The Potential Roles of Endogenous Retroviruses in Autoimmunity

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Abstract
Endogenous retroviruses (ERVs) are estimated to comprise up to 1% of human DNA. While the genome of many ERVs is interrupted by termination codons, deletions or frame shift mutations, some ERVs are transcriptionally active and recent studies reveal protein expression or particle formation by human ERVs. ERVs have been implicated as aetiological agents of autoimmune disease, because of their structural and sequence similarities to exogenous retroviruses associated with immune dysregulation and their tissue-specific or differentiation-dependent expression. In fact, retrovirus-like particles distinct from those of known exogenous retroviruses and immune responses to ERV proteins have been observed in autoimmune disease. Quantitatively or structurally aberrant expression of normally cryptic ERVs, induced by environmental or endogenous factors, could initiate autoimmunity through direct or indirect mechanisms. ERVs may lead to immune dysregulation as insertional mutagens or cis-regulatory elements of cellular genes involved in immune function. ERVs may also encode elements like tax in human T-lymphotrophic virus type I (HTLV-I) or tat in human immunodeficiency virus-I (HIV-I) that are capable of transactivating cellular genes. More directly, human ERV gene products themselves may be immunologically active, by analogy with the superantigen activity in the long terminal repeat (LTR) of mouse mammary tumour viruses (MMTV) and the non-specific immunosnppressive activity in mammalian type C retrovirus env protein. Alternatively, increased expression of an ERV protein, or expression of a novel ERV pro-tissue the result could be autoimmune disease. The adjective, paraneoplastic, would only seem appropriate if autoimmunity and tumour were temporally associated. Thus, ERVs could be viewed as being at the interface between tumour immunity and autoimmunity, the pivotal balance depending on the prevailing overlap between 'self and‘non-self. Although pure speculation, this hypothesis is consistent with the emerging body of molecular evidence that ERVs play a key role in regulating immune functions in health and disease.