Epstein-Barr virus

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The Epstein-Barr virus (EBV) or HHV4 is a herpesvirus. It infects 90% of adults worldwide.[1]

Initial infection[edit]

Age of infection[edit]

Typically young children who acquire EBV are either not symptomatic or have mild symptoms that are hard to distinguish from other mild, brief childhood illnesses. In adolescents and young adults, EBV can cause mononucleosis, also known as glandular fever.[2]

Several studies by Alberto Ascherio, MD, DrPH, and his team at the Harvard School of Public Health have suggested that Epstein-Barr virus is involved in multiple sclerosis, specifically in people with a certain immune-related gene and high levels of antibodies to EBV in their blood.[3]

Latency[edit]

In most adults, the virus remains latent for life in B cells. It is estimated that 1 in every one hundred thousand to one million circulating B cells carry EBV.[4] In healthy hosts, EBV populations are kept in check by CD4+ and CD8+ T-cell responses.

The equilibrium can be disrupted in individuals with compromised immune systems such as patients with AIDS or transplant patients taking immune system suppressing drugs.[5] It has been observed that these patients are more susceptible to EBV-related cancers, such as certain lymphomas and carcinomas.[6]

Natural killer T cells[edit]

It is thought that natural killer T cells (NKT) play a pivotal role in the control of EBV-infected B cells through their recognition of CD1d expressing cells.[7]

Neuronal infection[edit]

A 2015 study[8] demonstrated that human neuronal cells could be directly and actively infected with EBV and another herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV).

Neuronal cells were infected with EBV or KSHV viruses which had been combined with a fluorescent protein so that the infection could be observed. The infection was seen to produce new virus cells (productive) and spread efficiently. Significantly, it not only infected surrounding neuronal cells but also nearby peripheral blood mononuclear cells.

EBV is known to be linked to many neuronal diseases[9] but this is the first evidence of how this may occur. The researchers note that this research supports the presence of EBV in neuronal diseases, but does not indicate why this is so.

In human disease[edit]

Epstein-Barr virus may play a role in a wide number of diseases including Chronic fatigue syndrome, multiple sclerosis, and myasthenia gravis.

Chronic fatigue syndrome[edit]

A prospective study of 250 primary care patients revealed a higher prevalence of chronic fatigue syndrome after infectious mononucleosis (glandular fever) when compared to an ordinary upper respiratory tract infection.[10] Anti-early antigen titers to EBV were elevated in CFS patients and associated with worse symptoms.[11]

In 2016, a study by Williams, et al, looked at lytic proteins produced during reactivation of the Epstein-Barr virus, in particular the deoxyuridine triphosphate nucleotidohydrolases (dUTPase), as key modulators of the host innate and adaptive immune responses. They considered "the possibility that two or more herpesviruses may act synergistically and that virus-encoded proteins, rather than the viruses themselves, may act as drivers of or contribute to the pathophysiological alterations observed in a subset of patients with ME/CFS."[12]

Multiple sclerosis[edit]

Infection later in life, high serum titers against EBV, and mononucleosis have all been associated with an increased risk of multiple sclerosis. MS relapses are correlated with EBV reactivation.[13]

Myasthenia gravis[edit]

B cells from myasthenia gravis patient stimulated in vitro by Epstein-Barr virus produced acetylcholine autoantibodies.[14] Ongoing EBV infection of the thymus has been posited as a causative agent for the production of acetylcholine receptor autoantibodies in myasthenia gravis.[15][16]

Lyme Disease[edit]

Several herpesviruses including Epstein-Barr virus[17] may cause false positives on Lyme Disease tests.

X-MEN Disease[edit]

A 2014 study found chronic Epstein-Barr infection was linked to a magnesium transporter(MAGT-1) mutation. Dysfunction in this transporter also resulted in decreased NK cell function, and neoplasia (sometimes-cancerous growths). [18] This disorder, termed 'X-MEN' (for X-linked, EBV, and neoplasia) was identified as a recessive, X-linked disorder that would therefore be many times more common in men.

Since chronic Epstein-Barr virus infection has been associated with chronic fatigue syndrome, this error in magnesium transport may be worth considering in male patients, especially with slow onset and history of childhood infection.[18][19] However, in this disorder, EBV would be seen as an indicator of the illness rather than the cause.

Vitamin D[edit]

Some recent research is finding links between EBV and Vitamin D

An Epstein-Barr virus protein EBNA-3 has an affinity for VDR and may actually block the activation of VDR-dependent genes by Vitamin D.[20]

Vitamin D receptor may be required for the normal development of natural killer T cells that react to cells expressing CD1d, as in cells infected by EBV.[21]

As low Vitamin D is also a risk factor for MS, some studies have attempt to find a link between low Vitamin D status, EBV and MS. One study of healthy individuals found no link between EBV load and Vitamin D status. However, over half the subjects were Vitamin D deficient and none had optimal levels[22] (i.e., above 100 nmol/l)

Treatment[edit]

Epstein-barr is thought to persistent harmlessly in immunocompetent individuals but in those with compromised immune systems has been associated with certain cancers and possibly autoimmune disease.

