HERVs are part of a superfamily of repetitive and transposable elements. Transposable elements are sequences of DNA that can move or "jump" around the genome, sometimes replicating and inserting themselves in different locations.
There are 31 known families of HERVs, constituting approximately about 8% of the human genome of which HERV-W DNA encoding sequences specifically account for about 1% of the human genome. For comparison, this represents four times the amount of DNA allocated to protein coding genes.[1][2]
Most HERVs in the genome today are not able to replicate, because of genetic changes such as frame shifts, premature stop codons, and recombination in their long terminal repeats (LTRs).[3] Each HERV family is derived from a single infection of the human germline by an external retrovirus. After integrating into the human DNA, these retroviruses expanded and evolved over time.[4] A complete HERV includes specific genes – gag, pro, pol and env – flanked on either side by the long terminal repeats, which act like bookends. [clarification needed]
Phylogeny
It is common for viruses to incorporate pieces of their host's genome into their own, which can aid in 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.[3] Thus, all the progeny of the infected human ancestor had this viral genome integrated into every cell in their bodies.[3]
This new retroviral DNA can now be passed on from parent to child.[3] Furthermore, the integrated viral genome has transposable element features, meaning it can replicate 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.[citation needed]
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.[6] Since its integration, the 5’ and 3’ LTRs have followed independent evolution in each species.[citation needed]
HERV-W is named for the fact that many in the group use a tryptophantRNA at the primer binding site (PBS). The classification has been expanded into a HERVW9 group (HERV9, HERVW, HERV30, MER41, HERV35, LTR19) under the gammaretrovirus-like class I after a more robust phylogenetic study.[7] A proposed nomenclature suggests putting all such "class I" elements in a genus-level taxon separate from Gammaretrovirus.[8]
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).[9] Because of MSRV's retroviral nature, it was originally thought that MSRV had an exogenous viral origin.[9]
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 to which MSRV belonged.[10] 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.[11]
The primer binding site (PBS) of this HERV was discovered to be similar to avian retroviral PBSs, which use tRNATRP. This HERV was thus named HERV-W.[10] 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).[10] Overlapping cDNAs spanned a 7.6 kb complete HERV with RU5- gag- pol- env- U3R sequences, a polypurine tract, and a primer binding site (PBS).[10]
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 led 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.[10] This was confirmed by Ppol-MSRV, gag, and env probes.[10]
Performing a BLASTn query search with the expressed sequence tags (ESTs) database for the cDNA clones derived from the probes, revealed that 53% of related transcripts were found in placental cells.[10] 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.[12]
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).[6]
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.[13] 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.[14]
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 and TELac2 cells, to test for virus-cell and cell-cell fusion, respectively.[15] One-to-two days after transfection, numerous multinucleated giant cells, or syncytia, had formed, indicating the HERV-W env gene can cause homotypic and heterotypic cell-cell fusion.[15]
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.[15]
Retroviruses that infect human cells interact with different receptors,[16] 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), and 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.[15]
With the knowledge of HERV-W's highly fusogenic properties and its heightened expression in placental cells, a putative role for HERV-W in placental formation was suggested.[17] The cytotrophoblast cells proliferate and invade maternal endometrium, which is key to implantation and placental development.[18] 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.[19] 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, which is also called syncytin-1 because it induces the formation of syncytia (multinucleated cells).[15] Scientists began searching for ways that syncytin was involved in placental cytotrophoblast fusion and differentiation.[20] 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.[17]
They were then able to show that 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.[17]
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.[17]
Furthermore, HERV-W env glycoprotein has been shown to contain an immunosuppressive region.[21] This immunosuppressive nature of syncytin-1 and syncytin-2 (HERV-FRD) may be key in creating an immunologic barrier between the mother and the fetus.[22] Since the fetus only share half of the mother's DNA, it is critical that the mother's immune system does not attack the fetus.[23]
Analyzing 40 full-term placental tissues with immunohistochemical staining and RT in-situ PCR shows strong expression of syncytin-1 in syncytiotrophoblasts compared to cytotrophoblasts.[23] 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 through the production of cytokines and chemokines.[24] This suggests placental micro-vesicles can modulate the mother's immune system.[24] Today, it is still difficult to tell the exact mechanism that ERVWE-1 uses to suppress or activate the mother's immune system.[citation needed]
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.[25] The 5’ U3 region acts as a promoter and the 3’ R acts as a poly A signal.[25] It would be reasonable to assume that HERV-W genes could not be transcribed from HERV-W elements that have incomplete LTRs.[citation needed]
