View source for Human endogenous retrovirus-W

{{Short description|Viral elements in human DNA}}{{technical|date=November 2016}}
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'''Human Endogenous Retrovirus-W''' ('''HERV-W''') is a family of Human Endogenous Retroviruses, or [[HERV]]s.

[[HERV]]s are part of a [[Superfamily (molecular biology)|superfamily]] of [[Repetitive DNA|repetitive]] and [[transposable elements]]. Of the 31 known families of HERVs, together making up about 8% of the [[human genome]], 
HERV-W encoding sequences make up about 1% of the human genome.   For comparison, this is four times more DNA than is devoted to [[Coding region|protein coding genes]].<ref>{{cite journal|last1=Belshaw|first1=R|title=Physiological Role of Human Placental Growth Hormone|journal=Molecular and Cellular Endocrinology|date=1998|volume=140|issue=1–2|pages=121–27|doi=10.1016/s0303-7207(98)00040-9|pmid=9722179|s2cid=13346422}}</ref><ref>{{cite journal|last1=Gannet|first1=Lisa|title=The Human Genome Project|journal=Stanford Encyclopedia of Philosophy|date=Oct 2008}}</ref>

Most HERVs in the genome today are not replication-competent due to [[frame shift]]s, [[premature stop codon]]s and [[Genetic recombination|recombination]] in their [[long terminal repeat]]s (LTRs).<ref name="general_provirus">{{Cite journal |doi = 10.1038/35001700|pmid = 10693785|title = A provirus put to work|journal = Nature|volume = 403|issue = 6771|pages = 715–717|year = 2000|last1 = Stoye|first1 = Jonathan P.|last2 = Coffin|first2 = John M.|s2cid = 2836108|doi-access = free}}</ref> Each HERV family is derived from a single infection of the [[germline]] by an exogenous [[retrovirus]] that, once integrated, expanded and evolved.<ref>{{Cite book|pmid = 21433351|year = 1997|last1 = Boeke|first1 = J. D.|chapter= Retrotransposons, Endogenous Retroviruses, and the Evolution of Retroelements|last2 = Stoye|first2 = J. P.|title=Retroviruses|editor-last1= Coffin|editor-first1 = J. M.|editor-last2= Hughes|editor-first2= S. H.|editor-last3= Varmus|editor-first3 = H. E.|publisher=Cold Spring Harbor Laboratory Press}}</ref>  A complete HERV contains the [[Group-specific antigen|gag]], pro, [[Pol (HIV)|pol]] and [[Env (gene)|env]] genes, flanked either side by the long terminal repeats.{{clarify|date=September 2021}}

==Phylogeny==

It is common for viruses to incorporate pieces of their host's genome into their own, which can aid their success. On the other hand, hosts can also keep viral DNA in their genome, which may persist if advantageous or non-deleterious.  In the case of HERVs, viral DNA is integrated into the germ-line genome of a human ancestor.<ref name="general_provirus" /> Thus, all the progeny of the infected human ancestor had this viral genome integrated into every cell in their bodies.<ref name="general_provirus" />

This new retroviral DNA can now be passed on vertically from parent to child.<ref name="general_provirus" /> Furthermore, the integrated viral genome has [[transposable element]] features, meaning it can replicate and/or jump in the human ancestor genome. Looking to the genomes of many species related to humans helped determine how long ago this retroviral genome was integrated into the human ancestor.{{cn|date=November 2022}}

Performing [[southern blot]]s with [[primate]] [[blood sample]]s and gag, pol, and pro probes (from [[100MSRV]]{{clarify|date=November 2016}}) suggested HERV-W entered the genome of [[Catarrhini|catarrhines]] over 23 million years ago.<ref>{{cite journal|last1=Voisset|last2=Ceclie|last3=Bedin|last4=Duret|title=Chromosomal Distribution and Coding Capacity of the Human Endogenous Retrovirus HERV-W Family.|journal=AIDS Research and Human Retroviruses|volume=16.8|issue=2000|pages=731–40|doi=10.1089/088922200308738|pmid=10826480|year=2000|s2cid=3048491|url=https://semanticscholar.org/paper/b4ebcfadfdbf4535ba7592e857cda3ef12e6240d}}</ref>  Later, blood samples [[hominoid]]s, [[Old World monkeys]], [[New World monkeys]] and [[prosimian]]s were probed using a fluorescently labeled HERV-W element derived from the [[gorilla]] [[fosmid library]].<ref name ="Kim_2008">{{cite journal|last1=Kim|last2=Ahn|last3=Hirar|title=Molecular Characterization of the HERV-W Env Gene in Humans and Primates: Expression, FISH, Phylogeny, and Evolution.|journal=Molecules and Cells|volume=26|issue=1|pages=53–60|date=July 2008|pmid=18525236}}</ref> [[Fluorescence in situ hybridization]] (FISH) revealed HERV-W elements in all the primate blood samples except the [[tupaia (genus)|tupaia]].<ref name ="Kim_2008"/>

