It is believed that HERVs are the result of ancient viral infections. A number of HERVs have maintained some functionality and still contain intact open reading frames (ORF’s) which code for fully functional proteins. HERV-W is one of these endogenous retroviruses. Over the last few years several research projects have suggested that HERV-W may be involved with multiple sclerosis, bipolar disorder, schizophrenia, autism, and various tumors. The presence of HERV-W RNAs, proteins, and virions has been detected in association with these diseases.

1. Human Endogenous Retrovirus-W
HERV-W
Kevin B. Hugins
BIOL409-Virology
Nevada State College
Summer 2014

2. Viruses have been indirectly implicated in many complex human diseases. These include
cancers such as cutaneous T-cell lymphoma (CTCL), neurological disorders such as
schizophrenia (SZ) and bipolar disorder (BP), and autoimmune diseases such as multiple
sclerosis (MS). Research has shown that viruses including cytomegalovirus (CMV), Epstein-
Barr virus (EBV), and influenza viruses show a positive correlation with many of these diseases.
However, in many instances, researchers were unable to understand the precise relationship these
common viruses had with more complex diseases. For example, even though multiple studies
had suggested that EBV played a role in the onset of MS, researchers had been unable to prove
exactly how the two are connected.
When one thinks of viruses, the image that is generally conjured is infectious microscopic
particles that closely resemble the lunar lander that cause diseases such as herpes, AIDS,
hepatitis, or colds. Very few people would imagine viruses that exist persistently in their very
own chromosomes which they will pass down to future generations. Human Endogenous
Retroviruses (HERVs) are precisely that. Approximately 8% of DNA in the human genome is
viral DNA. These elements of human chromosomes include env, pol, and gag genes like those
found in exogenous retroviruses such as human immunodeficiency virus (HIV) and human T-cell
leukemia virus (HTLV).5
Env codes for retroviral coat proteins, pol for reverse transcriptase,
protease, and integrase, and gag codes for group specific antigens which include the structural
proteins of the virus. The human genome is littered with these viral genes.
It is believed that HERVs are the result of ancient viral infections. Retroviruses found
their way into germ cells of our ancestors and ultimately incorporated their DNA into egg or
sperm cells. The viral DNA was then able to replicate and transpose repeatedly in the human
genome, resulting in multiple copies of the virus’s genes spread throughout our chromosomes.

3. As evolution has progressed, most of these HERVs have mutated to the point that they are
unable to function or replicate properly due to nonsense mutations or major deletions. This has
not rendered HERVs benign however. HERVs that are not fully functional can still have
deleterious effects if they are integrated close to promoters or enhancers of functional genes.2
A number of HERVs have maintained some functionality and still contain intact open
reading frames (ORF’s) which code for fully functional proteins.8
HERV-W is one of these
endogenous retroviruses. Over the last few years several research projects have suggested that
HERV-W may be involved with multiple sclerosis, bipolar disorder, schizophrenia, autism, and
various tumors. The presence of HERV-W RNAs, proteins, and virions has been detected in
association with these diseases.5
Typically, HERV genes that code for functional proteins are
kept methylated and tightly bound up around histones to prevent their transcription and
translation. However, research has shown that these genes can become activated resulting in the
production of viral DNA/RNA and proteins which can be detected in our bodies just like the
DNA/RNA and proteins of “traditional” viruses can be.
HERV-W’s role in MS is the most studied and best understood. In 1987, Herve Perron, a
graduate student at Grenoble University in France, decided to take a new approach in
investigating the causes of MS. At that time, scientists felt that a virus was responsible for the
disease. Researchers had investigated EBV, CMV, HTLV and herpes hoping to identify the
virus that causes brain lesions associated with the MS. All those studies had left researchers
empty handed. Perron extracted cerebral spinal fluid from the spinal columns of multiple
sclerosis patients. Then, rather than try to track down a specific virus, Perron tested the spinal
fluid for the presence of reverse transcriptase in an attempt to work backward to ultimately
identify the cause of the disease. After 10 years of exhaustive research, Perron located and