However, using a luciferasereporter gene assay, HERV-Ws that have incomplete LTR's were still found to have promoter activity. This suggests that the transcription of HERVs can be activated not just by LTR-directed transcription but also by transcriptional leakage,[25] meaning if a nearby gene is being transcribed, the transcription factors and polymerase can keep moving along the DNA and reach 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 1/4 of HERV-W LTRs can be bound by transcription factor p56 (ENCODE Project). This indicates a reason behind HERV-W's cell-specific expression.[citation needed]
Different cell types transcribe various genes. If, for example, a highly transcribed gene for placental cells happens to be 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.[citation needed]
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-γ, and IL-6.[26] This experiment was performed with human astrocytic cells and showed that TNFa has the ability to activate the ERVWE-1 promoter through an NF-κB element.[26] Putative final mechanisms of control of ERVWE-1 are thought to be by CpG-promoter methylation and histone modification.[27] 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.[27] In placenta cells, ERVWE-1 must be de-methylated to become active.[27]
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 heightened expression in a cell-specific manner when infected; but no mechanism was revealed.[28] Also, when these cells are placed in stressful environments, such as serum deprivation, similar and increased expression of HERV-W is also recorded.[28]
This suggests that HERV-W is modulated by environmental effects. Another study of cells infected with influenza showed that this virus can transactivate HERV-W elements. Influenza produces glial cells missing 1 (GCM1) that can act as enhancers to reduce the repression of histone modification of HERV-Ws. This can lead to an increase in the transcription of HERV-W elements.[29]
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 the protein 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; such cells being critical to the immune system) cultures and in vivo in severe combined immunodeficiency (SCID) mouse models, illustrated a pro-inflammatory response.[30]
Inflammation can occur when the immune system recognizes an antigen and activates the immune response cascade.[31] The transcribed and translated products of the HERV-W Env gene come from retroviral DNA. Thus, the human body detects these proteins as antigens and triggers the immune response.[32] Specifically, cytokine production is elevated in the MS PBMC cultures as compared to the healthy controls and as mediated by the surface unit of the MSRV-Env protein.[30]
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 cells (cells that surround the neurons). The result is endoplasmic reticulum stress that leads to neuro-inflammation and the production of free radicals, which leads to further damage of nearby cells.[33]
Finally, it was discovered—through TLR-4 signaling assays, cytokine ELISAs, OPC cell cultures, and statistical analysis—that MSRV-Env is a highly potent TLR-4 activator.[34] MSRV-Env in vitro and in vivo induces TLR4 dependent pro-inflammatory stimulus and weakens the precursor cells of oligodendrocytes, which produce myelin thorougout the central nervous system (CNS).[34]
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 with 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 demyelinatedwhite matter.[32]
This data suggests that 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, researchers were able to better understand the mechanism for ERVWE-1 regulation in nerve tissue. They found through a CHIP assay that the cytokine TNFa causes the p65 transcription factor to bind to the promoter. This was confirmed by deleting the cellular enhancer, where p65 binds, which resulted in less transcription.[35]
A contrasting study performed a micro-array to analyze HERV transcription in human brains. Using 215 brain samples derived from schizophrenia (SZ), bipolar disorder (BD), and control patients, it was found that the expression of HERV – E/F/K was weakly correlated with SZ and BD and that ERVWE-1 expression remained unaffected in SZ and BD compared to controls.[36]
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 into 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 ORF thus a possible connection between Xq22.3 and MS was proposed.[37]
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 that 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 cerebrospinal fluid (CSF), compared to 1 in 20 patients with chronic schizophrenia.[36]
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.[36] They found a weak correlation between HERV's –K, -E, -F; and that env-W expression was constant in patients with schizophrenia and bipolar disorder (BD) compared to controls.[36] Today, it is still hard to tell if HERVs play a causal role, are correlated with, or are just a response to, neuropsychiatric diseases.[citation needed]
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.[38]
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.[34] This drug is still in its early stages of development.[citation needed]
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus. Many retroviruses cause serious diseases in humans, other mammals, and birds.
Retrotransposons are mobile elements which move in the host genome by converting their transcribed RNA into DNA through the reverse transcription. Thus, they differ from Class II transposable elements, or DNA transposons, in utilizing an RNA intermediate for the transposition and leaving the transposition donor site unchanged.
Lentivirus is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lentiviruses are distributed worldwide, and are known to be hosted in apes, cows, goats, horses, cats, and sheep as well as several other mammals.
