendrocytes leading to demyelination and axonal injury.

Fig. 4

Mammalian ER stress mechanisms. In the absence of ER stress, BiP is bound to all 3 ER stress cascade initiators (PERK, IRE1 and ATF6). When ER stress occurs, BiP dissociates from the ER stress cascade initiators and binds to the unfolded and misfolded proteins. PERK is a kinase that phosphorylates EIF2α which leads to the translocation of ATF4 and ultimately activation of CHOP promoter. Endonuclease, IRE1, splices XBP1 pre-mRNA into its mature transcript variant and also leads to the induction of CHOP. ATF6 is a transcription factor that gets cleaved twice before it translocates into the nucleus to enhance the transcription of CHOP and ER chaperone genes. Also ER stress can indirectly lead to increased iNOS and production of pro-inflammatory cytokines through oxidative stress.