Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses

The hypothesis that human endogenous retroviruses (HERVs) play a role in autoimmune diseases is subject to increasing attention. HERVs represent both putative susceptibility genes and putative pathogenic viruses in the immune-mediated neurological disease multiple sclerosis (MS). Gammaretroviral HERV sequences are found in reverse transcriptase-positive virions produced by cultured mononuclear cells from MS patients, and they have been isolated from MS samples of plasma, serum and CSF, and characterised to some extent at the nucleotide, protein/enzyme, virion and immunogenic level. Two types of sequences, HERV-H and HERV-W, have been reported. No known HERV-H or HERV-W copy contains complete ORFs in all prerequisite genes, although several copies have coding potential, and several such sequences are specifically activated in MS, apparently resulting in the production of complete, competent virions. Increased antibody reactivity to specific Gammaretroviral HERV epitopes is found in MS serum and CSF, and cell-mediated immune responses have also been reported. Further, HERV-encoded proteins can have neuropathogenic effects. The activating factor(s) in the process resulting in protein or virion production may be members of the Herpesviridae. Several herpes viruses, such as HSV-1, VZV, EBV and HHV-6, have been associated with MS pathogenesis, and retroviruses and herpes viruses have complex interactions. The current understanding of HERVs, and specifically the investigations of HERV activation and expression in MS are the major subjects of this review, which also proposes to synergise the herpes and HERV findings, and presents several possible pathogenic mechanisms for HERVs in MS.