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Epstein-Barr Virus (EBV)

EBV taxonomy

Viruses - dsDNA viruses, no RNA stage - Herpesvirales - Herpesviridae - Gammaherpesvirinae - Lymphocryptovirus - Human herpesvirus 4

Synonyms

• Epstein-Barr virus EBV
• Human herpesvirus type 4
• EPV
• HHV-4

Large family of herpesviruses is classified into 3 subfamilies (α, β and γ) based on their genome organization, growth characteristics and cell tropism. Herpesviruses have large double-stranded DNA genomes that contain many genes of host origin acquired during millions of years of co-evolution with their vertebrate hosts.

All herpesviruses have in common that, once the initial phase of virus multiplication has been resolved, they enter into a phase of lifelong persisting latency.

During latency the viral DNA circularizes and moves to the nucleus. It does not integrate, but replicates independently of the host cell. Very few viral genes are expressed during latency.

There are currently 8 herpesviruses known to infect humans. They are ubiquitous human infections and cause minimal clinical disease. Reactivation and virus shedding occurs periodically throughout life.

EBV belongs to a group of lymphoproliferative viruses, γ-herpesviruses (Gammaherpesvirinae). Two lymphotropic human γ-herpesviruses can cause lymphoproliferative disorders: Epstein-Barr virus (belongs to genus Lymphocryptovirus) and Kaposi sarcoma herpesvirus (KSHV, also called Human herpesvirus 8 belongs to genus Rhadinovirus).

Malignancies caused by Epstein-Barr virus (EBV) arise largely due to viral genes expressed during the latent phase of infection which transforms B-lymphocytes and renders them susceptible to DNA damage. In contrast, in the case of human herpesvirus 8 (HHV8), genes expressed during lytic infection appear to be central to the oncogenic processes.

Introduction

• Discovery & timeline

  • Epstein-Barr virus (EBV) was discovered in 1964 by electron microscopy of suspension cultures of African Burkitt lymphoma cells (Epstein et al. 1964). The virus now estimated to be present in 96% of these tumors.
  • The association between EBV and nasopharyngeal carcinoma (NPC) was first made on serological grounds in 1966 (Old et al. 1966) and this was later confirmed by demonstration of EBV DNA in the malignant epithelial cells (Wolf et al. 1973).
  • The ability to infect B lymphocytes and to induce their unlimited proliferation was discovered in 1967 by Henle et sl. (Henle et al. 1967). It is this transforming or immortalizing property of the virus which has attracted most of the interest of researchers because it is closely related to the pathogenicity and oncogenicity of the virus. The EBV was regarded as first human tumor virus. It took AIDS to reveal the second example, Kaposi's sarcoma herpes virus (KSHV).
  • In 1968, EBV was linked to infectious mononucleosis (IM).
  • An association between EBV and Hodgkin's lymphoma has been recognized since 1980. In the late 1980s, the association was confirmed by the demonstration of clonal EBV DNA in a subset of HL (Weiss et al. 1987) and EBV genome was subsequently localized to Reed-Sternberg cells (RSCs) (Wu et al. 1990).
  • EBV DNA was first demonstrated in T-cell lymphoma from 2 cases of chronic IM in 1988 (Jones et al. 1988) and since then, a variety of other T-cell lesions were found to be associated with the virus.

• Genome

  EBV virions have a double-stranded, linear 172 kb pair DNA genome that encodes approximately 100 genes. EBV genes are designated according to the position and orientation of the reading frame on the respective BamHI fragment. For example BZLF1 (the gene's product is responsible for lytic cycle induction) is the first leftward reading frame on EBV BamHI-Z fragment.
  EBV genome overview

• Structure

  The genomic DNA is packaged in a capsid, tegumen, and envelope composed principally of EBV-encoded homologues of conserved herpesvirus virion proteins.
  Based on analogy with Herpes simplex virus (HSV), capsid consists of 150 hexons and 12 pentons that are constructed from Major Capsid Proteins (MCPs), Minor Capsid Proteins (mCP), Smallest Capsid Proteins (sCP) ,and mCP-Binding Proteins (mCPBPs). After capsid assembly, herpes DNA enters it through a portal (BBRF1) dodecamer. Portal may orient the capsid for the application of specific tegumen proteins, movement through cellular compartments, envelopment, and DNA release near nuclear pores.
  Probable tegumen components include the EBV and γ-herpesvirus-encoded BLRF2, BRRF2, BDLF2 and BKRF4 proteins. Actin is also a major tegumen protein as well as cofilin, tubulin, heat shock protein 90, and heat shock protein 70. Capsids likely accumulate these proteins as mediators of morphogenesis.
  Envelope of mature extracellular virion is enriched for glycoprotein 350 (gp350) followed by glycoprotein gH, intact and furin-cleaved gB, gM, gp42, gL, gp78, gp150, and gN.
  EB nuclear antigen 1 (EBNA-1) responsible for persistent latent infection of EBV as well as Latent Membrane Protein 1 (LMP1) and Latent Membrane Protein 2 (LMP2) are not detectable in mature viral particles.
  Mature virions are approximately 120 to 180 nm in diameter.

