Human Endogenous Retrovirus Group E and Its Involvement in Diseases

Abstract

Human endogenous retrovirus group E (HERV-E) elements are stably integrated into the human genome, transmitted vertically in a Mendelian manner, and are endowed with transcriptional activity as alternative promoters or enhancers. Such effects are under the control of the proviral long terminal repeats (LTR) that are organized into three HERV-E phylogenetic subgroups, namely LTR2, LTR2B, and LTR2C. Moreover, HERV-E expression is tissue-specific, and silenced by epigenetic constraints that may be disrupted in cancer, autoimmunity, and human placentation. Interest in HERV-E with regard to these conditions has been stimulated further by concerns regarding the capacity of HERV-E elements to modify the expression of neighboring genes and/or to produce retroviral proteins, including immunosuppressive env peptides, which in turn may induce (auto)-antibody (Ab) production. Finally, better understanding of HERV-E elements may have clinical applications for prevention, diagnosis, prognosis, and therapy.

The contribution of HERV‐E clone 4‐1 and other HERV‐E members to the pathogenesis of rheumatic autoimmune diseases

“…HERV‐E members belong to the superfamily of ERV1 (http://herv.img.cas.cz/) that contributes for 25.15% to the whole HERV genetic make‐up in hg19/GRCh37 genome (77), and to the HERV‐E family that is characterized by the presence of a Glu‐tRNA as primer‐binding site specificity (78). These elements are included in the class I of the classification of human endogenous retroviruses, due to their similarity to gammaretrovirus, and have an antisense orientation, which confers a lower probability of being deleted and the property of positively or negatively modulating the neighboring genes (79‐81). HERV‐E have a high rate (~70%) of recombination with other elements belonging to the same class, giving raise to the so‐called noncanonical chains (82).…”

“…HERV‐E have a high rate (~70%) of recombination with other elements belonging to the same class, giving raise to the so‐called noncanonical chains (82). More than 1300 HERV‐E elements have been identified in human genome; however, less than 10% possess an intact ORF and appear as full‐length proviruses (81). On the contrary, the majority of HERV‐E are present as solitary LTRs (more than 60%) or truncated forms (around 28%).…”

“…According to a generative mixture model based on expressed sequence tag databases, about 20% HERV‐E elements seem to be constitutively active (83). HERV‐E sequences are physiologically transcribed in human placenta, with a LTR expression ranging between 4% and 91% (49,81). Using a combined microarray and RT‐PCR analysis, researchers reported the transcriptional activity of HERV‐E clone 4‐1 and Seq32 in 19 different normal human tissues with the exception of the rectum (23).…”

An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes

“…HERVs are remnants of viral infections of the primate germline millions of years ago, which have been transmitted to their progeny. Tens of HERV families have been described, representing 8% of the human genome -few of which have been associated with several autoimmune diseases such as systemic lupus erythematous, rheumatoid arthritis, MS, amyotrophic lateral sclerosis, and Sjögren's syndrome (13,24,(46)(47)(48). In particular, the HERV-W family has been involved in the pathogenesis of MS through its envelope protein HERV-W-Env, also known as MSRV-Env (23)(24)(25).…”

The role of molecular mimicry and other factors in the association of Human Endogenous Retroviruses and autoimmunity

“…Clearly, the Epstein-Barr virus can infect, remain in an opportune latent state but overall is a strong polyclonal B-cell activator which may stimu-late bystander cells to help break tolerance. Consequently, a synergistic relationship may exist between HERVs and other exogenous viruses to mediate their effects (71).…”