Endogenous retrovirus
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Endogenous retroviruses (ERVs) are endogenous viral elements in the genome that closely resemble and can be derived from retroviruses. They are abundant in the genomes of jawed vertebrates, and they comprise up to 5–8% of the human genome (lower estimates of ~1%).[1][2]
ERVs are a vertically inherited
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. This means that not all ERVs may have originated as an insertion by a retrovirus but that some may have been the source for the genetic information in the retroviruses they resemble.[8] When integration of viral DNA occurs in the germ-line, it can give rise to an ERV, which can later become fixed in the gene pool of the host population.[1][9]
Formation
The replication cycle of a
The general retrovirus genome consists of three genes vital for the invasion, replication, escape, and spreading of its viral genome. These three genes are gag (encodes for structural proteins for the viral core), pol (encodes for
Over time, the genome of ERVs not only acquire point mutations, but also shuffle and recombine with other ERVs.[11] ERVs with a decayed sequence for the env become more likely to propagate.[12]
Role in genomic evolution
Endogenous retroviruses can play an active role in shaping genomes. Most studies in this area have focused on the genomes of humans and higher primates, but other vertebrates, such as mice and sheep, have also been studied in depth.
About 90% of endogenous retroviruses are solo LTRs, lacking all open reading frames (ORFs). Solo LTRs and LTRs associated with complete retroviral sequences have been shown to act as transcriptional elements on host genes. Their range of action is mainly by insertion into the 5' UTRs of protein coding genes; however, they have been known to act upon genes up to 70–100 kb away.[13][17][18][19] The majority of these elements are inserted in the sense direction to their corresponding genes, but there has been evidence[20] of LTRs acting in the antisense direction and as a bidirectional promoter for neighboring genes.[21][22] In a few cases, the LTR functions as the major promoter for the gene.
For example, in humans AMY1C has a complete ERV sequence in its promoter region; the associated LTR confers salivary specific expression of the digestive enzyme amylase.[23] Also, the primary promoter for bile acid-CoA:amino acid N-acyltransferase (BAAT), which codes for an enzyme that is integral in bile metabolism, is of LTR origin.[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.[26]
Most of the time, however, the LTR functions as one of many alternate promoters, often conferring tissue-specific expression related to reproduction and development. In fact, 64% of known LTR-promoted transcription variants are
The best-characterized instance of placental protein expression comes not from an alternatively promoted host gene but from a complete co-option of a retroviral protein. 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
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. These rearrangements have been shown to induce gene duplications and deletions that largely contribute to genome plasticity and dramatically change the dynamic of gene function.
The characteristic of
Another example of ERV exploiting cellular mechanisms is p53, a tumor suppressor gene (TSG). DNA damage and cellular stress induces the p53 pathway, which results in cell apoptosis. Using chromatin immunoprecipitation with sequencing, thirty-percent of all p53-binding sites were located within copies of a few primate-specific ERV families. 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.[7]
Finally, the insertion of ERVs or ERV elements into genic regions of host DNA, or overexpression of their transcriptional variants, has a much higher potential to produce deleterious effects than positive ones. Their appearance into the genome has created a
Role in disease
The majority of ERVs that occur in vertebrate genomes are ancient, inactivated by mutation, and have reached genetic fixation in their host species. For these reasons, they are extremely unlikely to have negative effects on their hosts except under unusual circumstances. 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.[37] This has led researchers to propose a role for ERVs in several forms of human cancer and autoimmune disease, although conclusive evidence is lacking.[38][39][40][41]
Neurological disorders
In humans, ERVs have been proposed to be involved in
In 2004 it was reported that antibodies to HERVs were found in greater frequency in the
Immunity
ERVs have been found to be associated to disease not only through disease-causing relations, but also through immunity. The frequency of ERVs in long terminal repeats (LTRs) likely correlates to viral adaptations to take advantage of immunity signaling pathways that promote viral transcription and replication. A study done in 2016 investigated the benefit of ancient viral DNA integrated into a host through gene regulation networks induced by
HERVs also play various roles shaping the human
Gene regulation