With this information and the divergence values of the 5’ and 3’ LTRs, the construction of a [[phylogenetic tree]] was possible. This data implies that the HERV-W genome integrated into its host's germ-line around 63 million years ago, expanded in the era of Old and New World monkeys, and then evolved independently.<ref name="Kim_2008"/> Since its integration, the 5’ and 3’ LTR have followed independent evolution in each species.{{cn|date=November 2022}}

HERV-W is named for the fact that many in the group use a [[tryptophan]] [[tRNA]] in the primer binding site (PBS). The classification has been expanded into a HERVW9 (HERV9, HERVW, HERV30, MER41, HERV35, LTR19) group under the gammaretrovirus-like class I after a more robust phylogenetic study.<ref name="pmid26800882">{{cite journal |last1=Vargiu |first1=L |last2=Rodriguez-Tomé |first2=P |last3=Sperber |first3=GO |last4=Cadeddu |first4=M |last5=Grandi |first5=N |last6=Blikstad |first6=V |last7=Tramontano |first7=E |last8=Blomberg |first8=J |title=Classification and characterization of human endogenous retroviruses; mosaic forms are common. |journal=Retrovirology |date=22 January 2016 |volume=13 |pages=7 |doi=10.1186/s12977-015-0232-y |pmid=26800882 |pmc=4724089 |doi-access=free }}</ref> A proposed nomenclature suggests putting all such "class I" elements in a genus-level taxon separate from ''Gammaretrovirus''.<ref>{{cite journal |last1=Gifford |first1=RJ |last2=Blomberg |first2=J |last3=Coffin |first3=JM |last4=Fan |first4=H |last5=Heidmann |first5=T |last6=Mayer |first6=J |last7=Stoye |first7=J |last8=Tristem |first8=M |last9=Johnson |first9=WE |title=Nomenclature for endogenous retrovirus (ERV) loci. |journal=Retrovirology |date=28 August 2018 |volume=15 |issue=1 |pages=59 |doi=10.1186/s12977-018-0442-1 |pmid=30153831|pmc=6114882 |doi-access=free }}</ref>

==Discovery==

HERV-W was discovered because of its connection to [[multiple sclerosis]] (MS).  In [[macrophage]] cell cultures of patients with MS, several retroviral-like particles with [[reverse transcriptase]] (RT) activity were detected and given the name multiple sclerosis retroviruses (MSRVs).<ref name="Perron_1999">{{cite journal|last1=Perron|first1=H|last2=Seigneurin|first2=Jm|title=Human Retroviral Sequences Associated with Extracellular Particles in Autoimmune Diseases: Epiphenomenon or Possible Role in Aetiopathogenesis?|journal=Microbes and Infections|date=1999|volume=1|issue=4|pages=309–22|doi=10.1016/s1286-4579(99)80027-6|pmid=10602665}}</ref> Because of MSRV's retroviral nature, it was originally thought that MSRV had an exogenous viral origin.<ref name="Perron_1999"/>

However, MSRV's phylogenetic and experimental similarities to human endogenous retroviruses (HERVs) quickly revealed themselves. Thus, many labs began searching for the specific HERV family of which MSRV belonged.<ref name="Blond_1999">{{Cite journal |pmid = 9882319|pmc = 103938|year = 1999|last1 = Blond|first1 = J. L.|title = Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family|journal = Journal of Virology|volume = 73|issue = 2|pages = 1175–85|last2 = Besème|first2 = F.|last3 = Duret|first3 = L.|last4 = Bouton|first4 = O.|last5 = Bedin|first5 = F.|last6 = Perron|first6 = H.|last7 = Mandrand|first7 = B.|last8 = Mallet|first8 = F.|doi = 10.1128/JVI.73.2.1175-1185.1999}}</ref> Using the consensus sequence for retroviral pol and “panretro” RT-PCR extensions from the pol region of MSRV (retroviral RNA), the discovery of a HERV with gag, pol and env was made possible.<ref name="Kom_1999">{{cite journal|last1=Komurian-Pradel|last2=Paranhos-Baccala|last3=Bedin|last4=Sodoyer|last5=Ounanian-Paraz|last6=Ott|last7=Rajoharison|last8=Garcia|last9=Mallet|last10=Mandrand|last11=Perron|title=Molecular Cloning and Characterization of MSRV-Related Sequences Associated with Retrovirus-like Particles.|journal=Virology|volume=260|date=1999|issue=1|pages=1–9|doi=10.1006/viro.1999.9792|pmid=10405350|doi-access=free}}</ref>

The [[Primer (molecular biology)|primer binding site]] (PBS) of this HERV discovered is similar to avian retroviral PBSs, which use tRNATRP. This HERV was thus named HERV-W.<ref name="Blond_1999"/>  In hopes of finding the open reading frames (ORFs) of this HERV, healthy tissues were probed with reverse transcribed Ppol-, gag- and env-MSRV sequences (cDNAs).<ref name="Blond_1999"/>  Overlapping cDNAs spanned a 7.6 kb complete HERV with RU5- gag- pol- env- [[U3R sequence]]s, a [[polypurine tract]], and a primer-binding site (PBS).<ref name="Blond_1999"/>

