R, but statistically insignificant, tendency, while the TREX1 gene seemed inert.
R, but statistically insignificant, tendency, while the TREX1 gene seemed inert. These retroviral restriction factors, protecting the host from exogenous retroviral infection, may also recognize products of endogenous proviruses [30-33]. Current models of MS pathogenesis implicate the immune system as the ultimate effector, but combine it with neurodegeneration [34]. How this might be related to the endogenous retroviruses is unknown, but severalNissen et al. BMC Neurology 2013, 13:111 http://www.biomedcentral.com/1471-2377/13/Page 3 ofpossibilities can be suggested. HERVs in general are defective. However, since some are able to produce proteins they may be able to start an infectious-like process either through complementation or recombination. Thus, it might be the entire endogenous retroviral repertoire that determines infectivity and not the individual locus. If activated, the endogenous viruses PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28549975 could trigger the adaptive immune system or, equally likely, the innate immune system. The human genome contains several sets of genes encoding dozens of proteins constituting anti-retroviral defense mechanisms. One such set includes the TRIM proteins. TRIM5 protein activation is PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28914615 mediated by the incoming viral capsid. Recently, Jeremy Luban’s group reported that TRIM5-binding of the capsid activates signal transduction, stimulating the innate immune system [35]. As described above, markers in and around the TRIM5 gene are associated with the risk of MS [22 and Nex?et al. manuscript submitted]. Thus, it would be interesting to investigate the possibility that HERVs with potential Gag expression, e.g. HERV-Fc1, via TRIM could stimulate the innate immune system. Alternative mechanisms for the activation of the innate immune system may exist. Un-integrated DNA in the cytosol is known to trigger innate immune signaling [36]. RNA components of internalized viral sequences activate the innate immune system by stimulating Tolllike receptors in the endosomes [37]. The triggering of TLRs by HERVs in MS has previously been proposed [38]. Moreover, triggering of the innate cellular antiviral system by membrane-fusion of nucleic acid devoid virus-like-particles and cell, may act via the adaptor STING [39]. Finally, an entirely different mechanism was described in a recent paper; Dysregulation of the heterochromatin factor HP1 binding sites was shown to occur in MS. HP1 was again shown to influence both expression of HERVs and immune factors [40]. Thus, the endogenous viruses are mobile subcellular structures that span the divide between self and foreign. We specifically suggest that HERVs, though now a part of self, to some extent have retained the ability to trigger innate immune sensors of foreign patterns. This in turn could lead to stimulation of an adaptive autoimmune response. A combination of the above mechanisms could conceivably lead to a response, initially elicited by the endogenous viruses, but AZD4547 chemical information ultimately reacting to a broad range of cellular components. Noticeably, none of these models require actual productive infection cycles; a steady supply of virus-like particles performing the initial parts of an infection would be enough. Therefore, our induction experiments, which show that high levels of viral mRNA expression can be achieved from the endogenous loci when cells are exposed to drugs, take on a special significance. However,we sorely miss the identification of normo-physiological mechanisms other than actual replication that can enhan.