Human Endogenous Retrovirus

Kevin B. HuginsBIOL409-Virology

Nevada State CollegeSummer 2014

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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

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

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

Multiple Sclerosis1987- 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 patientso 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 viruso 1997 HERV-W was identified as the virus causing MS

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

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

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

http://schizophreniabulletin.oxfordjournals.org/content/37/5/988/F11.expansion.html

SchizophreniaHuang 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

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 downregulationBalestrieri et al.● Also found correlation between HERV-W and ASD

○ Suggested DNA methylation associated with HERV-W contributes to ASD development

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

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

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……..

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http://www.nature.com/nature/journal/v403/n6771/fig_tab/403715a0_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

HERV-W

Can’t live with it……

Can’t live without it…..

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: 10.1186/1742-4690-10-1322.  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.00488313.  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.00300544.  Fox, D. (2010, June). The Insanity Virus. Discover. Retrieved from Http://discovermagazine.com/2010/jun/03-the-insanity-virus5.  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: 10.1186/1742-4690-11-26.  Hegyi, H. (2013). GABBR1 Has a HERV-W LTR in Its Regulatory Region – a Possible Implication for Schizophrenia. Biology Direct, 8(1), 5. Doi: 10.1186/1745-6150-8-57.  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/sbp1668.  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/s11262-013-0939-69.  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.007628110. 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.007847411. 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.2012.12512. 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.0b013e31819640f913. Sugimoto, J., & Schust, D. J. (2009). Review: Human Endogenous Retroviruses and the Placenta. Reproductive Sciences, 16(11), 1023-1033. Doi: 10.1177/1933719109336620