Endogenous retroviruses and multiple sclerosis

Human endogenous retroviruses (HERVs) are DNA sequences (retroelements) present throughout human chromosomes that by some estimates comprise up to 7% percent of the genome. Given their characteristic retroviral organization, with long terminal repeats (LTRs) flanking gag, pol, and env genes, it has been proposed that they are derived from ancestral infectious agents long integrated into human DNA. All identified HERVs—and there are hundreds—are defective; that is, they do not encode infectious particles, are not known to be transmissible, and frequently do not even encode functional proteins. Nevertheless, many are transcriptionally active. Additionally, some HERVs are associated with particle formation, and there is a theoretical possibility that HERV genomes can be transcomplemented, resulting in full-fledged virion formation. Their persistence in the primate and human genome—some authorities place the introduction of primate ERVs back millions of years—argues for a strong selective pressure against a generally pathogenic phenotype. HERVs have been categorized in several ways, and one frequently used scheme divides HERVs according to the transfer RNA (tRNA) that is potentially used to prime the synthesis of a DNA copy of the (presumed) ancestral RNA genome. For example, HERV-W contains a primer binding site that binds the tRNA for tryptophan (single-letter amino acid code W); HERV-K is potentially primed by lysine tRNA; and so forth. Their persistence in the human genome has led some investigators to search for functional roles for HERVs. Perhaps the most compelling evidence for their involvement in a normal cellular function is the expression of HERV-W envelope (termed syncytin) in normal placental syncytiotrophoblasts. Mi and colleagues demonstrated that high levels of syncytin in placental cytotrophoblasts mediate fusion of the cytotrophoblasts, suggesting a role for this protein in normal human placental development. Moreover, syncytin was not found in any other tissues, with the exception of testis (from which it was originally cloned). To our knowledge, there is no other evidence for positive selection for HERVs. Similarly, there is no conclusive proof that any HERVs play a role in human disease, although investigators have posited several possible pathogenetic mechanisms. For example, HERVs could enhance the transcription of cellular genes placed downstream of the HERV long terminal repeats (LTRs). The LTRs contain the promoter elements and associated regulatory sequences that interact with transcriptional factors; these are themselves often regulated by various inflammatory cytokines and other cellular proteins. Alternatively, HERVs may encode superantigens that result in enhanced inflammatory responses, or they could mimic self-antigens and subsequently lead to the development of autoimmune phenomena such as those associated with systemic lupus erythematosus or multiple sclerosis (MS). Retroviruses have by no means escaped the long list of potential pathogens associated with MS by different investigative groups. For example, a decade ago, human T lymphotropic virus type 1 (HTLV-1) was implicated by polymerase chain reaction amplification from patients with MS. Perron and colleagues first proposed the importance of an MS-associated retrovirus that formed morphologically appropriate particles. The MS-associated retrovirus was eventually found to be related to an endogenous retroelement, ERV-9, which led to the discovery of the family of HERV-W retroelements. The increased expression of HERV RNA had been suggested to play a role in multiple sclerosis as well as schizophrenia, without clear causality. The article by Johnston and colleagues in this issue of the Annals of Neurology (pp. 434–442) presents clear evidence for increased expression of certain HERV sequences, specifically HERV-W and HERV-K, in the brains of individuals with MS or human immunodeficiency virus (HIV)-1 infection. It further concludes that increased HERV expression is not associated with specific disease pathology. Using both an in vitro model system and pathological analyses of autopsied brain, the authors conclude that the observed change in HERV expression is likely to be the result, and not the cause, of inflammatory diseases within the brain, by showing an association between monocyte/ macrophage activation in vitro and induced expression of certain HERV RNAs. MS and AIDS are two conditions associated with macrophage activation, tumor necrosis factor-a (TNF-a) expression, and transendothelial migration of monocytes and lymphocytes into the central nervous system (CNS); these events could trigger the expression of HERVs, as suggested by Johnston and colleagues. Because the increased expression occurs in conditions with such varied cause and pathology, it is unlikely that specific pathological changes or disease entities are associated with the enhanced transcription of these retroelements. The authors appropriately indicate that this study does not preclude a more generic role for HERVs in inflammatory CNS disease, but rather argue against a specific cause-effect relationship. Additionally, the failure to detect significant differences in HERV expression between control brains and those from patients with AlzEDITORIALS