The pol and gag ORFs are not replication-competent due to frame shifts and stop codons, but the env ORF is complete.  Performing multiple-tissue Northern Blots on a variety of human tissues lead to the discovery of 8-, 3.1- and 1.3-kb transcripts in placental tissue not expressed in heart, brain, lung, liver, skeletal muscle, kidney or pancreas cells.<ref name="Blond_1999"/> This was confirmed by Ppol-MSRV, gag and env probes.<ref name="Blond_1999"/>

Performing a [[BLASTn]] query search with the ESTs (expressed sequence tags) database for the cDNA clones derived from the probes, revealed that 53% of related transcripts were found in placental cells.<ref name="Blond_1999"/>  A southern blot using hybridization of gag, pro, env derived probes revealed a complex distribution of HERV-Ws in the human haploid genome with 70 gag, 100 pro, and 30 env regions.<ref name="Voisset_2000">{{cite journal|last1=Voisset|last2=Bouton|last3=Bedin|last4=Duret|last5=Mandrand|last6=Mallet|last7=Paranhos-Baccalà|title=Chromosomal Distribution and Coding Capacity of the Human Endogenous Retrovirus HERV-W Family.|journal=AIDS Research and Human Retroviruses|date=2000|volume=16|issue=8|pages=731–740|doi=10.1089/088922200308738|pmid=10826480|s2cid=3048491|url=https://semanticscholar.org/paper/b4ebcfadfdbf4535ba7592e857cda3ef12e6240d}}</ref>

With [[in vitro]] transcription techniques three suggested ORFs on [[chromosome 3]] (gag), 6 (pro) and 7 (env) were detected and further analyzed, revealing that the ORF on [[chromosome 7]]q21.2 uniquely encoded a glycosylated Env protein.<ref name="Voisset_2000"/>  Performing RealTime [[RT-PCR]] on [[adrenal gland]], [[bone marrow]], [[cerebellum]], whole brain, fetal brain, fetal liver, heart, [[kidney]], [[liver]], lung, [[placenta]], [[prostate]], [[salivary gland]], [[skeletal muscle]], [[spinal cord]], [[testis]], [[thymus]], [[thyroid gland]], [[trachea]], and [[uterus]] cells revealed 22 complete HERV-W families on chromosomes 1–3, 5–8, 10–12, 15, 19 and X.<ref name="Kim_2008"/>

[[In silico]] expression data revealed that these HERV-W elements are randomly expressed in various tissues (brain, mammary gland, cerebrum, skin, testis, eye, embryonic tissue, pancreatic islet, pineal gland, endocrine, retina, adipose tissue, placenta, and muscle).<ref name="Kim_2008"/>

Further, human tissues that lack some sort of HERV expression could not be found, which suggests that HERVs are permanent members of the human [[transcriptome]].<ref>{{cite journal|last1=Seifarth|first1=Wolfgang|last2=Frank|first2=Oliver|last3=Zeilfelder|first3=Udo|last4=Spiess|first4=Birgit|last5=Greenwood|first5=Alex|last6=Hehlmann|first6=Rudiger|last7=Leib-Mosch|first7=Christine|title=Comprehensive Analysis of Human Endogenous Retrovirus Transcriptional Activity in Human Tissues with a Retrovirus-Specific Microarray|journal=Journal of Virology|volume=79|issue=1|pages=341–352|date=January 2005|doi=10.1128/jvi.79.1.341-352.2005|pmid=15596828|pmc=538696}}</ref>  Although expression of HERV-W is prevalent in the whole body, there are two tissues whose expression levels are higher than the rest. The HERV-W derived element of chromosome 12p11.21 and 7q21.2 had 42 hits from the env gene in pancreatic islet tissues and 224 hits  (11 gag, 41 pol, 164 env) in placenta, testis, and embryotic tissues, respectively. The HERV-W element on 7q21.2 encodes for ERVWE-1, which was named syncytin-1.<ref>{{cite journal|last1=Schmitt|first1=Katja|last2=Richter|first2=Christin|last3=Backes|first3=Christina|last4=Meese|first4=Echart|last5=Ruprecht|first5=Klemens|last6=Mayer|first6=Jens|title=Comprehensive Analysis of Human Endogenous Retrovirus Group HERV-W Locus Transcription in Multiple Sclerosis Brain Lesions by High-Throughput Amplicon Sequencing Katja Schmitt,a Christin Richter,a Christina|journal=Journal of Virology|volume=87|issue=24|pages=13837–13852|date=December 2013|doi=10.1128/jvi.02388-13|pmid=24109235|pmc=3838257}}</ref>

==Biological function==
Upon realizing that HERV-W was prevalent in the human genome and can form viable transcripts, scientists began searching for HERV-W's biological significance.  The HERV-W Env gene expressed in a vector was [[transfected]] into TELCeB6 cells, and TELac2 cells, to test for virus-cell and cell-cell fusion respectively.<ref name="Blond_2000">{{cite journal|last1=Blond|first1=JL|last2=Lavillette|first2=D|last3=Cheynet|first3=V|last4=Bouton|first4=O|last5=Oriol|first5=G|last6=Chapel-Fernandes|first6=S|last7=Mandrandes|first7=S|last8=Mallet|first8=F|last9=Cosset|first9=FL|title=An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor.|journal=J. Virol.|date=7 April 2000 |volume=74|issue=7|pages=3321–9|doi=10.1128/jvi.74.7.3321-3329.2000|pmid=10708449|pmc=111833}}</ref>  One to two days after transfection numerous multinucleated giant cells, or syncytia, formed indicating the HERV-W env gene can cause homotypic and heterotypic cell-cell fusion.<ref name="Blond_2000"/>

