Endogenous Retroviruses as Modulators of Innate Immunity

Abstract

Endogenous retroviruses (ERVs), or LTR retrotransposons, are a class of transposable elements that are highly represented in mammalian genomes. Human ERVs (HERVs) make up roughly 8.3% of the genome and over the course of evolution, HERV elements underwent positive selection and accrued mutations that rendered them non-infectious; thereby, the genome could co-opt them into constructive roles with important biological functions. In the past two decades, with the help of advances in sequencing technology, ERVs are increasingly considered to be important components of the innate immune response. While typically silenced, expression of HERVs can be induced in response to traumatic, toxic, or infection-related stress, leading to a buildup of viral transcripts and under certain circumstances, proteins, including functionally active reverse transcriptase and viral envelopes. The biological activity of HERVs in the context of the innate immune response can be based on the functional effect of four major viral components: (1) HERV LTRs, (2) HERV-derived RNAs, (3) HERV-derived RNA:DNA duplexes and cDNA, and 4) HERV-derived proteins and ribonucleoprotein complexes. In this review, we will discuss the implications of HERVs in all four contexts in relation to innate immunity and their association with various pathological disease states.

HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity

“…Analysis of differential gene expression in the exact same samples provided advantageous evidence of HERV-associated immune changes in the ME/CFS group as compared to FM, comorbidity, or healthy controls, further supporting the existence of two ME/CFS subgroups. Our analysis of the correlation between deregulated HERV and gene profiles, combined with overrepresentation analysis of HERVome-associated genes, suggests the involvement of aberrantly expressed HERV in immune processes of ME/CFS, FM, and comorbid groups, a finding already reported for other diseases ( 41 ) and supported by HERV-mediated regulation of immune response ( 61, 62 ). Strikingly, all upregulated HERV in ME/CFS (n=251) correlated with genes (n=34) involved in alpha-beta T cell activation and T-helper 17 cell commitment, in good agreement with the literature reporting alterations in these cell populations of ME/CFS ( 63–65 ), and which seem especially relevant in autoimmune disorders ( 66 ).…”

The white-footed deermouse, an infection-tolerant reservoir for several zoonotic agents, tempers interferon responses to endotoxin in comparison to the mouse and rat

“…A xenotropic MLV-related retrovirus has been discounted as a cause of chronic fatigue syndrome (60) . However, production of whole virions need not occur for there to be PRR signaling in response to cytoplasmic Env protein, single stranded RNA, or cDNA (78) .…”

State‐of‐the‐art in transposable element modulation affected by drugs in malignant prostatic cancer cells

“…4 The second class (Class II) consists of DNA transposons (2.8% in the human genome), which are mobile DNA segments found in various genomic locations due to the action of the transposase enzyme. 7,9 Figure 1 presents a schematic illustration of TEs. We underline that the classification of DNA transposons, based on the type of transposition system used, is less precise than that of retrotransposons because of the lack of conserved protein domains among DNA-TEs.…”

“…Consequently, Class I TEs contribute to genome size expansion. 7,9 Instead, TEs of Class II were nicknamed "cut and paste" elements because they completely excise DNA fragments before inserting them elsewhere in the human genome. However, some DNA transposons can use replicative/recombination pathways to lead transposon copies to a new position.…”

“…ERVs are further classified into three subgroups based on their correlation with the structure of exogenous retroviruses. 9,16,17 The youngest human ERV (HERV) of the subfamily HERVK (also named HML-2), derives from an ancestral virus infection in the human genome. Its structure is peculiar and akin to that of common HIV retroviruses, it uses an analogous replication mechanism but without an extracellular stage or functional envelope proteins.…”