Dendrogram of various classes of endogenous retroviruses
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 proviral sequence and a subclass of a type of gene called a transposon, which can normally be packaged and moved within the genome to serve a vital role in gene expression and in regulation.[3][4] ERVs however lack most transposon function, are typically not infectious and are often defective genomic remnants of the retroviral replication cycle.[5][6] They are distinguished as germline provirus retroelementsdue to their integration and reverse-transcription into the nuclear genome of the host cell. 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]
Porcine endogenous retrovirus[edit]
For humans, porcine endogenous retroviruses (PERVs) pose a concern when using porcine tissues and organs in xenotransplantion, the transplanting of living cells, tissues, and organs from an organism of one species to an organism of different species. Although pigs are generally the most suitable donors to treat human organ diseases due to practical, financial, safety, and ethical reasons,[50] PERVs previously could not be removed from pigs due to its viral nature of integrating into the host genome and being passed into offspring until the year 2017 when Dr. George Church's lab removed all 62 retroviruses from the pigs genome.[53] The consequences of cross-species transmission remains unexplored and has very dangerous potential.[54]
Researchers 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 on 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 polytropic and can infect human cells in vitro, while PERV-C is ecotropic and does not replicate on human cells. The major differences between the classes is in the receptor binding domain of the env protein and the long terminal repeats (LTRs) that influence the replication of each class. PERV-A and PERV-B display LTRs that have repeats in the U3 region. However, PERV-A and PERV-C show repeatless LTRs. Researchers found that PERVs in culture actively adapted to the repeat structure of their LTR in order to match the best replication performance a host cell could perform. At the end of their study, researchers concluded that repeatless PERV LTR evolved from the repeat-harboring LTR. This was likely to have occurred from insertional mutation and was proven through use of data on LTR and env/Env. It is thought that the generation of repeatless LTRs could be reflective of an adaptation process of the virus, changing from an exogenous to an endogenous lifestyle.[55]
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[edit]
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. 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]
Human endogenous retroviruses were discovered by accident using a couple of different experiments. Human genomic libraries were screened under low-stringency conditions using probes from animal retroviruses, allowing the isolation and characterization of multiple, though defective, proviruses, that represented various families. Another experiment depended on oligonucleotides with homology to viral primer binding sites.[1]
HERVs are classified based on their homologies to animal retroviruses. Families belong to Class I are similar in sequence to mammalian Gammaretroviruses (type C) and Epsilonretroviruses (Type E). Families belonging to Class II show homology to mammalian Betaretroviruses (Type B) and Deltaretroviruses(Type D). Families belong to Class III are similar to foamy viruses. For all classes, if homologies appear well conserved in the gag, pol, and env gene, they are grouped into a superfamily. There are more Class I families known to exist.[1][11] The families themselves are named in a less uniform manner, with a mixture of naming based on an exogenous retrovirus, the priming tRNA (HERV-W, K), or some neighboring gene (HERV-ADP), clong number (HERV-S71), or some amino acid motif (HERV-FRD). A proposed nomenclature aims to clean up the sometimes paraphyletic standards.[58]
There are two proposals for how HERVs became fixed in the human genome. The first assumes that 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 widespread distribution of retroviral DNA. The second hypothesis claims the continuous evolution of retro-elements from more simple structured ancestors.[1]
Nevertheless, one family of viruses has been active since the divergence of humans and chimpanzees. This family, termed HERV-K (HML2), makes up less than 1% of HERV elements but is one of the most studied. There are indications it has even been active in the past few hundred thousand years, e.g., some human individuals carry more copies of HML2 than others.[59] Traditionally, age estimates of HERVs are performed by comparing the 5' and 3' LTR of a HERV; however, this method is only relevant for full-length HERVs. A recent method, called cross-sectional dating,[60] uses variations within a single LTR to estimate the ages of HERV insertions. This method is more precise in estimating HERV ages and can be used for any HERV insertions. Cross-sectional dating has been used to suggest that two members of HERV-K(HML2), HERV-K106 and HERV-K116, were active in the last 800,000 years and that HERV-K106 may have infected modern humans 150,000 years ago.[61] However, the absence of known infectious members of the HERV-K(HML2) family, and the lack of elements with a full coding potential within the published human genome sequence, suggests to some that the family is less likely to be active at present. In 2006 and 2007, researchers working independently in France and the US recreated functional versions of HERV-K(HML2).[62][63]
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.[64]
Immunological studies have shown some evidence for T cell immune responses against HERVs in HIV-infected individuals.[65] 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.[65]
There are a few classes of human endogenous retroviruses that still have intact open reading frames. For example, the expression of HERV-K, a biologically active family of HERV, produces proteins found in placenta. Furthermore, the expression of the envelope genes of HERV-W (ERVW-1)and HERV-FRD (ERVFRD-1) produces syncytins which are important for the generation of the syncytiotrophoblast cell layer during placentogenesis by inducing cell-cell fusion.[66] The HUGO Gene Nomenclature Committee (HGNC) approves gene symbols for transcribed human ERVs.[67]
Techniques for characterizing ERVs[edit]
Whole genome sequencing[edit]
Example: A porcine ERV (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. The observed number of nucleotide substitutions and among the different genome sequences helped researchers determine an estimate age that PERV-A-BM was integrated into its host genome, which was found to be of an evolutionary age earlier than the European-born pigs isolates.[54]
Chromatin immunoprecipitation with sequencing (ChIP-seq)[edit]
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.[34] DNA methylation has been shown to be vital to maintain silencing of ERVs in mouse somatic cells, while histone marks are vital for the same purpose in embryonic stem cells (ESCs) and early embryogenesis.[7]
Applications[edit]
Constructing phylogenies[edit]
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[edit]
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[edit]
Epigenetic variability[edit]
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]
Immunological problems of xenotransplantation[edit]
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.[50]
Risk factors of HERVs in gene therapy[edit]
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[edit]
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[edit]
- Avian sarcoma leukosis virus (ASLV)
- Endogenous viral element
- ERV3
- HERV-FRD
- Horizontal gene transfer
- Jaagsiekte sheep retrovirus (JSRV)
- Koala retrovirus (KoRV)
- Mouse mammary tumor virus (MMTV)
- Murine leukemia virus (MLV) and xenotropic murine leukemia virus-related virus (XMRV)
- Paleovirology
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