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

Gerwyn Morris, Michael Maes, Marianna Murdjeva, Basant K. Puri

The gammaretroviral human endogenous retrovirus (HERV) families MRSV/HERV-W and HERV-H (including the closely related HERV-Fc1) are associated with an increased risk of multiple sclerosis (MS). Complete HERV sequences betray their endogenous retroviral origin, with open reading frames in gag, pro, pol and env being flanked by two long terminal repeats containing promoter and enhancer sequences with the capacity to regulate HERV transactivation and the activity of host genes in spite of endogenous epigenetic repression mechanisms. HERV virions, RNA, cDNA, Gag and Env, and antibodies to HERV transcriptional products, have variously been found in the blood and/or brain and/or cerebrospinal fluid of MS patients, with the HERV expression level being associated with disease status. Furthermore, some HERV-associated single nucleotide polymorphisms (SNPs), such as rs662139 T/C in a 3-kb region of Xq22.3 containing a HERV-W env locus, and rs391745, upstream of the HERV-Fc1 locus on the X chromosome, are associated with MS susceptibility, while a negative association has been reported with SNPs in the tripartite motif-containing (TRIM) protein-encoding genes TRIM5 and TRIM22. Factors affecting HERV transcription include immune activation and inflammation, since HERV promoter regions possess binding sites for related transcription factors; oxidative stress, with oxidation of guanine to 8-oxoguanine and conversion of cytosine to 5-hydroxymethylcytosine preventing binding of methyl groups transferred by DNA methyltransferases; oxidative stress also inhibits the activity of deacetylases, thereby favouring the acetylation of histone lysine residues favouring gene expression; interferon beta; natalizumab treatment; impaired epigenetic regulation; and the sex of patients.