Epstein-Barr virus

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The Epstein-Barr virus (EBV) or HHV4 is a herpesvirus. It is the most common cause of infectious mononucleosis or "glandular fever," and infects 90% of adults worldwide.[1] It has been implicated in numerous immune diseases and chronic illnesses, including chronic fatigue syndrome, multiple sclerosis, myasthenia gravis, and systemic lupus erythematosus. It is known to turn on "risk genes" for autoimmune disease in the cells it infects.[2][3]

Initial infection[edit | edit source]

A stained sample of Epstein-Barr virus.

Symptoms of EBV infection include:

Age of infection[edit | edit source]

Most people acquire EBV in early childhood. Typically, young children who acquire EBV are either not symptomatic or have mild symptoms that are hard to distinguish from a cold or other other mild, childhood illnesses.

In adolescents and young adults, EBV can cause infectious mononucleosis (IM), also known as glandular fever.[4] IM is characterized by fever, sore throat, swollen lymph nodes, body aches, and fatigue. It generally resolves with rest and only rarely causes serious complications. It typically occurs in people who have not been exposed to EBV in early childhood, and in comparison, is more severe than infection in childhood (i.e., it can last for months).

Following initial infection, EBV can reactivate and has been shown to have many connections with various chronic illnesses. Relative to initial infections, reactivated EBV is much more severe.

Transmission[edit | edit source]

EBV is transmitted through bodily fluids, most commonly through saliva. The first time a person is infected with EBV, the person is contagious for weeks (even when not displaying symptoms). The virus then transitions to the latent or inactive form, and stays in the body. If the virus reactivates, the person will be contagious again.[4]

Diagnosis[edit | edit source]

EBV infection is confirmed with blood tests that detect presence of antibodies. Nine out of ten adults have these antibodies, indicating that they have a current or past EBV infection.[4]

Latency[edit | edit source]

In healthy adults, the virus remains latent for life in memory B cells. It is estimated that 1 in every one hundred thousand to one million circulating B cells carry EBV.[5] 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.[6] It has been observed that these patients are more susceptible to EBV-related cancers, such as certain lymphomas and carcinomas.[7] In immunocompromised patients, EBV can induce lymphoproliferation, lymphoma, and hemophagocytic lymphohistiocytosis (HLH).[8]

Natural killer T cells[edit | edit source]

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.[6]

Neuronal infection[edit | edit source]

A 2015 study[9] 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[10] 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 | edit source]

Epstein-Barr virus has been associated with a wide number of immune diseases including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus,[11]Chronic fatigue syndrome, and myasthenia gravis. EBV was recently discovered to turn on "risk genes" for autoimmune disease in the cells it infects. EBNA2, a protein produced by EBV-infected cells, and its related transcription factors activate half the human genes known to be associated with the risk for lupus as well as genes associated with several other autoimmune diseases including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease. EBV activation can thus increase the risk of developing these diseases.[2][3]

Chronic fatigue syndrome[edit | edit source]

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.[12] Anti-early antigen titers to EBV were elevated in CFS patients and associated with worse symptoms.[13] A 2006 Australian prospective study found that 11% of subjects infected by EBV met the criteria for Chronic fatigue syndrome six months after their infection. (The same rate held true for Ross River virus and Q fever).Cite error: The opening <ref> tag is malformed or has a bad name

Multiple sclerosis[edit | edit source]

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.[14]

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.[15]

Systemic lupus erythematosus[edit | edit source]

In a study of young patients with lupus, 99% had EBV as compared to 70% of healthy controls.[16] Another study found that patients with SLE had an ∼40-fold increase in EBV viral loads compared with controls, likely stemming from altered t cell responses against EBV.[17]

Myasthenia gravis[edit | edit source]

B cells from myasthenia gravis patient stimulated in vitro by Epstein-Barr virus produced acetylcholine autoantibodies.[18] Ongoing EBV infection of the thymus has been posited as a causative agent for the production of acetylcholine receptor autoantibodies in myasthenia gravis.[19][20]

Gastrointestinal disease[edit | edit source]

One study of EBV in patients with gastritis, Crohn's disease, and ulcerative colitis and normal controls found essentially undetectable levels of EBV in normal gastric mucosa. However, EBV was detected in 46% of gastritis lesions, 44% of normal colonic mucosa, 55% of Crohn’s disease, and 64% of ulcerative colitis samples.[21]

Lyme disease[edit | edit source]

Several herpesviruses including Epstein-Barr virus[22] may cause false positives on Lyme disease tests.

