Epstein-Barr Virus

Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. The initial infection can present as infectious mononucleosis, and reactivation (often in patients who are HIV positive) can cause oral hairy leukoplakia. An important feature of EBV infections is the ability to transform B cells, which provides immortalization and proliferation. Thus, EBV is associated with lymphoproliferative disorders and malignancies, such as Burkitt lymphoma, Hodgkin lymphoma, hemophagocytic lymphohistiocytosis, post-transplant lymphoproliferative disease, certain gastric cancers, and nasopharyngeal carcinoma.

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Classification

DNA virus classification flowchart

Identification of DNA viruses:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. Viruses with a DNA genome can be further characterized as single or double stranded. “Enveloped” viruses are covered by a thin coat of cell membrane, which is usually taken from the host cell. If the coat is absent, however, the viruses are called “naked” viruses. Some enveloped viruses translate DNA into RNA before incorporating into the genome of the host cell.

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General Characteristics and Epidemiology

Basic features of Epstein-Barr virus (EBV)

  • Also known as human herpesvirus 4
  • Taxonomy:
    • Family: Herpesviridae
    • Subfamily: Gammaherpesvirinae
    • Genus: Lymphocryptovirus
  • DNA virus
    • Linear
    • Double stranded
    • > 85 genes
  • Structure:
    • Core (contains DNA)
    • Icosahedral protein nucleocapsid 
    • Tegument (contains viral proteins and enzymes)
    • Lipid envelope and glycoprotein spikes

Associated diseases

  • Acute infectious mononucleosis
  • Oral hairy leukoplakia
  • Lymphoproliferative disorders and malignancies:
    • Burkitt lymphoma
    • Hodgkin lymphoma
    • Hemophagocytic lymphohistiocytosis
    • Post-transplant lymphoproliferative disease
    • Nasopharyngeal carcinoma
    • EBV-associated gastric carcinoma
  • Other inflammatory conditions:
    • Myocarditis
    • Pancreatitis
    • Hepatitis
    • Meningoencephalitis

Epidemiology

  • Antibodies are found in all population groups worldwide.
  • > 90% of adults are seropositive for EBV antibodies.

Pathogenesis

Reservoir

Humans are the only reservoir.

Transmission

  • Contact with bodily secretions from an infected individual
    • Saliva (“kissing disease”)
    • Blood
    • Semen
  • Blood transfusion
  • Organ transplantation

Viral replication cycle

Cell entry:

  • EBV binds to receptors on the cell surface (particularly CD21 on B cells)
  • Fusion with the cell membrane → nucleocapsid released into the cytoplasm
  • Transported to the cell’s nucleus → can enter lytic replication or latency

Latency:

  • After entry into nucleus → DNA becomes circular
  • Only a portion of genes are expressed → no virions are produced
  • Can reactivate → lytic replication (trigger is unclear)

Lytic replication:

  • After latency or entry into nucleus → DNA becomes linear
  • Replication with viral DNA polymerase → assembly → bud out from the nuclear membrane
  • Outer envelope obtained from the cell membrane

Pathophysiology

Cell types infected:

  • B lymphocytes
  • Epithelial cells

Primary infection:

  • EBV infects epithelial cells in the oropharynx → replication 
  • Released into saliva 
  • B cells infected in lymphoid-rich tissue → allows for dissemination
  • Immune system:
    • Produces IgM heterophile antibodies
    • T cell activation → destruction of lytic-infected cells 
  • Latency helps the virus evade the immune system → indefinite persistence

Lymphoproliferative disorders:

  • Latent mechanism of gene expression → production of viral proteins 
  • Transformation of B cells to lymphoblastoid cells → proliferation 
  • In states with ↓ cytotoxic T cells → ↑ infected B cells
  • Can lead to malignancy
  • Note: a similar process can occur in epithelial cells → epithelial malignancies

Diseases Caused by EBV

Acute infectious mononucleosis

Presentation:

  • Fever
  • Tonsillitis (swollen and erythematous tonsils that may be covered in exudate)
  • Cervical lymphadenopathy (most commonly the posterior cervical and posterior auricular chains)
  • Headache 
  • General malaise and fatigue
  • Petechiae present at the junction between the hard and soft palates
  • Hepatosplenomegaly
  • Maculopapular rash (similar to measles, present in approximately 5% of cases)

Diagnosis:

  • Clinical
  • Confirmed with:
    • Heterophile antibody testing
    • Serology

Management:

  • Supportive
  • No available antiviral therapy

Oral hairy leukoplakia

Oral hairy leukoplakia is caused by the reactivation of latent EBV and occurs mostly in patients who are HIV positive.

