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.

Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

“…Several exogenous and endogenous infectious agents have been implicated in MS pathogenesis including human herpes viruses, human coronaviruses, and human endogenous retroviruses (HERVs) (21). Among the HERVs, the MS retrovirus, HERV-H, and the HERV-W envencoded glycoprotein, Syncytin-1, have been reported to participate in MS neuropathogenesis (22)(23)(24)(25)(26).…”

Mechanisms of Immunological Tolerance Disruption

“…В ранних ис-следованиях было показано, что EBV может способствовать поликлональной В-клеточ-ной активации у больных РА [Klatt et al, 2005], клональной экспансии EBNA-1 специфических Т-клеток, которые распознают антигены мие-лина у больных РС [Lunemann et al, 2008]. Ряд исследований свидетельствуют о иммунопато-генной связи вирионов HERV-W с РС, поскольку белок его оболочки (ENV) может способство-вать не только массовой неспецифической ак-тивации Т-лимфоцитов Antony et al, 2011], но также вызывать спонтанную ак-тивацию врожденного иммунитета через Tolllike Receptor-4 (TLR4) и CD14 .…”

The aliens inside human DNA: HERV-W/MSRV/syncytin-1 endogenous retroviruses and neurodegeneration

“…A key problem is differentiating this expression as the cause or effect of a particular disease. While for various HERV families, only expression of transcripts (and rarely of proteins) [6,15] were reported for the HERV-W family; several independent studies went further, reproducing in vitro and in animal models pathogenic mechanisms of the linked disease.…”

“…Conversely, HERVs can contribute to the generation of inherited diseases by induction of gene instability and variability, recombination, gene disruption by insertion of HERV sequences, autoimmunity, superantigenic stimulation, production of immunosuppressive factors, cancer through interactions with oncogenes, and activation/inactivation of growth controlling genes [6,15].…”