As a control a gene known to be [[hyperfusogenic]], [[A-Rless]], was transfected into the cell-line. Upon transfection of cells with this vector, there was only a 6% fusion of cells as opposed to a 48% fusion with the HERV-W vector, thus revealing the gene encoded by HERV-W env is a highly fusogenic membrane glycoprotein.<ref name="Blond_2000"/>

Retroviruses that infect human cells interact with different receptors,<ref>{{cite journal|last1=Sommerfelt|first1=MA|title=Retrovirus receptors.|journal=J Gen Virol|volume=80|date=December 1999 |issue=12|pages=3049–64|doi=10.1099/0022-1317-80-12-3049|pmid=10567635|doi-access=free}}</ref> thus investigation began to find with which receptor HERV-W interacts.  The HERV-W envelope glycoprotein could fuse parental TE671 cells (human embryo cells, identical to human rhabdomyosarcoma RD cells), PiT-1 and PiT-2-blocked cells (PiT1/2 are retroviral (RV) receptors), but not retroviral type D receptor-blocked cells.  It was concluded that HERV-W may recognize and interact with the type D mammalian retroviral receptors expressed in humans.<ref name="Blond_2000"/>

With the knowledge of HERV-W's highly fusogenic properties and its heightened expression in placental cell a putative role for HERV-W in placental formation was suggested.<ref name="Frendo_2003">{{cite journal|last1=Frendo|first1=JL|last2=Olivier|first2=D|last3=Cheynet|first3=V|last4=Blond|first4=JL|last5=Bounton|first5=O|last6=Vidaud|first6=M|last7=Rabreau|first7=M|last8=Evain-Brion|first8=D|last9=Mallet|first9=F|title=Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation.|journal=Mol Cell Biol|date=May 2003|volume=23|issue=10|pages=3566–74|doi=10.1128/mcb.23.10.3566-3574.2003|pmid=12724415|pmc=164757}}</ref> The cytotrophoblast cells proliferate and invade maternal [[endometrium]], which is key to implantation and placental development.<ref>{{cite journal|last1=Fisher|first1=S|last2=T.-Y. Cui|last3=Zhang|first3=L|last4=Hartman|first4=L|last5=Grahl|first5=K|last6=Gou-Yang|first6=Z|last7=Tarpey|first7=J|last8=Damsky|first8=C|title=Adhesive and degradative properties of human placental cytotrophoblast cells in vitro.|journal=J. Cell Biol.|date=1989|volume=109|issue=2|pages=891–902|doi=10.1083/jcb.109.2.891|pmid=2474556|pmc=2115717}}</ref> Furthermore, cytotrophoblasts fuse and differentiate into multinucleated synctiotrophoblast cells that are surrounded by maternal blood and cover the embryo. Synctiotrophoblast help with nutrient circulation, ion exchange, and hormone synthesis, which are all key to development.<ref>{{cite journal|last1=Alsat|first1=E|last2=Wyplosz|first2=P|last3=Malassine|first3=A|last4=Guibourdenche|first4=J|last5=Porquet|first5=D|last6=Nessmann|first6=C|last7=Evain-Brion|first7=D|title=Hypoxia impairs cell fusion and differentiation process in human cytotrophoblast, in vitro.|journal=J. Cell. Physiol.|date=1996|volume=168|issue=2|pages=346–353|doi=10.1002/(sici)1097-4652(199608)168:2<346::aid-jcp13>3.0.co;2-1|pmid=8707870|s2cid=24741946}}</ref> These multinucleated cells appear very similar to virally induced syncytia.

HERV-W's main gene expression is [[ERVWE-1]] which is a highly fusogenic env [[glycoprotein]] also called [[syncytin-1]] because it induces the formation of [[syncytia]] (multinucleated cells).<ref name="Blond_2000"/>  Scientists began searching for ways that syncytin was involved in placental [[cytotrophoblast]] fusion and differentiation.<ref>{{cite journal|last1=Mi|first1=S|last2=Lee|first2=X|last3=Li|first3=X-P|last4=Veldman|last5=Finnerty|last6=Racie|last7=LaVallie|last8=Tang|last9=Edouard|last10=Howes|last11=Keith|last12=McCoy|title=Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis.|journal=Nature|volume=403|issue=6771|pages=785–789|doi=10.1038/35001608|pmid=10693809|year=2000|bibcode=2000Natur.403..785M|s2cid=4367889|doi-access=free}}</ref>  Using monoclonal fluorescently labeled antibodies the Frendo Lab was able to visualize the Env-W expression at the [[apical membrane]] of the synctiotrophoblast in first-trimester placentas.<ref name="Frendo_2003"/>

They were then able to show syncytin affected both the fusion of the [[trophoblast]] to the uterus and the differentiation of the trophoblast. To do this they stained cells with anti-[[desmoplakin]] antibodies to reveal cell boundaries. As the cells differentiate into syncytiotrophoblasts the ability to see desmoplakin decreases, meaning that cells are fusing together.<ref name="Frendo_2003"/>