4. identified the retrovirus responsible for MS. That virus was not one that invaded the patient
from the outside. That virus was HERV-W, a retrovirus that each of us has dozens of copies of
within our own genome.4
Now that Perron had shown that MS was caused by a virus that all of us have inside us,
researchers next had to discover what activated HERV-W. At that time EBV was thought to
play a role in MS. A history of late infectious mononucleosis and high levels of anti-EBV
antibodies are factors that increase the risk of MS onset. However, EBV could be latent in the
patient and anti-EVB levels could fall to levels similar to that of non-MS subjects while the
patient’s MS continued to progress. Mameli et al. have since shown that HERV-W env proteins
and RNA are consistently present in high levels in MS patients and fluctuations in HERV-W
protein and RNA levels have been shown to parallel disease behavior of progressing MS stages
and active or remission phases of the disease.10
During their research, Mameli et al. discovered how HERV-W linked EBV to MS. They
found that HERV-W is activated in blood mononuclear cells of infectious mononucleosis
patients.10
EBV was necessary to activate HERV-W. EBV was a factor in the onset of MS but
was not required to remain active for the condition to progress.
The understanding of HERV-W’s involvement in MS has potentially answered another
question about the development of the disease. MS strikes women at a rate of 2:1 over men. A
complete copy of HERV-W is located on chromosome 7. That copy is generally the one
implicated in HERV-W activation. However, a copy of HERV-W with an almost complete open
reading frame resides on the X chromosome, at Xq22.3. Garcia-Montojo et al. found that there
are 3 polymorphisms of that HERV-W copy. Their research showed that one of those

5. polymorphisms was associated with higher susceptibility and severity of MS in women in their
study.5
This suggests that even an incomplete gene sequence of HERV-W can exert a biological
effect.
Around the same time Perron was investigating MS, Fuller Torrey at The National
Institute of Mental Health in Washington DC, and Robert Yolken at John Hopkins University,
began to investigate possible viral causes for schizophrenia.4
As was the case with MS, Torrey
and Yolken found that most schizophrenics had antibodies against EBV and CMV but did not
have active infections. They began to approach their research the same way Perron did,
searching for reverse transcriptase rather than trying to prove certain viruses were responsible for
the condition. In 2001 they found HERV-W was the culprit.
Huang et al. found that HERV-W retroviral pol genes and DNA/RNA were found in the
plasma and cerebral spinal fluid in just over 1/3 of subjects with recent-onset schizophrenia. No
HERV-W associated genes or proteins were detected in the plasma or CSF of the control
subjects. Their study also suggested that HERV-W increased promoter activation of genes
BDNF, NTRK2 and DRD3. Increased expression of these genes contributes to the onset of
schizophrenia.7
Recent studies by Perron et al. show a correlation between HERV-W and
schizophrenia as well as bipolar disorder. They also found that HERV-W can be activated by T.
gondii and influenza virus.11
Dysfunction of GABA receptors has been implicated in schizophrenia. Hegyi et al.
found that in postmortem studies of the brains of schizophrenics and autistic patients, GABBR1
on chromosome 6 was down regulated. An HERV-W gene is located in the regulatory region of
GABBR1. It is hypothesized that hyper methylation of the HERV-W region in response to halt

6. its expression also affected GABBR1 expression, resulting in down regulation of that gene also.6
Balestrieri et al. also found a correlation between HERV-W and autism spectrum disorders.2
They too suggested that DNA methylation associated with HERV-W genes may contribute to the
development of autism spectrum disorders.
Maliniemi et al. investigated the correlation between mycosis fungoides (MF) and
HERV-W. MF is the most common type of primary cutaneous T-cell lymphoma (CTCL).
Biopsies were taken from the lesions of patients with MF, unaffected regions of skin from those
same patients, and the same locations from unaffected control subjects. The MF biopsies
showed significantly increased HERV-W transcription over the other two types of samples in all
patients. The transcribed HERV-W loci were found in chromosomes 6q21 and 7q21.2, regions
typically altered in CTCL.9
Assinger et al. found that human cytomegalovirus (HCMV) and
HERV-W are present together in many cancers including glioblastoma, neuroblastoma, and
breast and prostate cancer.1
Their research showed a direct correlation between levels of HCMV
and HERV-W in tumors. If HCMV levels went up, HERV-W did as well.
Study after study has shown that HERV-W is implicated in multiple human diseases and
disorders. In each instance, an inflammatory immune response resulting from a viral or bacterial
co-infection has been responsible for activating HERV-W. However, as is the case with most
viruses, HERV-W has some unexpected tricks up its sleeve.
Liu et al. found that caffeine and aspirin could increase the expression of HERV-W env
and gag in human neuroblastoma cells and caffeine could even activate the HERV-W env
promoter.8
Diem et al. found that valproic acid, which is typically prescribed for seizures and
mood disorders, significantly increased HERV-W transcription.3

7. In spite of HERV-W’s role in so many diseases, without it, humans would not exist.
HERV-W env glycoprotein gene codes for syncytin-1. Syncytin-1 is vital in fetal cellular
differentiation creating syncytiotrophoblasts which are responsible for anchoring fetal cells to
maternal cells in the placenta.13
HERV-W env also has an immunosuppressive region. It is
believed that this plays a role in preventing the rejection of fetal cells by the mother’s immune
system.12
When the human genome was first mapped and studied, due to characteristics like long
terminal repeats, genes such as HERV-W were considered junk DNA. As research techniques
have advanced, scientists have progressively found more and more functions, some positive,
some pathogenic, of HERV-W. As research continues to move forward and our understanding
of genetics advances, researchers will most certainly find that other areas of endogenous viral
DNA which play a role in human health and development.