Another idea proposed was that ERVs from the same family played a role in recruiting multiple genes into the same network of regulation. It was found that MER41 elements provided addition redundant regulatory enhancement to the genes located near STAT1 binding sites.[1]
Role in medicine
Porcine endogenous retrovirus
For humans,
Researchers have indicated that infection of human tissues by PERVs is very possible, especially in immunosuppressed individuals. 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. Although known infectious pathogens present in the donor organ/tissue can be eliminated by breeding pathogen-free herds, unknown retroviruses can be present in the donor. These retroviruses are often latent and asymptomatic in the donor, but can become active in the recipient. Some examples of endogenous viruses that can infect and multiply in human cells are from baboons (BaEV), cats (RD114), and mice.[50]
There are three different classes of PERVs, PERV-A, PERV-B, and PERV-C. PERV-A and PERV-B are
A clinical trial study performed in 1999 sampled 160 patients who were treated with different living pig tissues and observed no evidence of a persistent PERV infection in 97% of the patients for whom a sufficient amount of DNA was available to PCR for amplification of PERV sequences. This study stated that retrospective studies are limited to find the true incidence of infection or associated clinical symptoms, however. It suggested using closely monitored prospective trials, which would provide a more complete and detailed evaluation of the possible cross-species PERV transmission and a comparison of the PERV.[56]
Human endogenous retroviruses
Human endogenous retroviruses (HERV) comprise a significant part of the human genome, with approximately 98,000 ERV elements and fragments making up 5–8%.[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). This is because most HERVs are merely traces of original viruses, having first integrated millions of years ago. An analysis of HERV integrations is ongoing as part of the 100,000 Genomes Project.[57]
A 2023 study found HERV can become awakened from dormant states and contribute to aging which could be blocked by neutralizing antibodies.[58][59]
Human endogenous retroviruses 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.[1]
Classification
HERVs are classified based on their homologies to animal retroviruses. Families belonging to Class I are similar in sequence to mammalian
Origin
Sometime during human evolution, exogenous progenitors of HERV inserted themselves into germ line cells and then replicated along with the host's genes using and exploiting the host's cellular mechanisms. Because of their distinct genomic structure, HERVs were subjected to many rounds of amplification and transposition, which lead to a more widespread distribution of retroviral DNA.[1]
Nevertheless, one family of viruses has been active since the divergence of
Expression of HERV proteins
The expression of HERV-K, a biologically active family of HERV, produces proteins found in placenta. Furthermore, the expression of the envelope genes of
Functional impact
MER41.AIM2 is an HERV that regulates the transcription of AIM2 (Absent in Melanoma 2) which encodes for a sensor of foreign cytosolic DNA. This acts as a binding site for AIM2, meaning that it is necessary for the transcription of AIM2. Researchers had shown this by deleting MER41.AIM2 in HeLa cells using CRISPR/Cas9, leading to an undetectable transcript level of AIM2 in modified HeLa cells. The control cells, which still contained the MER41.AIM2 ERV, were observed with normal amounts of AIM2 transcript. In terms of immunity, researchers concluded that MER41.AIM2 is necessary for an inflammatory response to infection.[67]
Activation by exogenous viruses
Considerable evidence indicate that HERVs can be reactivated by viral infections, such as:
1) retroviruses –
2) RNA viruses – influenza A virus, hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus-2 (SARSCoV-2);
3) DNA viruses –
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
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 in astrocytes - cells that are involved in pathogenesis of multiple sclerosis.[70] Monocytes, especially after their differentiation into macrophages, appeared to be the most responsive to EBVgp350, expressing even higher levels of HERV-Wenv than B cells. 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.[71]
Immune response to HERVs
Despite having been integrated into genomes of vertebrates for millions of years, ERVs represent an intermediate stage between exogenous viruses and the host genome; it is suggested that immunological tolerance to HERV-derived proteins and peptides is imperfect due to the epigenetic silencing of HERV in the thymus and bone marrow, which prevents deletion of all HERV-specific T and B cells.
On a level of the innate immune sensing of nucleic acids, single-stranded RNA (
When retrotranscribed into DNA, retroviruses can be sensed by cyclic GMP-AMP
The recognition of nucleic acids through PRRs provides a very efficient strategy to fight against viral infections, at the same time imposing the host to a risk due to the possibility of recognizing self-nucleic acids and promotion of autoimmunity.