Furthermore, as the cytotrophoblast differentiates the expression of HERV-W env mRNA and glycoprotein both increase collinearly suggesting HERV-W env expression is correlated with the fusion and differentiation of cells. This data suggests the factor that regulates trophoblast differentiation also regulates HERV-W env mRNA and protein expression and that a retroviral infection long ago may have been a pivotal event in mammalian evolution.<ref name="Frendo_2003"/>

Furthermore, HERV-W env glycoprotein has been shown to contain an [[immunosuppressive]] region.<ref>{{Cite journal |pmid = 15033302|year = 2004|last1 = Muir|first1 = A.|title = Expression and functions of human endogenous retroviruses in the placenta: An update|journal = Placenta|volume = 25 Suppl A|pages = S16-25|last2 = Lever|first2 = A.|last3 = Moffett|first3 = A.|doi = 10.1016/j.placenta.2004.01.012}}</ref>  This immunosuppressive nature of syncytin-1 and/or syncytin-2 (HERV-W) may be key in creating an immunologic barrier between the mother and the fetus.<ref>{{cite journal|last1=Cheynet|first1=V|last2=Ruggieri|first2=A|last3=Oriol|first3=G|last4=Blond|first4=J-L|last5=Boson|first5=B|last6=Vachot|first6=L|last7=Verrier|first7=B|last8=Cosset|first8=F.-L|last9=Mallet|first9=F|title=Synthesis, Assembly, and Processing of the Env ERVWE1/Syncytin Human Endogenous Retroviral Envelope|journal=Journal of Virology|date=2005|volume=79|issue=9|pages=5585–593|doi=10.1128/jvi.79.9.5585-5593.2005|pmid=15827173|pmc=1082723}}</ref> Since the fetus only share half of the mother's DNA it is critical that the mother's immune system does not reject or attack the fetus.<ref name="Nooralit_2009">{{cite journal|last1=Noorali|first1=S|last2=Rotar|first2=IC|last3=Lewis|first3=C|last4=Pestaner|first4=JP|last5=Pace|first5=DG|last6=Sison|first6=A|last7=Bagasra|first7=O|title=Role of HERV-W syncytin-1 in placentation and maintenance of human pregnancy.|journal=Appl. Immunohistochem Mol Morphol.|date=July 2009|volume=17|issue=4|pages=319–28|doi=10.1097/pai.0b013e31819640f9|pmid=19407656|s2cid=34049000}}</ref>

Analyzing 40 full-term placental tissues with [[immunohistochemical staining]] and RT in situ PCR, shows strong expression of syncytin-1 in synctiotrophoblasts compared to cytotrophoblasts.<ref name="Nooralit_2009"/> This suggests a symbiotic relationship between HERV expression and the host.

In contrast to this data, placental micro-vesicles, which also have high expression of syncytin-1 have been shown through peripheral blood mononuclear cell assays to activate the immune system thought the production of cytokines and chemokines.<ref name="Holder_2012">{{cite journal|last1=Holder|first1=BS|last2=Tower|first2=CL|last3=Forbes|first3=K|last4=Mulla|first4=MJ|last5=Aplin|first5=JD|last6=Abrahams|first6=VM|title=Immune cell activation by trophoblast-derived microvesicles is mediated by syncytin 1.|journal=Immunology|date=June 2012|volume=136|issue=2|pages=184–91|doi=10.1111/j.1365-2567.2012.03568.x|pmid=22348442|pmc=3403269}}</ref>  This suggests placental micro-vesicles can modulate the mother's immune system.<ref name="Holder_2012"/>  Today, it is still difficult to tell the exact mechanism that ERVWE-1 uses to suppress and/or activate the mother's immune system.{{cn|date=November 2022}}

==Mechanism of Expression and Environmental Factors==
The mechanism of expression for HERV-W genes is still not completely understood. The 780 bp LTR's that flank the env, pro, pol and gag, genes provide a range of regulatory sequences such as promoters, enhancers, and transcription factor binding sites.<ref name="Li_2016"/>  The 5’ U3 region acts as a promoter and the 3’ R acts as a poly A signal.<ref name="Li_2016">{{cite journal|last1=Li|first1=F|last2=Karlsson|first2=H|title=Expression and regulation of human endogenous retrovirus W elements.|journal=APMIS|date=January 2016|volume=124|issue=1–2|pages=52–66|doi=10.1111/apm.12478|pmid=26818262|doi-access=free}}</ref>  It would be reasonable to assume that HERV-W genes could not be transcribed from HERV-W elements that have incomplete LTRs.{{cn|date=November 2022}}

However, using a [[luciferase]] [[reporter gene]] assay HERV-Ws that have incomplete LTR's were still found to have promoter activity. This suggests that the transcription of HERV's can be activated not just by LTR-directed transcription but also by transcriptional leakage.<ref name="Li_2016"/>  Meaning if a nearby gene is being transcribed the transcription factors and polymerase can just keep moving along the DNA reaching the nearby HERV, where they can then transcribe it.  In fact, by doing a Chip-seq analysis of HERV-W LTR's it was found that ¼ of HERV-W LTR's can be bound by transcription factor p56 (ENCODE Project). This indicates a reason behind HERV-W's cell-specific expression.{{cn|date=November 2022}}