Gammaretrovirus is a genus in the Retroviridae family. Example species are the murine leukemia virus and the feline leukemia virus. They cause various sarcomas, leukemias and immune deficiencies in mammals, reptiles and birds.
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.
Jaagsiekte sheep retrovirus (JSRV) is a betaretrovirus which is the causative agent of a contagious lung cancer in sheep, called ovine pulmonary adenocarcinoma.
Human foamy virus (HFV) is a retrovirus in the genus Spumavirus. The spumaviruses are complex and significantly different from the other six genera of retroviruses in several ways. The foamy viruses derive their name from the characteristic ‘foamy’ appearance of the cytopathic effect (CPE) induced in the cells. Foamy virus in humans occurs only as a result of zoonotic infection.
Simian foamy virus (SFV) is a species of the genus Spumavirus that belongs to the family of Retroviridae. It has been identified in a wide variety of primates, including prosimians, New World and Old World monkeys, as well as apes, and each species has been shown to harbor a unique (species-specific) strain of SFV, including African green monkeys, baboons, macaques, and chimpanzees. As it is related to the more well-known retrovirus human immunodeficiency virus (HIV), its discovery in primates has led to some speculation that HIV may have been spread to the human species in Africa through contact with blood from apes, monkeys, and other primates, most likely through bushmeat-hunting practices.
A long terminal repeat (LTR) is a pair of identical sequences of DNA, several hundred base pairs long, which occur in eukaryotic genomes on either end of a series of genes or pseudogenes that form a retrotransposon or an endogenous retrovirus or a retroviral provirus. All retroviral genomes are flanked by LTRs, while there are some retrotransposons without LTRs. Typically, an element flanked by a pair of LTRs will encode a reverse transcriptase and an integrase, allowing the element to be copied and inserted at a different location of the genome. Copies of such an LTR-flanked element can often be found hundreds or thousands of times in a genome. LTR retrotransposons comprise about 8% of the human genome.
Env is a viral gene that encodes the protein forming the viral envelope. The expression of the env gene enables retroviruses to target and attach to specific cell types, and to infiltrate the target cell membrane.
Syncytin-1 also known as enverin is a protein found in humans and other primates that is encoded by the ERVW-1 gene. Syncytin-1 is a cell-cell fusion protein whose function is best characterized in placental development. The placenta in turn aids in embryo attachment to the uterus and establishment of a nutrient supply.
HERV-R_7q21.2 provirus ancestral envelope (Env) polyprotein is a protein that in humans is encoded by the ERV3 gene.
Neutral amino acid transporter B(0) is a protein that in humans is encoded by the SLC1A5 gene.
HERV-K_19q12 provirus ancestral Pol protein is a protein that in humans is encoded by the ERVK6 gene.
Syncytin-2 also known as endogenous retrovirus group FRD member 1 is a protein that in humans is encoded by the ERVFRD-1 gene. This protein plays a key role in the implantation of human embryos in the womb.
Mason-Pfizer monkey virus (M-PMV), formerly Simian retrovirus (SRV), is a species of retroviruses that usually infect and cause a fatal immune deficiency in Asian macaques. The ssRNA virus appears sporadically in mammary carcinoma of captive macaques at breeding facilities which expected as the natural host, but the prevalence of this virus in feral macaques remains unknown. M-PMV was transmitted naturally by virus-containing body fluids, via biting, scratching, grooming, and fighting. Cross contaminated instruments or equipment (fomite) can also spread this virus among animals.
An endogenous viral element (EVE) is a DNA sequence derived from a virus, and present within the germline of a non-viral organism. EVEs may be entire viral genomes (proviruses), or fragments of viral genomes. They arise when a viral DNA sequence becomes integrated into the genome of a germ cell that goes on to produce a viable organism. The newly established EVE can be inherited from one generation to the next as an allele in the host species, and may even reach fixation.
Human endogenous retrovirus K (HERV-K) or Human teratocarcinoma-derived virus (HDTV) is a family of human endogenous retroviruses associated with malignant tumors of the testes. Phylogenetically, the HERV-K group belongs to the ERV2 or Class II or Betaretrovirus-like supergroup. Over the past several years, it has been found that this group of ERVs play an important role in embryogenesis, but their expression is silenced in most cell types in healthy adults. The HERV-K family, and particularly its subgroup HML-2, is the youngest and most transcriptionally active group and hence, it is the best studied among other ERVs. Reactivation of it or anomalous expression of HML-2 in adult tissues has been associated with various types of cancer and with neurodegenerative diseases such as amytrophic lateral sclerosis (ALS). Endogenous retrovirus K (HERV-K) is related to mammary tumor virus in mice. It exists in the human and cercopithecoid genomes. Human genome contains hundreds of copies of HERV-K and many of them possess complete open reading frames (ORFs) that are transcribed and translated, especially in early embryogenesis and in malignancies. One notable location of HERV-K is the C4 gene of RCCX module. HERV-K is also found in apes and Old World monkeys. It is uncertain how long ago in primate evolution the full-length HERV-K proviruses which are in the human genome today were created.
