Human endogenous retrovirus-W
 | This article may be too technical for most readers to understand. (November 2016) |
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| Human endogenous retrovirus W | |
|---|---|
Virus classification 
| |
| (unranked): | Virus |
| Realm: | Riboviria |
| Kingdom: | Pararnavirae |
| Phylum: | Artverviricota |
| Class: | Revtraviricetes |
| Order: | Ortervirales |
| Family: | Retroviridae |
| Genus: | Gammaretrovirus (?) |
| (unranked): | Human endogenous retrovirus W |
Human Endogenous Retrovirus-W (HERV-W) is a family of Human Endogenous Retroviruses, or
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 like
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.[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 vertically from parent to child.[3] 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.[citation needed]
Performing
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’ LTR have followed independent evolution in each species.[citation needed]
HERV-W is named for the fact that many in the group use a
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 of 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 discovered is 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 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.[10] This was confirmed by Ppol-MSRV, gag and env probes.[10]
Performing a
With
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
As a control a gene known to be
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), 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 cell 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
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.[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
Analyzing 40 full-term placental tissues with
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.[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 and/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 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.[25] 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.[citation needed]
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.[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-y, 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 a NF-κB element.[26] Final putative mechanisms of control of ERVWE-1 are 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 heighted 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 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.[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 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.[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 triggering the immune response.[32] 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.[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
Finally, it was discovered through
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
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
A contrasting study performed a
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 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 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.[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
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
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]
On Jan 2019 the drug GNbAC1 was granted the name Temelimab by the World Health Organization (WHO)[39]
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