Different cell types transcribe varying genes, if a highly transcribed gene for placental cells, for example, happens to fall adjacent to a HERV-W element transcriptional leakage could explain HERV-W's heightened expression in this case. This mechanism of transcription is still being studied.{{cn|date=November 2022}}

Since there is a correlation between high cytokine production and MS, a study was done to test the regulation of a syncytin-1 promoter by MS-related cytokines such as TNFa, IFN-y, and IL-6.<ref name="Mameli_2007">{{cite journal|last1=Mameli|first1=G|last2=Astone|first2=V|last3=Khalili|first3=K|last4=Serra|first4=C|last5=Sawaya|first5=BE|last6=Dolei|first6=A|title=Regulation of the syncytin-1 promoter in human astrocytes by multiple sclerosis-related cytokines|journal=Virology|volume=362|issue=1|pages=120–130|date=January 29, 2007|doi=10.1016/j.virol.2006.12.019|pmid=17258784|doi-access=free}}</ref>  This experiment was performed with human astrocytic cells and showed that TNFa has the ability to activate the ERVWE-1 promoter through a NF-κB element.<ref name="Mameli_2007"/>  Final putative mechanisms of control of ERVWE-1 are by CpG promoter methylation and histone modification.<ref name="Mat_2006">{{cite journal|last1=Matouskova|first1=M|last2=Blazkova|first2=J|last3=Pajer|first3=P|last4=Pavlicek|first4=A|last5=Hejnar|first5=J|title=CpG methylation suppresses transcriptional activity of human syncytin-1 in non-placental tissues|journal=Exp. Cell Res.|date=April 15, 2006|volume=312|issue=7|pages=1011–20|doi=10.1016/j.yexcr.2005.12.010|pmid=16427621}}</ref>  Overexpression of ERVWE-1, which produces snyctin-1, would be dangerous in many adult cells. Thus, the promoter is methylated and histone modification occurs in non-placental cells to keep the expression of HERV-W low.<ref name="Mat_2006"/> In placenta cells, ERVWE-1 must be de-methylated to become active.<ref name="Mat_2006"/>

It is also thought that environmental factors can influence the expression of HERV-W.  Through qPCR methods and infection of cells with influenza and human herpes simplex 1 it was found that HERV-W has a heighted expression in a cell-specific manner when infected but no mechanism was revealed.<ref name="Nell_2006">{{cite journal|last1=Nellaker|first1=C|last2=Yao|first2=Y|last3=Jones-Brando|first3=L|last4=Mallet|first4=F|last5=Yolken|first5=RH|last6=Karisson|first6=H|title=Transactivation of elements in the human endogenous retrovirus W family by viral infection|journal=Retrovirology|date=July 6, 2006|volume=4|page=44|doi=10.1186/1742-4690-3-44|pmid=16822326|pmc=1539011|doi-access=free}}</ref>  Also, when these cells are placed in stressful environments such as serum deprivation similar and increased expression of HERV-W is also recorded.<ref name="Nell_2006"/>

This suggests that HERV-W is modulated by environmental effects. Another study also infected cells with influenza to show that this virus can transactivate HERV-W elements.  Influenza produces Glial Cells missing 1 (GCM1) that can act as an enhancer to reduce the repression of histone modification on HERV-Ws. This can lead to an increase in the transcription of HERV-W elements.<ref>{{cite journal|last1=Li|first1=F|last2=Nellaker|first2=C|last3=Sabunciyan|first3=S|last4=Yolken|first4=RH|last5=Jones-Brando|first5=L|last6=Johansson|first6=AS|last7=Owe-Larsson|first7=B|last8=Karlsson|first8=H|title=Transcriptional derepression of the ERVWE1 locus following influenza A virus infection|journal=J. Virol.|date=29 January 2014|volume=88|issue=8|pages=4328–37|doi=10.1128/jvi.03628-13|pmid=24478419|pmc=3993755}}</ref>

==HERV-W’s role in multiple sclerosis==
Since the detection of MSRV Env protein in the plasma of [[multiple sclerosis]] patients and the realization that is a member of the HERV-W family, the questions of how HERV-W was related to Multiple sclerosis and what caused transcription of HERV-W were investigated.  Both the expression of MSRV in vitro with peripheral blood mononuclear cell (PBMC; which are critical to the immune system) cultures and [[in vivo]] in [[severe combined immunodeficiency]] (SCID) mouse models, illustrated a pro-inflammatory response.<ref name="Rolland_2005">{{cite journal|last1=Rolland|first1=A|last2=Jouvin-Marche|first2=E|last3=Saresella|first3=M|last4=Ferrante|first4=P|last5=Cavaretta|first5=R|last6=Creange|first6=A|last7=Marche|first7=P|last8=Perron|first8=H|title=Correlation between disease severity and in vitro cytokine production mediated by MSRV (multiple sclerosis associated retroviral element) envelope protein in patients with multiple sclerosis|journal=Neuroimmunology|date=March 2005|volume=160|issue=1–2|pages=195–203|doi=10.1016/j.jneuroim.2004.10.019|pmid=15710473|s2cid=42118010}}</ref>