• Transmission pathways

  • Through oral contact (kissing);
  • Through items that facilitate salivary exchange (toys, bottles, etc.);
  • Blood transmission;
  • Transplantation of hematopoietic cells and solid organs;
  • Possibly through genital sexual intercourse.

• Virus-host interaction in vivo

  In contrast to other herpesviruses, Epstein-Barr virus uses a dual strategy to ensure infection of a large number of cells for the maintenance of latency:
  1. it drives infected cells into cell cycle and proliferation, thus increasing the number of the viral genome-carrying cells;
  2. it replicates producing mature infectious viral particles and is able to initiate a new round of infection.

• Three phases of EBV life cycle

  1. expansion of infected cells maintaining the viral genome in an episomal state;
  2. establishment of in vivo latency;
  3. reactivation, replication and synthesis of viral progeny.

• Epidemiology

  Before the age of 10, primary infection is usually asymptomatic. In adolescents and young adults primary EBV infection frequently produces acute illness termed infectious mononucleosis by Sprunt and Evans in 1920. In general, >90% of adults worldwide are seropositive for EBV maintaining life-long latent infection. Primary EBV infection occurs at a younger age among persons from lower versus higher socioeconomic backgrounds. Healthy individuals harbor between 1 and 10 latently infected B cells within 10⁶ peripheral blood mononuclear cells and also continue to shed EBV during their life time.

• EBV-associated diseases

  The association between Epstein-Barr virus and a large number of benign and malignant diseases is unique among DNA viruses.

  • Non-malignant disease
    • Infectious mononucleosis (IM)
    • Chronic Active EBV (CAEBV)
    • EBV-associated Chronic Fatigue Syndrome (CFS)
    • Severe Chronic Active EBV (SCAEBV)
    • Oral hairy leukoplakia
  • Autoimmune diseases
    • Multiple sclerosis (MS)
    • Rheumatoid arthritis (RA)
    • Systemic Lupus Erythematosus (SLE)
  • Malignant disease
    • Immunosuppressed host
      • B-cell malignancies
        • Acquired immunodeficiency
          • Acquired immunodeficiency AIDS-associated B-cell lymphomas
          • Post Transplant Lymphoproliferative Disorder (PTLD)
          • Lymphomatoid granulomatosis
          • Methotrexate-associated B-cell lymphoma
        • Congenital immunodeficiency
          • Severe combined immunodeficiency-associated B-cell lymphomas
          • Wiskott-Aldrich syndrome-associated B-cell lymphomas
          • X-linked lymphoproliferative disorder-associated B-cell lymphomas
      • Mesenchymal malignancies
        • Leiomyosarcoma
    • Immunocompetent host
      • B-cell malignancies
        • Burkitt's lymphoma (BL)
        • Classical Hodgkin's lymphoma
      • T-cell malignancies
        • Extranodal NK/T cell lymphoma, nasal type (ENKTL)
        • Virus-associated hemophagocytic syndrome T-cell lymphomas
      • Epithelial cell malignancies
        • Nongladular nasopharyngeal carcinoma
        • Lymphoepithelioma-like carcinoma (salivary, thymus, lungs, stomach)
        • Breast carcinoma
        • Hepatocellular carcinoma
      • Mesenchymal malignancies
        • Follicular dendritic cell sarcoma

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Approximate % of EBV associations with some malignancies

EBV in medical literature (PubMed database)

• Herspesviridae[Majr]
• Gammaherpesvirinae[Majr]
• Lymphocryptovirus[Majr]
• "Herpesvirus 4, Human"[Majr]
• "Infectious Mononucleosis"[Majr]
• "Epstein-Barr Virus Infections"[Mesh] AND "Burkitt Lymphoma"[Majr]
• "Leukoplakia, Hairy"[Majr]
• "Hodgkin Disease"[Majr] AND "Epstein-Barr Virus Infections"[Majr]