Clinical presentation:

  • Not premalignant
  • White patches on the tongue
  • “Hairy” appearance (due to hyperkeratosis and epithelial hyperplasia)
  • Does not scrape off

Diagnosis:

  • Clinical
  • Confirmed using histology and identification of EBV within epithelial cells

Management:

  • Treatment is not required.
  • Antiretroviral therapy for HIV

Lymphoproliferative disorders and malignancies

Table: Conditions associated with EBV
DiseaseCharacteristicsClinical presentationManagement
Burkitt lymphoma
  • AIDS-defining condition
  • t(8;14)
  • Overexpression of c-myc oncogene
  • Constitutional symptoms
  • Rapidly growing extranodal mass
  • Chemotherapy
  • Immunotherapy
  • Radiation
Hodgkin lymphoma Reed-Sternberg cells
  • Asymptomatic lymphadenopathy
  • Constitutional symptoms
  • Chemotherapy
  • Radiation
  • Autologous stem cell transplant
Hemophagocytic lymphohistiocytosis
  • Sustained, aberrant activation of cytotoxic CD8+ T cells
  • ↑ Cytokine release
  • Fever
  • Lymphadenopathy
  • Hepatosplenomegaly
  • Cytopenias
  • Multiorgan failure
  • Chemotherapy
  • Hematopoietic stem cell transplant
Post-transplant lymphoproliferative disease
  • Can progress to B cell lymphoma
  • Constitutional symptoms
  • Lymphadenopathy
  • Extranodal mass
  • Organ dysfunction
↓ Immunosuppressive therapy
Nasopharyngeal carcinoma
  • Epithelial malignancy
  • Lymphadenopathy
  • Nasal or oral bleeding
  • Obstructed nasal breathing
  • Recurrent ear infections
  • Radiation
  • Chemotherapy
EBV-associated gastric carcinoma
  • Epithelial malignancy
  • Better prognosis than EBV-negative cancer
  • Asymptomatic
  • Postprandial fullness
  • Anorexia
  • Nausea
  • Weight loss
  • Surgical resection
  • Chemotherapy

Comparison of Herpesviruses

There are 115 different total known species of herpesviruses that are grouped into 3 families: 

  • Alpha (infect epithelial cells and produce latent infections in post-mitotic neurons)
  • Beta (infect and produce latent infections in several cell types)
  • Gamma (produce latent infections mainly in lymphoid cells)
Table: Comparison of the 9 herpesviruses considered endemic in humans
HHVCommon namePrimary target cellsLatency siteClinical presentation*
1
(alpha group)
HSV-1 Mucoepithelial cells Dorsal root ganglia
  • Gingivostomatitis
  • Keratitis
  • Herpetic whitlow
  • Encephalitis
  • Hepatitis
  • Esophagitis
  • Pneumonitis
2
(alpha group)
HSV-2
  • Genital herpes
  • Meningitis
  • Proctitis
3
(alpha group)
VZV
  • Chickenpox
  • Herpes zoster
4
(gamma group)
EBV
  • Epithelial cells
  • B cells
Memory B cells
  • Infectious mononucleosis
  • Hodgkin lymphoma
  • Burkitt lymphoma
  • Oral hairy leukoplakia
  • EBV-associated gastric cancer
5
(beta group)
CMV
  • Monocytes
  • Lymphocytes
  • Epithelial cells
Hematopoietic progenitor cells in bone marrow
  • CMV mononucleosis
  • CMV retinitis
  • CMV colitis
  • CMV encephalitis
6A, 6B
(beta group)
HHV-6 T cells Monocytes Roseola
7
(beta group)
HHV-7 T cells
8
(gamma group)
KSHV
  • Lymphocytes
  • Epithelial cells
B cellsKaposi sarcoma
* Bold in “clinical presentation” column: AIDS-defining illnesses
CMV: cytomegalovirus
EBV: Epstein-Barr virus
HHV: human herpesvirus
HSV: herpes simplex virus
KSHV: Kaposi sarcoma-associated herpesvirus
VZV: varicella zoster virus

References

  1. Sullivan, J.L. (2019). Clinical manifestations and treatment of Epstein-Barr virus infection. UpToDate. Retrieved May 19, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-treatment-of-epstein-barr-virus-infection
  2. Smith, M.C., et al. (2014). The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder. International Journal of Clinical and Experimental Pathology, 7(9), 5738-5749. https://pubmed.ncbi.nlm.nih.gov/25337215/
  3. Lee, J.H., et al. (2009). Clinicopathological and molecular characteristics of Epstein-Barr virus-associated gastric carcinoma: A meta-analysis. Journal of Gastroenterology and Hepatology, 24(3), 354-365. https://pubmed.ncbi.nlm.nih.gov/19335785/
  4. Lauwers, G. (2020). Gastric cancer pathology and molecular pathogenesis. UpToDate. Retrieved May 19, 2021, from https://www.uptodate.com/contents/gastric-cancer-pathology-and-molecular-pathogenesis
  5. Sullivan, J.L. (2021). Virology of Epstein-Barr virus. UpToDate. Retrieved May 19, 2021, from https://www.uptodate.com/contents/virology-of-epstein-barr-virus
  6. Shetty, K., Benge, E., Josef, V.E., and Vaghefi, R. (2021). Epstein-Barr virus (EBV) infectious mononucleosis (mono). Medscape. Retrieved May 21, 2021, from https://emedicine.medscape.com/article/222040-overview
  7. Hoover, K., and Higginbotham, K. (2020). Epstein Barr virus. https://www.ncbi.nlm.nih.gov/books/NBK559285/
  8. Fugl, A., and Andersen, C.K. (2019). Epstein-Barr virus and its association with disease – a review of relevance to general practice. BMC Family Practice 20(62). https://doi.org/10.1186/s12875-019-0954-3
  9. Ayee, R., Oforiwaa Ofori, M.E., Wright, E., and Quaye, O. (2020). Epstein Barr virus associated lymphomas and epithelial cancers in humans. Journal of Cancer 11(7), 1737-1759. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052849/

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