The enzootic nasal tumor virus of the betaretrovirus genus is a carcinogenic retrovirus that causes enzootic nasal adenocarcinoma in sheep and goats. Strain ENTV-1 is found in sheep and strain ENTV-2 is found in goats. The virus causes tumor growth in the upper nasal cavity and is closely related to JSRV which also causes respiratory tumors in ovine. The disease, enzootic nasal adenocarcinoma is common in North America and is found in sheep and goats on every continent except New Zealand and Australia. There are more than 27 betaretroviruses similar to ENVT and JSRV in the ovine genome. In the future, research on ENTV may become important in studying viruses that cause human lung cancer.
Suppressyn (SUPYN) is a protein that in humans is encoded by the ERVH48-1 gene.
↑ Boeke, J. D.; Stoye, J. P. (1997). "Retrotransposons, Endogenous Retroviruses, and the Evolution of Retroelements". In Coffin, J. M.; Hughes, S. H.; Varmus, H. E. (eds.). Retroviruses. Cold Spring Harbor Laboratory Press. PMID21433351.
↑ Voisset; Ceclie; Bedin; Duret (2000). "Chromosomal Distribution and Coding Capacity of the Human Endogenous Retrovirus HERV-W Family". AIDS Research and Human Retroviruses. 16.8 (2000): 731–40. doi:10.1089/088922200308738. PMID10826480. S2CID3048491.
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1 2 Voisset; Bouton; Bedin; Duret; Mandrand; Mallet; Paranhos-Baccalà (2000). "Chromosomal Distribution and Coding Capacity of the Human Endogenous Retrovirus HERV-W Family". AIDS Research and Human Retroviruses. 16 (8): 731–740. doi:10.1089/088922200308738. PMID10826480. S2CID3048491.
↑ Mi, S; Lee, X; Li, X-P; Veldman; Finnerty; Racie; LaVallie; Tang; Edouard; Howes; Keith; McCoy (2000). "Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis". Nature. 403 (6771): 785–789. Bibcode:2000Natur.403..785M. doi:10.1038/35001608. PMID10693809. S2CID4367889.
↑ Muir, A.; Lever, A.; Moffett, A. (2004). "Expression and functions of human endogenous retroviruses in the placenta: An update". Placenta. 25 Suppl A: S16-25. doi:10.1016/j.placenta.2004.01.012. PMID15033302.
1 2 Rolland, A; Jouvin-Marche, E; Saresella, M; Ferrante, P; Cavaretta, R; Creange, A; Marche, P; Perron, H (March 2005). "Correlation between disease severity and in vitro cytokine production mediated by MSRV (multiple sclerosis associated retroviral element) envelope protein in patients with multiple sclerosis". Neuroimmunology. 160 (1–2): 195–203. doi:10.1016/j.jneuroim.2004.10.019. PMID15710473. S2CID42118010.
↑ Firestein, Gary; Budd, Ralph; Sherine, E (2005). Kelly and Firestein's Textbook of Rheumatology. ISBN978-0721601410.
1 2 Perron, H.; Lazarini, F.; Ruprecht, K.; Péchoux-Longin, C.; Seilhean, D.; Sazdovitch, V.; Créange, A.; Battail-Poirot, N.; Sibaï, G.; Santoro, L.; Jolivet, M.; Darlix, J. L.; Rieckmann, P.; Arzberger, T.; Hauw, J. J.; Lassmann, H. (2005). "Human endogenous retrovirus (HERV)-W ENV and GAG proteins: Physiological expression in human brain and pathophysiological modulation in multiple sclerosis lesions". Journal of Neurovirology. 11 (1): 23–33. doi:10.1080/13550280590901741. PMID15804956. S2CID37490334.
↑ Antony, J. M.; Ellestad, K. K.; Hammond, R.; Imaizumi, K.; Mallet, F.; Warren, K. G.; Power, C. (2007). "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 of Immunology. 179 (2): 1210–24. doi:10.4049/jimmunol.179.2.1210. PMID17617614.
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