Endogenous retrovirus
Researchers have suggested that retroviruses evolved from a type of transposon called a retrotransposon, a Class I element;[7] these genes can mutate and instead of moving to another location in the genome, they can become exogenous or pathogenic.
[13][14][15][16] The long terminal repeat (LTR) sequences that flank ERV genomes frequently act as alternate promoters and enhancers, often contributing to the transcriptome by producing tissue-specific variants.
[18][24] The insertion of a solo ERV-9 LTR may have produced a functional open reading frame, causing the rebirth of the human immunity related GTPase gene (IRGM).
[25] ERV insertions have also been shown to generate alternative splice sites either by direct integration into the gene, as with the human leptin hormone receptor, or driven by the expression of an upstream LTR, as with the phospholipase A-2 like protein.
[18] Furthermore, the neuronal apoptosis inhibitory protein (NAIP), normally widespread, has an LTR of the human ERV-P (HERV-P) family acting as a promoter that confers expression to the testis and prostate.
[28] Other proteins, such as nitric oxide synthase 3 (NOS3), interleukin-2 receptor B (IL-2RB), and another mediator of estrogen synthesis, HSD17B1, are also alternatively regulated by LTRs that confer placental expression, but their specific functions are not yet known.
Retroviral fusogenic env proteins, which play a role in the entry of the virion into the host cell, have had an important impact on the development of the mammalian placenta.
[30] In addition, the insertion of ERVs and their respective LTRs have the potential to induce chromosomal rearrangement due to recombination between viral sequences at inter-chromosomal loci.
[26] It has been shown that HERVs have contributed to the formation of extensively duplicated duplicon blocks that make up the human leukocyte antigen (HLA) class 1 family of genes.
[32] More specifically, HERVs primarily occupy regions within and between the break points of these blocks, suggesting that considerable duplication and deletion events, typically associated with unequal crossover, facilitated their formation.
A study suggested that this benefits retroviruses because p53's mechanism provides a rapid induction of transcription, which leads to the exit of viral RNA from the host cell.
Zinc-finger genes, particularly those that include a (Krüppel associated box) KRAB domain, exist in high copy number in vertebrate genomes, and their range of functions are limited to transcriptional roles.
[35] It has been shown in mammals, however, that the diversification of these genes was due to multiple duplication and fixation events in response to new retroviral sequences or their endogenous copies to repress their transcription.
Nevertheless, it is clear from studies in birds and non-human mammal species including mice, cats and koalas, that younger (i.e., more recently integrated) ERVs can be associated with disease.
[36] The number of active ERVs in the genome of mammals is negatively related to their body size, suggesting a contribution to Peto's paradox through cancer pathogenesis.
A specific association between MS and the ERVWE1, or "syncytin" gene, which is derived from an ERV insertion, has been reported, along with the presence of an "MS-associated retrovirus" (MSRV), in patients with the disease.
Additionally, the cerebrospinal fluid of people with recent onset schizophrenia contained levels of a retroviral marker, reverse transcriptase, four times higher than control subjects.
A study done in 2016 investigated the benefit of ancient viral DNA integrated into a host through gene regulation networks induced by interferons, a branch of innate immunity.
For example, IFN-stimulated genes were found to be greatly enriched with ERVs bound by signal transducer and activator of transcription 1 (STAT1) and/or Interferon regulatory factor (IRF1) in CD14+ macrophages.
An immunosuppressed condition could potentially permit a more rapid and tenacious replication of viral DNA, and would later have less difficulty adapting to human-to-human transmission.
[1] According to a study published in 2005, no HERVs capable of replication had been identified; all appeared to be defective, containing major deletions or nonsense mutations (not true for HERV-K).
[58][59] HERVs were originally discovered when human genomic libraries were screened under low-stringency conditions using either probes from animal retroviruses or by using oligonucleotides with similarity to virus sequences.
[67] Considerable evidence indicates that HERVs can be reactivated by viral infections, such as: Several studies have shown that EBV is able to transactivate the expression of the normally inactive HERV-K18 Env protein, e.g., interacting with resting B cells via the CD21 receptor.
[69] It has also been shown that in vitro binding of the EBV gp350 protein caused activation of MSRVenv and syncytin-1 in B-cells, monocytes, macrophages, and astrocytes - cells that are involved in pathogenesis of multiple sclerosis.
This finding is concordant with another study, which demonstrated that during infectious mononucleosis, EBV promoted the strongest activation of HERV-W/MSRV expression in monocytes compared to other blood cell types.
[72] As evidence of this, immunization of non-human primates with ERV-derived antigens mounted robust polyfunctional cytotoxic T cell response as well as high antibody titers.
According to phylogenetic studies, among 30 HERV families existing in the human genome, HERV-K (HML-2) elements which integrated most recently are the most intact and biologically active forms.
[78] Example: A PERV Chinese-born minipig isolate, PERV-A-BM, was sequenced completely and along with different breeds and cell lines in order to understand its genetic variation and evolution.
[55] Researchers could analyze individual epigenomes and transcriptomes to study the reactivation of dormant transposable elements through epigenetic release and their potential associations with human disease and exploring the specifics of gene regulatory networks.
[7] Little is known about an effective way to overcoming hyperacute rejection (HAR), which follows the activation of complement initiated by xenoreactive antibodies recognizing galactosyl-alpha1-3galatosyl (alpha-Gal) antigens on the donor epithelium.