8. Works Cited
1. Assinger, A., Yaiw, K., Göttesdorfer, I., Leib-Mösch, C., & Söderberg-Nauclér, C. (2013). Human
Cytomegalovirus (HCMV) Induces Human Endogenous Retrovirus (HERV) Transcription.
Retrovirology, 10(1), 132. Doi: 10.1186/1742-4690-10-132
2. Balestrieri, E., Arpino, C., Matteucci, C., Sorrentino, R., Pica, F., Alessandrelli, R., ... Sinibaldi-
Vallebona, P. (2012). HERVs Expression in Autism Spectrum Disorders (G. M. Mcalonan,
Ed.). PLoS ONE, 7(11), E48831. Doi: 10.1371/journal.pone.0048831
3. Diem, O., Schäffner, M., Seifarth, W., & Leib-Mösch, C. (2012). Influence of Antipsychotic Drugs on
Human Endogenous Retrovirus (HERV) Transcription in Brain Cells (K. Hashimoto, Ed.).
PLoS ONE, 7(1), E30054. Doi: 10.1371/journal.pone.0030054
4. Fox, D. (2010, June). The Insanity Virus. Discover. Retrieved from
Http://discovermagazine.com/2010/jun/03-the-insanity-virus
5. García-Montojo, M., Hera, B. D., Varadé, J., Encarnación, A. D., Camacho, I., Domínguez-Mozo, M.,
... Alvarez-Lafuente, R. (2014). HERV-W Polymorphism in Chromosome X Is Associated
with Multiple Sclerosis Risk and with Differential Expression of MSRV. Retrovirology, 11(1),
2. Doi: 10.1186/1742-4690-11-2
6. Hegyi, H. (2013). GABBR1 Has a HERV-W LTR in Its Regulatory Region – a Possible Implication
for Schizophrenia. Biology Direct, 8(1), 5. Doi: 10.1186/1745-6150-8-5
7. Huang, W., Li, S., Hu, Y., Yu, H., Luo, F., Zhang, Q., & Zhu, F. (2011). Implication of the Env Gene
of the Human Endogenous Retrovirus W Family in the Expression of BDNF and DRD3 and
Development of Recent-Onset Schizophrenia. Schizophrenia Bulletin, 37(5), 988-1000. Doi:
10.1093/schbul/sbp166
8. Liu, C., Chen, Y., Li, S., Yu, H., Zeng, J., Wang, X., & Zhu, F. (2013). Activation of Elements in
HERV-W Family by Caffeine and Aspirin. Virus Genes, 47(2), 219-227. Doi:
10.1007/s11262-013-0939-6
9. Maliniemi, P., Vincendeau, M., Mayer, J., Frank, O., Hahtola, S., Karenko, L., ... Ranki, A. (2013).
Expression of Human Endogenous Retrovirus-W Including Syncytin-1 in Cutaneous T-Cell
Lymphoma (M. Schindler, Ed.). PLoS ONE, 8(10), E76281. Doi:
10.1371/journal.pone.0076281
10. Mameli, G., Madeddu, G., Mei, A., Uleri, E., Poddighe, L., Delogu, L. G., ... Dolei, A. (2013).
Activation of MSRV-Type Endogenous Retroviruses during Infectious Mononucleosis and
Epstein-Barr Virus Latency: The Missing Link with Multiple Sclerosis? (J. P. Stewart, Ed.).
PLoS ONE, 8(11), E78474. Doi: 10.1371/journal.pone.0078474
11. Perron, H., Hamdani, N., Faucard, R., Lajnef, M., Jamain, S., Daban-Huard, C., ... Leboyer, M.
(2012). Molecular Characteristics of Human Endogenous Retrovirus Type-W in Schizophrenia
and Bipolar Disorder. Translational Psychiatry, 2(12), E201. Doi: 10.1038/tp.2012.125
12. Noorali, S., Rotar, I. C., Lewis, C., Pestaner, J. P., Pace, D. G., Sison, A., & Bagasra, O. (2009). Role
of HERV-W Syncytin-1 in Placentation and Maintenance of Human Pregnancy. Applied
Immunohistochemistry & Molecular Morphology, 17(4), 319-328. Doi:
10.1097/PAI.0b013e31819640f9
13. Sugimoto, J., & Schust, D. J. (2009). Review: Human Endogenous Retroviruses and the Placenta.
Reproductive Sciences, 16(11), 1023-1033. Doi: 10.1177/1933719109336620