X-MEN Disease[edit | edit source]

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).[23] 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.[23][24] However, in this disorder, EBV would be seen as an indicator of the illness rather than the cause.

Vitamin D[edit | edit source]

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.[25]

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.[26]

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[27] (i.e., above 100 nmol/l).

Treatment[edit | edit source]

There is no specific treatment for EBV, only treatment of symptoms, such as taking over-the-counter medications for pain and fever.[4] EBV is thought to persistent harmlessly in immunocompetent individuals, but in those with compromised immune systems it has been associated with certain cancers and possibly autoimmune disease.

Antivirals[edit | edit source]

Several antivirals are active against EBV including valganciclovir, valacyclovir[28], acyclovir[29] and spironolactone.[30]

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.[31]

Rituximab[edit | edit source]

Rituximab may be effective in completely eliminating Epstein-Barr virus infection from the peripheral blood.[32] 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 and nutraceuticals[edit | edit source]

Herbs shown to have antiviral properties against EBV including licorice.[33]Vitamin C and Vitamin D[34] might also decrease duration and severity of the symptoms of EBV infection.[35]

Vaccine[edit | edit source]

A vaccine for the prevention of Epstein-Barr virus is being explored.[36]

Notable studies[edit | edit source]

  • 1996, MMPI profiles of patients with chronic fatigue syndrome[13] - (Abstract)
  • 1998, Incidence, risk and prognosis of acute and chronic fatigue syndromes and psychiatric disorders after glandular fever[12] - (Abstract)
  • 2019, EBV-requisitioning physicians' guess on fatigue state 6 months after acute EBV infection[37] - (Abstract)
  • 2019, Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study[38] - (Abstract)
  • 2019, Lifestyle factors during acute Epstein-Barr virus infection in adolescents predict physical activity six months later[39] - (Abstract)
  • 2019, Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome[40] - (Full text)

References[edit | edit source]

