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. This power point presentation was created to be used in conjunction with the associated paper.

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

2. http://microproject.jjht.org/wp-content/uploads/2012/12/Virus-Shapes.jpg
Viruses have been indirectly implicated in complex diseases such as:
● Multiple Sclerosis
● Schizophrenia
● Cutaneous T-Cell Lymphoma
● Diabetes Mellitus
● etc.
A positive correlation
has been shown
between the onset of
these diseases and
common viruses such
as:
● Cytomegalovirus
● Epstein-Barr virus
● Influenzavirus

3. What If A Retrovirus Were To Infect A Germ Cell?
Human Endogenous Retroviruses (HERVs) are believed to be the result of
ancient viral infections of germ cells that ultimately led to the viral DNA
being incorporated into the host sperm or ovum.
● Approximately 8% of human genome is composed of HERVs
● Include viral env, pol, and gag genes
● Most are nonfunctional due to:
○ Nonsense mutations
○ Major Deletions
● HERVs with intact open reading frames (ORFs) can have functionality
○ Expression typically supressed by histone methylation
● Can be activated
○ HERV DNA, RNA and proteins detected in blood and spinal fluid

4. HERV-W
Has been associated with:
● Multiple Sclerosis (MS)
● Schizophrenia (SZ)
● Bipolar Disorder (BD)
● Autism Spectrum Disorders (ASD)
● Cutaneous T-Cell Lymphoma (CTCL)
● Diabetes Mellitus
● Rheumatoid Arthritis
● Various Tumors

5. Multiple Sclerosis
1987- Herve Perron- Grenoble University France
● Researchers suspected a virus was responsible for brain lesions in MS
patients. Research involving several viruses led to dead ends.
o Epstein-Barr Virus (EBV)
o Cytomegalovirus (CMV)
o Human T-Cell Leukemia Virus (HTLV)
o Human Herpes Virus (HHV)
● Perron analyzed spinal fluid of patients
o Rather than look for a specific virus, Perron looked for reverse
transcriptase (RT) to identify any virus whether known or not yet
known to science
o When RT was detected, Perron worked backward to identify virus
o 1997 HERV-W was identified as the virus causing MS

6. Additional MS Research
EBV factors linked to MS onset
● Late infectious mononucleosis (IM)
● High levels of anti-EBV immunoglobulins
○ Anti-EBV did not remain constant after MS established
Mameli et al.
● Elevated HERV-W env and RNA levels throughout disease
○ Levels paralleled MS progression in active or remission phases
● Found that HERV-W was activated in blood mononuclear cells
during IM.
○ The missing link between EBV and MS

7. Additional MS Research
Garcia-Montojo et al.
● MS strikes women at a rate of 2:1 over men
● Copy of HERV-W located on X chromosome
○ Contains almost complete ORF
○ 3 polymorphisms of gene at that location
■ One of those was associated with higher susceptibility and
severity of MS in women that were homozygous for that
polymorphism

8. Schizophrenia
1980’s: Fuller Torrey- National Institute of Mental Health, Washington DC
Robert Yolken- John Hopkins University
● Suspected SZ had viral causes
○ All patients had anti-EBV and anti-CMV immunoglobulins
■ None had current infections
● Like Perron looked for reverse transcriptase in plasma and spinal fluid
● 2001 identified HERV-W

9. http://schizophreniabulletin.oxfordjournals.org/content/37/5/988/F11.expansion.html
Schizophrenia
Huang et al.
● HERV-W retroviral pol genes and DNA/RNA found in plasma and spinal
fluid of ⅓ of subjects with recent onset SZ
○ None in any of the control subjects
● HERV-W increased promoter
activation of genes:
○ BDNF
○ NTRK2
○ DRD3
● Increased expression of
those genes contribute to
onset of SZ

10. Schizophrenia and Autism Spectrum Disorders
Dysfunction of GABA receptors is implicated in many neurological and
psychiatric disorders.
Hegyi et al.
● Postmortem studies of brains of SZ and ASD patients
○ GABBR1 on chromosome 6 downregulated
○ HERV-W gene located in regulatory region of GABBR1
○ Hypothesized that hypermethylation of HERV-W region as a
response to halt its expression resulted in GABBR1 downregulation
Balestrieri et al.
● Also found correlation between HERV-W and ASD
○ Suggested DNA methylation associated with HERV-W contributes to
ASD development

11. Cancer
Maliniemi et al.
● Mycosis Fungoides (MF)
○ Most common type of CTCL
● Biopsies taken from
○ MF lesions of patients
○ Unaffected skin regions of patients
○ Same locations in control subjects
● HERV-W transcription in lesions significantly higher than other samples
Assinger et al.
● CMV and HERV-W present together in many cancers
○ glioblastoma, neuroblastoma, breast and prostate cancer
● If CMV levels rose, HERV-W levels rose as well

12. Other Substances That Increase HERV-W Transcription
Liu et al.
● Caffeine and aspirin increases expression of HERV-W env and gag
● Caffeine can activate HERV-W env promoter
Diem et al.
● Valproic acid (prescribed for seizures and mood disorders)
increases HERV-W transcription
Noorali et al.
● Progesterone significantly upregulates HERV-W env expression

13. With so many diseases associated with HERV-W
scientists should focus on a way to permenantly block
transcription of the virus.
Before they do that, they must first learn how to do
this……..

14. http://www.annegeddes.com/wp-content/gallery/until-now/ekc182t_x.jpg

15. http://www.nature.com/nature/journal/v403/n6771/fig_tab/403
715a0_F1.html#figure-title
HERV-W env codes for Syncytin-1
● Vital in fetal cellular differentiation
○ Trophoblast
Syncytiotrophoblast
○ Anchors fetal cells to maternal
cells in placenta
● Also has an immunosuppressive
region
○ Prevents rejection of fetal cells by
mother’s immune system

16. HERV-W
Can’t live with it……
Can’t live without it…..

17. 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