On a protein level, a direct interaction between TLRs and certain HERV proteins has been shown. For example, the surface unit of HERV-W Env (also known as Multiple sclerosis-associated retroviral element (MSRV) env) was found to bind to
Immunological studies have shown some evidence for T cell immune responses against HERVs in HIV-infected individuals.[78] The hypothesis that HIV induces HERV expression in HIV-infected cells led to the proposal that a vaccine targeting HERV antigens could specifically eliminate HIV-infected cells. The potential advantage of this novel approach is that, by using HERV antigens as surrogate markers of HIV-infected cells, it could circumvent the difficulty inherent in directly targeting notoriously diverse and fast-mutating HIV antigens.[78]
Techniques for characterizing ERVs
Whole genome sequencing
Example: A porcine ERV (PERV) Chinese-born
Chromatin immunoprecipitation with sequencing (ChIP-seq)
This technique is used to find histone marks indicative of promoters and enhancers, which are binding sites for DNA proteins, and repressed regions and trimethylation.
Applications
Constructing phylogenies
Because most HERVs have no function, are selectively neutral, and are very abundant in primate genomes, they easily serve as phylogenetic markers for linkage analysis. They can be exploited by comparing the integration site polymorphisms or the evolving, proviral, nucleotide sequences of orthologs. To estimate when integration occurred, researchers used distances from each phylogenetic tree to find the rate of molecular evolution at each particular locus. It is also useful that ERVs are rich in many species genomes (i.e. plants, insects, mollusks, fish, rodents, domestic pets, and livestock) because its application can be used to answer a variety of phylogenetic questions.[9]
Designating the age of provirus and the time points of species separation events
This is accomplished by comparing the different HERV from different evolutionary periods. For example, this study was done for different hominoids, which ranged from humans to apes and to monkeys. This is difficult to do with PERV because of the large diversity present.[55]
Further research
Epigenetic variability
Researchers could analyze individual epigenomes and
Immunological problems of xenotransplantation
Little is known about an effective way to overcoming
Risk factors of HERVs in gene therapy
Because retroviruses are able to recombine with each other and with other endogenous DNA sequences, it would be beneficial for gene therapy to explore the potential risks HERVs can cause, if any. Also, this ability of HERVs to recombine can be manipulated for site-directed integration by including HERV sequences in retroviral vectors.[1]
HERV gene expression
Researchers believe that RNA and proteins encoded for by HERV genes should continue to be explored for putative function in cell physiology and in pathological conditions. This would make sense to examine in order to more deeply define the biological significance of the proteins synthesized.[1]
See also
- Avian sarcoma leukosis virus (ASLV)
- Endogenous viral element
- Endogeny (biology)
- ERV3
- HERV-FRD
- Horizontal gene transfer
- Jaagsiekte sheep retrovirus (JSRV)
- Koala retrovirus (KoRV)
- Mouse mammary tumor virus (MMTV)
- xenotropic murine leukemia virus-related virus(XMRV)
- Paleovirology
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It appears that the transition from nonviral retrotransposon to retrovirus has occurred independently at least eight times, and the source of the envelope gene responsible for infectious ability can now be traced to a virus in at least four of these instances. This suggests that potentially, any LTR retrotransposon can become a virus through the acquisition of existing viral genes.
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Further reading
- Löwer R, Löwer J, Kurth R (May 1996). "The viruses in all of us: characteristics and biological significance of human endogenous retrovirus sequences". Proceedings of the National Academy of Sciences of the United States of America. 93 (11): 5177–5184. PMID 8643549.
- Molès JP, Tesniere A, Guilhou JJ (July 2005). "A new endogenous retroviral sequence is expressed in skin of patients with psoriasis". The British Journal of Dermatology. 153 (1): 83–89. S2CID 6642536.
- Seifarth W, Frank O, Zeilfelder U, Spiess B, Greenwood AD, Hehlmann R, Leib-Mösch C (January 2005). "Comprehensive analysis of human endogenous retrovirus transcriptional activity in human tissues with a retrovirus-specific microarray". Journal of Virology. 79 (1): 341–352. PMID 15596828.
- Knerr I, Beinder E, Rascher W (February 2002). "Syncytin, a novel human endogenous retroviral gene in human placenta: evidence for its dysregulation in preeclampsia and HELLP syndrome". American Journal of Obstetrics and Gynecology. 186 (2): 210–213. PMID 11854637.
- Gifford R, Tristem M (May 2003). "The evolution, distribution and diversity of endogenous retroviruses" (PDF). Virus Genes. 26 (3): 291–315. S2CID 34639116. Archived from the original(PDF) on 2013-02-15. Retrieved 2008-01-16.
External links
- Endogenous+Retroviruses at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- HERVd – human endogenous retrovirus database