Antivirals[edit]

Several antivirals are active against EBV including valganciclovir and spironolactone[23].

Acyclovir, an antiviral drug which inhibits (but does not destroy) herpesviruses, was shown to also inhibit the virus production. This suggests that EBV replicates via lytic replication.

A theoretical immunotherapy treatment proposes that inducing CD1d expression on EBV-infected B cells could prompt effective immune suppression of EBV by NKT cells.[24]

Rituximab[edit]

Rituximab may be effective in completely eliminated Epstein-Barr virus infection from the peripheral blood.[25] A study of seventeen patients with low-grade B cell lymphoma found that after three cycles of Rituximab, the virus had been completely eliminated from the peripheral blood in all but one patient.

Herbs[edit]

Herbs shown to have antiviral properties against EBV include licorice[26], X, and X.

References[edit]

  1. Saha, Abhik; Robertson, Erle S (2011-05-15), "Epstein-Barr Virus–Associated B-cell Lymphomas: Pathogenesis and Clinical Outcomes", Clinical Cancer Research, 17 (10): 3056–3063, ISSN 1557-3265, PMID 21372216, doi:10.1158/1078-0432.CCR-10-2578 
  2. http://www.cdc.gov/epstein-barr/about-ebv.html
  3. http://www.nationalmssociety.org/What-is-MS/What-Causes-MS/Viruses
  4. http://www.ncbi.nlm.nih.gov/pubmed/10781747/
  5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063158/
  6. http://www.ncbi.nlm.nih.gov/pubmed/17049016
  7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063158/
  8. Jha, HC; Mehta, D; et al. (2016-12-01), "Gammaherpesvirus Infection of Human Neuronal Cells", mBio, 6 (6), PMID 26628726, doi:10.1128/mBio.01844-15 
  9. Kleines, M; Schiefer, J; Stienen, A; Blaum, M; Ritter, K; Häusler, M (2011-05-15), "Expanding the spectrum of neurological disease associated with Epstein-Barr virus activity", European Journal of Clinical Microbiology & Infectious Diseases, 30 (12): 1561–1569, ISSN 1435-4373, doi:10.1007/s10096-011-1261-7 
  10. http://www.ncbi.nlm.nih.gov/pubmed/9926075
  11. http://www.ncbi.nlm.nih.gov/pubmed/8730646
  12. Williams, Marshall V.; Cox, Brandon; Ariza, Maria Eugenia (2017), "Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP) Proteins with Implications for Human Disease", Pathogens, 6 (1): 2, doi:10.3390/pathogens6010002 
  13. www.sciencedirect.com/science/article/pii/S0306987707003167
  14. http://www.ncbi.nlm.nih.gov/pubmed/2553772
  15. http://www.academia.edu/20258853/Epstein-barr_virus_Trigger_for_autoimmunity/
  16. http://journals.lww.com/neurologynow/_layouts/15/oaks.journals.mobile/post.aspx?blogId=2&postId=10
  17. Goossens, HA; Nohlmans, MK; van den Bogaard, AE, "Epstein-Barr virus and cytomegalovirus infections cause false-positive results in IgM two-test protocol for early Lyme borreliosis", Infection, 27:231 (1999), PMID 10378140 
  18. 18.0 18.1 Li, F.-Y.; Chaigne-Delalande, B; Su, H; Matthews, H; Lenardo, M.J. (2014), "XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus.", Blood, doi:10.1182/blood-2013-11-538686 
  19. Ravell, J; Chaigne-Delalande, B; Lenardo, M (2014), "XMEN disease: a combined immune deficiency with magnesium defect.", Current Opinion in Pediatrics, doi:10.1097/MOP.0000000000000156 
  20. http://www.ncbi.nlm.nih.gov/pubmed/20593215
  21. http://www.pnas.org/content/105/13/5207.short
  22. http://www.ncbi.nlm.nih.gov/pubmed/24192216?dopt=Abstract
  23. Verma, Dinesh; Thompson, Jacob; Swaminathan, Sankar (2016-03-29), "Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function", Proceedings of the National Academy of Sciences, 113 (13): 3609–3614, ISSN 1091-6490, PMID 26976570, doi:10.1073/pnas.1523686113 
  24. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063158/
  25. http://www.ncbi.nlm.nih.gov/pubmed/24324119
  26. http://www.ncbi.nlm.nih.gov/pubmed/18423902


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From MEpedia, a crowd-sourced encyclopedia of ME and CFS science and history