[[Inflammation]] can occur when the [[immune system]] recognizes an [[antigen]] and activates the [[immune response]] cascade.<ref>{{cite book|last1=Firestein|first1=Gary|last2=Budd|first2=Ralph|last3=Sherine|first3=E|title=Kelly and Firestein's Textbook of Rheumatology|isbn=978-0721601410|year=2005}}</ref> The transcribed and translated products of the HERV-W Env gene come from retroviral DNA thus the human body detects these proteins as antigens triggering the immune response.<ref name="Perron_2005">{{Cite journal |pmid = 15804956|year = 2005|last1 = Perron|first1 = H.|title = Human endogenous retrovirus (HERV)-W ENV and GAG proteins: Physiological expression in human brain and pathophysiological modulation in multiple sclerosis lesions|journal = Journal of Neurovirology|volume = 11|issue = 1|pages = 23–33|last2 = Lazarini|first2 = F.|last3 = Ruprecht|first3 = K.|last4 = Péchoux-Longin|first4 = C.|last5 = Seilhean|first5 = D.|last6 = Sazdovitch|first6 = V.|last7 = Créange|first7 = A.|last8 = Battail-Poirot|first8 = N.|last9 = Sibaï|first9 = G.|last10 = Santoro|first10 = L.|last11 = Jolivet|first11 = M.|last12 = Darlix|first12 = J. L.|last13 = Rieckmann|first13 = P.|last14 = Arzberger|first14 = T.|last15 = Hauw|first15 = J. J.|last16 = Lassmann|first16 = H.|doi = 10.1080/13550280590901741|s2cid = 37490334}}</ref>  Specifically, [[cytokine]] production is elevated in the MS PBMC cultures as compared to the healthy controls and mediated by the surface unit of the MSRV Env protein.<ref name="Rolland_2005"/>

This suggests that the MSRV Env protein may induce abnormal cytokine secretion, which leads to inflammation. A further explanation of how the expression of MSRV causes inflammation is found when looking at overexpression of syncytin-1 in [[glia cell]]s (cells that surround the neurons).  The result is [[endoplasmic reticulum]] stress that leads to [[neuro-inflammation]] and the production of [[free radical]]s, which leads to further damage of nearby cells.<ref>{{Cite journal |pmid = 17617614|year = 2007|last1 = Antony|first1 = J. M.|title = The human endogenous retrovirus envelope glycoprotein, syncytin-1, regulates neuroinflammation and its receptor expression in multiple sclerosis: A role for endoplasmic reticulum chaperones in astrocytes|journal = Journal of Immunology |volume = 179|issue = 2|pages = 1210–24|last2 = Ellestad|first2 = K. K.|last3 = Hammond|first3 = R.|last4 = Imaizumi|first4 = K.|last5 = Mallet|first5 = F.|last6 = Warren|first6 = K. G.|last7 = Power|first7 = C.|doi = 10.4049/jimmunol.179.2.1210|doi-access = free}}</ref>

Finally, it was discovered through [[TLR-4]] signaling assays, cytokine ELISAs, OPC cell cultures and statistical analysis that MSRV-Env is a highly potent [[TLR4|TLR-4]] activator.<ref name="Maderia_2016"/> MSRV-Env in vitro and in vivo induces TLR4 dependent pro-inflammatory stimulus and weakens the precursor cells of oligodendrocytes (produce myelin in CNS).<ref name="Maderia_2016">{{Cite journal |pmid = 26857492|year = 2016|last1 = Madeira|first1 = A.|title = MSRV envelope protein is a potent, endogenous and pathogenic agonist of human toll-like receptor 4: Relevance of GNbAC1 in multiple sclerosis treatment|journal = Journal of Neuroimmunology|volume = 291|pages = 29–38|last2 = Burgelin|first2 = I.|last3 = Perron|first3 = H.|last4 = Curtin|first4 = F.|last5 = Lang|first5 = A. B.|last6 = Faucard|first6 = R.|doi = 10.1016/j.jneuroim.2015.12.006|doi-access = free}}</ref>

This suggests a positive feedback loop where cytokines promote HERV-W transcription and then the transcription of HERV-W leads to a higher cytokine production.
Comparing Gag and Env expression in control patients and patients with MS it was found that Gag and Env are expressed at physiological levels in cells of the CNS under normal conditions. However, in patients with MS lesions there is a large accumulation of Gag proteins in [[demyelinate]]d [[white matter]].<ref name="Perron_2005"/>