  1. Saha, Abhik; Robertson, Erle S (May 15, 2011), "Epstein-Barr Virus–Associated B-cell Lymphomas: Pathogenesis and Clinical Outcomes", Clinical Cancer Research, 17 (10): 3056–3063, doi:10.1158/1078-0432.CCR-10-2578, ISSN 1557-3265, PMID 21372216 
  2. 2.02.1 Harley, John (Apr 16, 2018). "Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity". Nature genetics. 
  3. 3.03.1 "Epstein-Barr virus protein can "switch on" risk genes for autoimmune diseases". National Institutes of Health. Apr 16, 2018. 
  4. 4.04.14.24.34.4 "Epstein-barr | Mononucleosis | About Virus | Mono | CDC". www.cdc.gov. May 10, 2018. Retrieved Nov 14, 2018. 
  5. Hsu, J. L.; Glaser, S. L. (Apr 2000). "Epstein-barr virus-associated malignancies: epidemiologic patterns and etiologic implications". Critical Reviews in Oncology/Hematology. 34 (1): 27–53. ISSN 1040-8428. PMID 10781747. 
  6. 6.06.1 Priatel, John J; Chung, Brian K; Tsai, Kevin; Tan, Rusung (Apr 9, 2014). "Natural killer T cell strategies to combat Epstein–Barr virus infection". Oncoimmunology. 3. doi:10.4161/onci.28329. ISSN 2162-4011. PMC 4063158Freely accessible. PMID 25050206. 
  7. Pattle, Samuel B.; Farrell, Paul J. (Nov 2006). "The role of Epstein-Barr virus in cancer". Expert Opinion on Biological Therapy. 6 (11): 1193–1205. doi:10.1517/14712598.6.11.1193. ISSN 1744-7682. PMID 17049016. 
  8. Tangye, Stuart (Jan 20, 2017). "Human immunity against EBV—lessons from the clinic". Journal of Experimental Medicine. 
  9. Jha, HC; Mehta, D; et al. (Dec 1, 2016), "Gammaherpesvirus Infection of Human Neuronal Cells", mBio, 6 (6), doi:10.1128/mBio.01844-15, PMID 26628726 
  10. Kleines, M; Schiefer, J; Stienen, A; Blaum, M; Ritter, K; Häusler, M (May 15, 2011), "Expanding the spectrum of neurological disease associated with Epstein-Barr virus activity", European Journal of Clinical Microbiology & Infectious Diseases, 30 (12): 1561–1569, doi:10.1007/s10096-011-1261-7, ISSN 1435-4373 
  11. Lossius, Andreas (December 2012). "Epstein-Barr Virus in Systemic Lupus Erythematosus, Rheumatoid Arthritis and Multiple Sclerosis—Association and Causation". Virus. 
  12. 12.012.1 White, P. D.; Thomas, J. M.; Amess, J.; Crawford, D. H.; Grover, S. A.; Kangro, H. O.; Clare, A. W. (Dec 1998). "Incidence, risk and prognosis of acute and chronic fatigue syndromes and psychiatric disorders after glandular fever". The British Journal of Psychiatry: The Journal of Mental Science. 173: 475–481. ISSN 0007-1250. PMID 9926075. 
  13. 13.013.1 Schmaling, K. B.; Jones, J. F. (Jan 1996). "MMPI profiles of patients with chronic fatigue syndrome". Journal of Psychosomatic Research. 40 (1): 67–74. ISSN 0022-3999. PMID 8730646. 
  14. Holmøy, Trygve (2008). "Vitamin D status modulates the immune response to Epstein Barr virus: Synergistic effect of risk factors in multiple sclerosis". Medical Hypotheses. 70. 
  15. "Viruses". National Multiple Sclerosis Society. Retrieved Nov 14, 2018. 
  16. James, JA (Dec 15, 1997). "An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus". The Journal of Clinical Investigation. 
  17. Kang, Insoo (Jan 15, 2004). "Defective Control of Latent Epstein-Barr Virus Infection in Systemic Lupus Erythematosus". The Journal of Immunology. 
  18. Brenner, T.; Timore, Y.; Wirguin, I.; Abramsky, O.; Steinitz, M. (Oct 1989). "In vitro synthesis of antibodies to acetylcholine receptor by Epstein-Barr virus-stimulated B-lymphocytes derived from patients with myasthenia gravis". Journal of Neuroimmunology. 24 (3): 217–222. ISSN 0165-5728. PMID 2553772. 
  19. J., Kaminski, Henry; Janos, Minarovits,. "Epstein-barr virus: Trigger for autoimmunity?". Annals of Neurology. ISSN 0364-5134. 
  20. "Official Brain & Life Home Page". journals.lww.com. Retrieved Nov 15, 2018. 
  21. Ryan, Julie (2013). "Epstein-Barr Virus Infection is Common in Inflamed Gastrointestinal Mucosa". Dig Dis Sci. 
  22. 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 
  23. 23.023.1 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 
  24. 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 
  25. Yenamandra, Surya Pavan; Hellman, Ulf; Kempkes, Bettina; Darekar, Suhas Deoram; Petermann, Sabine; Sculley, Tom; Klein, George; Kashuba, Elena (Dec 2010). "Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes". Cellular and molecular life sciences: CMLS. 67 (24): 4249–4256. doi:10.1007/s00018-010-0441-4. ISSN 1420-9071. PMID 20593215. 
