Classification
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.
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
Simplified diagram of the structure of the Epstein-Barr virus
Image: “Simplified diagram of the structure of EBV” by Ben Taylor. License: Public Domain
Transmission electron microscopic image showing the presence of numerous Epstein-Barr virus (EBV) virions, members of the Herpesviridae virus family:
Image: “Transmission electron microscopic image showing the presence of numerous Epstein-Barr virus (EBV) virions, members of the Herpesviridae virus family” by CDC. License: Public Domain
At the core of its proteinaceous capsid, EBV contains a double-stranded DNA linear genome.
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
Pathogenesis of norovirus infection
Image by Lecturio. License: CC BY-NC-SA 4.0
The EBV can infect both B cells and oropharyngeal epithelial cells:
Image by Lecturio. License: CC BY-NC-SA 4.0
The virus enters B cells by binding to the cellular receptor CD21, allowing fusion of the viral envelope with the cell membrane.
The lytic cycle results in the production of infectious virions in both B cells and oropharyngeal epithelial cells. In B cells, lytic replication normally only takes place after reactivation from latency, whereas in oropharyngeal epithelial cells, lytic replication often directly follows viral entry.
During lytic replication, viral DNA polymerase is responsible for synthesizing the viral genome. This contrasts with latency, in which host-cell DNA polymerase copies the viral genome. However, latency does not result in the production of virions, since only a portion of EBV’s genes are expressed.
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
White, hairy patch on a patient’s tongue due to oral hairy leukoplakia
Image: “Advanced oral hairy leukoplakia (OHL)” by CDC. License: Public Domain
Lymphoproliferative disorders and malignancies
| Disease | Characteristics | Clinical presentation | Management |
|---|---|---|---|
| Burkitt lymphoma |
|
|
|
| Hodgkin lymphoma | Reed-Sternberg cells |
|
|
| Hemophagocytic lymphohistiocytosis |
|
|
|
| Post-transplant lymphoproliferative disease |
|
| ↓ Immunosuppressive therapy |
| Nasopharyngeal carcinoma |
|
|
|
| EBV-associated gastric carcinoma |
|
|
|
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)
| HHV | Common name | Primary target cells | Latency site | Clinical presentation* |
|---|---|---|---|---|
| 1 (alpha group) | HSV-1 | Mucoepithelial cells | Dorsal root ganglia |
|
| 2 (alpha group) | HSV-2 |
| ||
| 3 (alpha group) | VZV |
| ||
| 4 (gamma group) | EBV |
| Memory B cells |
|
| 5 (beta group) | CMV |
| Hematopoietic progenitor cells in bone marrow |
|
| 6A, 6B (beta group) | HHV-6 | T cells | Monocytes | Roseola |
| 7 (beta group) | HHV-7 | T cells | ||
| 8 (gamma group) | KSHV |
| B cells | Kaposi sarcoma |
CMV: cytomegalovirus
EBV: Epstein-Barr virus
HHV: human herpesvirus
HSV: herpes simplex virus
KSHV: Kaposi sarcoma-associated herpesvirus
VZV: varicella zoster virus
References
- 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
- 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/
- 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/
- 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
- 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
- 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
- Hoover, K., and Higginbotham, K. (2020). Epstein Barr virus. https://www.ncbi.nlm.nih.gov/books/NBK559285/
- 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
- 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/