This data suggests HERV-W env and gag genes in MS patients either have a distinct regulation of their inherited HERV-W copies or that HERV-W is infectious in MS patients.  By examining the regulation of a syncytin-1 promoter the [[Mameli Lab]] was able to better understand the mechanism for ERVWE1 regulation in nerve tissue. They found through a [[CHIP assay]] that TNFa (a cytokine) causes the [[RELA|p65]] transcription factor to bind to the promoter. This was confirmed by deleting the cellular enhancer, where p65 binds, which resulted in less transcription <ref>{{cite journal|last1=Mameli|first1=G|last2=Astone|first2=V|last3=Khalili|first3=K|last4=Serra|first4=C|last5=Sawaya|first5=BE|last6=Dolei|first6=A|title=Regulation of the syncytin-1 promoter in human astrocytes by multiple sclerosis-related cytokines|journal=Virology|volume=362|issue=1|pages=120–130|date=May 25, 2007|doi=10.1016/j.virol.2006.12.019|pmid=17258784|doi-access=free}}</ref>

A contrasting study performed a [[micro-array]] to analyze HERV transcription in human brains. Using 215 brain samples derived from SZ, BD and control patients it was found that the expression of HERV – E/F/K were weakly correlated with SZ and BD and that ERVWE-1 expression remained unaffected in SZ and BD compared to controls.<ref name="Frank_2005">{{Cite journal |pmid = 16103141|pmc = 1193590|year = 2005|last1 = Frank|first1 = O.|title = Human endogenous retrovirus expression profiles in samples from brains of patients with schizophrenia and bipolar disorders|journal = Journal of Virology|volume = 79|issue = 17|pages = 10890–901|last2 = Giehl|first2 = M.|last3 = Zheng|first3 = C.|last4 = Hehlmann|first4 = R.|last5 = Leib-Mösch|first5 = C.|last6 = Seifarth|first6 = W.|doi = 10.1128/JVI.79.17.10890-10901.2005}}</ref>

It is still not known today if MSRV plays a causal or reactive role in MS.
Another step in understanding the genomic origin of the HERV-W member transcribed in MS patients was made when looking to the HERV-W element of the Xq22.3.  Since women are twice as likely to have MS compared to men and the [[Xq22.3]] has almost a complete [[Open reading frame|ORF]] thus a possible connection between  Xq22.3 and MS was proposed.<ref>{{cite journal|last1=Garcia-Montoio|first1=M|last2=de la Hera|first2=B|last3=Matesanz|first3=F|last4=Alvarez-Lafuente|first4=R|title=HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRV|journal=Retrovirology|volume=11|pages=2|date=Jan 9, 2014|doi=10.1186/1742-4690-11-2|pmid=24405691|pmc=3892049|doi-access=free}}</ref>

==HERV-W and schizophrenia==

To date, not much hard evidence has been found to support a strong correlation between HERV-W transcripts and [[schizophrenia]] (SZ).  One study found 10 out of 35 individuals with recent onset schizophrenia had retroviral pol gene HERV-W transcripts and [[murine leukemia virus]] gene transcripts in cell-free CSF and 1 in 20 patients with chronic schizophrenia.<ref name="Frank_2005"/>

This was significant when compared to the 22 non-inflammatory patients and the 30 healthy patients who had no retroviral transcripts. Contrasting this data a [[micro-array]] was performed to analyze HERV transcription activity in human brains.<ref name="Frank_2005"/> They found a weak correlation between HERV's [[Human endogenous retrovirus K|–K]], [[Human endogenous retrovirus E|-E]], [[Human endogenous retrovirus F|-F]] and that env-W expression was constant in patients with schizophrenia and [[bipolar disorder]] (BD) compared to controls.<ref name="Frank_2005"/>  Today, it is still hard to tell if HERVs play a causal role, are correlated with or are just a response to in [[neuropsychiatric disease]]s.{{cn|date=November 2022}}

==Drug Production==
As knowledge about the mechanism of production for HERV-W transcripts is growing, scientists are beginning to synthesize drugs that can interrupt the MSRV pathway.  A [[humanized monoclonal antibody]] called GNbAc1 of the [[IgG4]] class binds with high specificity and affinity to the [[extracellular domain]] of the MSRV-Env protein.<ref>{{Cite journal |pmc = 4623301|year = 2014|last1 = Curtin|first1 = F.|title = Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein|journal = mAbs|volume = 7|issue = 1|pages = 265–275|last2 = Perron|first2 = H.|last3 = Kromminga|first3 = A.|last4 = Porchet|first4 = H.|last5 = Lang|first5 = A. B.|pmid = 25427053|doi = 10.4161/19420862.2014.985021}}</ref>

When performing experiments another humanized IgG4 class antibody was used as a control.  It was found through many experiments that GNbAc1 is able to antagonize all the MSRV-Env effects.<ref name="Maderia_2016"/>  This drug is still in its early stages of development.{{cn|date=November 2022}}

On Jan 2019 the drug GNbAC1 was granted the name [[Temelimab]] by the World Health Organization (WHO)<ref>GeNeuro Announces Positive Results from Temelimab (GNbAC1) Phase 1 High-dose Clinical Trial, International Nonproprietary Name “temelimab” Assigned to GNbAC1, Press Release, [http://www.geneuro.com/data/news/GeNeuro-PR-Phase-I-dose-elevee-EN.pdf]</ref>

==References==
{{Reflist}}

{{Taxonbar|from=Q28401403}}

==External links==
[https://www.discovermagazine.com/mind/the-insanity-virus/ The Insanity Virus]

[[Category:Endogenous retroviruses]]
[[Category:Retroviridae]]