  26. Yu, Sanhong; Cantorna, Margherita T. (Apr 1, 2008). "The vitamin D receptor is required for iNKT cell development". Proceedings of the National Academy of Sciences. 105 (13): 5207–5212. doi:10.1073/pnas.0711558105. ISSN 0027-8424. PMID 18364394. 
  27. Ramien, Caren; Pachnio, Annette; Sisay, Sofia; Begum, Jusnara; Leese, Alison; Disanto, Giulio; Kuhle, Jens; Giovannoni, Gavin; Rickinson, Alan (May 2014). "Hypovitaminosis-D and EBV: no interdependence between two MS risk factors in a healthy young UK autumn cohort". Multiple Sclerosis (Houndmills, Basingstoke, England). 20 (6): 751–753. doi:10.1177/1352458513509507. ISSN 1477-0970. PMID 24192216. 
  28. Hoshino, Yo. "Long-Term Administration of Valacyclovir Reduces the Number of Epstein-Barr Virus (EBV)-Infected B Cells but Not the Number of EBV DNA Copies per B Cell in Healthy Volunteers". Journal of Virology. 
  29. Rafaillidis, Pl (Nov 2013). "Antiviral treatment for severe EBV infections in apparently immunocompetent patients". Journal of Clinical Virology. 
  30. Verma, Dinesh; Thompson, Jacob; Swaminathan, Sankar (Mar 29, 2016), "Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function", Proceedings of the National Academy of Sciences, 113 (13): 3609–3614, doi:10.1073/pnas.1523686113, ISSN 1091-6490, PMID 26976570 
  31. Priatel, John J; Chung, Brian K; Tsai, Kevin; Tan, Rusung (Apr 9, 2014). "Natural killer T cell strategies to combat Epstein–Barr virus infection". Oncoimmunology. 3. doi:10.4161/onci.28329. ISSN 2162-4011. PMC 4063158Freely accessible. PMID 25050206. 
  32. Diamantopoulos, Panagiotis T.; Polonyfi, Katerina; Sofotasiou, Maria; Papadopoulou, Vasiliki; Kalala, Fani; Iliakis, Theodoros; Zervakis, Kostantinos; Tsilimidos, Gerassimos; Kouzis, Panagiotis (Dec 2013). "Rituximab in the treatment of EBV-positive low grade B-cell lymphoma". Anticancer Research. 33 (12): 5693–5698. ISSN 1791-7530. PMID 24324119. 
  33. Lin, Jung-Chung; Cherng, Jaw-Ming; Hung, Man-Shan; Baltina, Lidia A.; Baltina, Lia; Kondratenko, Rimma (Jul 2008). "Inhibitory effects of some derivatives of glycyrrhizic acid against Epstein-Barr virus infection: structure-activity relationships". Antiviral Research. 79 (1): 6–11. doi:10.1016/j.antiviral.2008.01.160. ISSN 0166-3542. PMID 18423902. 
  34. Rolf, L (July 2017). "Exploring the effect of vitamin D3 supplementation on the anti-EBV antibody response in relapsing-remitting multiple sclerosis". Multiple Sclerosis. 
  35. Mikirova, N (May 2014). "Effect of high dose vitamin C on Epstein-Barr viral infection". Med Sci Monit. 
  36. "NIH researchers make progress toward Epstein-Barr virus vaccine". National Institutes of Health (NIH). Apr 9, 2019. Retrieved Apr 10, 2019. 
  37. Asprusten, Tarjei Tørre; Pedersen, Maria; Skovlund, Eva; Wyller, Vegard Bruun (2019). "EBV-requisitioning physicians' guess on fatigue state 6 months after acute EBV infection". BMJ paediatrics open. 3 (1): e000390. doi:10.1136/bmjpo-2018-000390. ISSN 2399-9772. PMID 30957026. 
  38. Pedersen, Maria; Asprusten, Tarjei Tørre; Godang, Kristin; Leegaard, Truls Michael; Osnes, Liv Toril; Skovlund, Eva; Tjade, Trygve; Øie, Merete Glenne; Wyller, Vegard Bruun Bratholm (Jan 2019). "Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study". Brain, Behavior, and Immunity. 75: 94–100. doi:10.1016/j.bbi.2018.09.023. ISSN 1090-2139. PMID 30261303. 
  39. Pedersen, Maria; Asprusten, Tarjei Tørre; Godang, Kristin; Leegaard, Truls Michael; Osnes, Liv Toril; Skovlund, Eva; Tjade, Trygve; Øie, Merete Glenne; Wyller, Vegard Bruun Bratholm (Jan 27, 2019). "Lifestyle factors during acute Epstein-Barr virus infection in adolescents predict physical activity six months later". Acta Paediatrica (Oslo, Norway: 1992). doi:10.1111/apa.14728. ISSN 1651-2227. PMID 30685875. 
  40. Williams, Marshall V.; Cox, Brandon; Lafuse, William P.; Ariza, Maria Eugenia (May 2019). "Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome". Clinical Therapeutics. 41 (5): 848–863. doi:10.1016/j.clinthera.2019.04.009. PMC 6525645Freely accessible. PMID 31040055. 

Antibodies or immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response. [1]

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