Epstein–Barr virus

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Epstein–Barr
Two Epstein–Barr virions
Virus classification
Group:
Group I (dsDNA)
Family:
Herpesviridae
Subfamily:
Gammaherpesvirinae
Genus:
Lymphocryptovirus
Species:
Human herpesvirus 4 (HHV-4)

The Epstein–Barr virus (EBV), also called human herpesvirus 4 (HHV-4), is a virus of the herpes family, and is one of the most common viruses in humans.

It is best known as the cause of infectious mononucleosis (glandular fever). It is also associated with particular forms of cancer, such as Hodgkin's lymphoma, Burkitt's lymphoma, nasopharyngeal carcinoma, and conditions associated with human immunodeficiency virus (HIV) such as hairy leukoplakia and central nervous system lymphomas.[1][2] There is evidence that infection with the virus is associated with a higher risk of certain autoimmune diseases,[3] especially dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome,[4][5] and multiple sclerosis.[6]

Infection with EBV occurs by the oral transfer of saliva[7] and genital secretions.

Most people become infected with EBV and gain adaptive immunity. In the United States, about half of all five-year-old children and 90 to 95 percent of adults have evidence of previous infection.[8] Infants become susceptible to EBV as soon as maternal antibody protection disappears. Many children become infected with EBV, and these infections usually cause no symptoms or are indistinguishable from the other mild, brief illnesses of childhood. In the United States and other developed countries, many people are not infected with EBV in their childhood years. When infection with EBV occurs during adolescence or teenage years, it causes infectious mononucleosis 35 to 50 percent of the time.[9]

EBV infects B cells of the immune system and epithelial cells. Once the virus's initial lytic infection is brought under control, EBV latently persists in the individual's B cells for the rest of the individual's life.[7]

Virology

Structure and genome

A mature EBV viral particle has a diameter of approximately 120 nm to 180 nm. It is composed of a double stranded, linear DNA genome enclosed by a protein capsid. The capsid is surrounded by a protein tegument, which in turn is surrounded by a lipid envelope.[10]

The EBV genome is about 192 thousand base pairs in length and contains about 85 genes.[7]

The viral envelope is embedded with glycoproteins essential to viral entry into the cell.[10]

In laboratory and animal trials in 2000, it was shown that both antagonism of RA-mediated growth inhibition and promotion of LCL proliferation were efficiently reversed by the glucocorticoid receptor (GR) antagonist RU486.[11]

The Epstein–Barr virus transcriptome and epigenome have been extensively mapped.[12]

Tropism

The term viral tropism refers to which cell types EBV infects. EBV can infect a number of different cell types, including B cells and epithelial cells. Under certain cases, it may infect T cells, natural killer cells, and smooth muscle cells.

The viral three-part glycoprotein complexes of gHgLgp42 mediate B cell membrane fusion; while the two-part complexes of gHgL mediate epithelial cell membrane fusion. EBV that are made in the B cells have low numbers of the gHgLgp42 complexes as the three-part complexes interact with HLA class II in the endoplasmic reticulum and are degraded. In contrast, EBV from epithelial cells are rich in the three-part complexes because these cells do not have MHC class II. As a result, EBV made from B cells are more infectious to epithelial cells, and EBV made from epithelial cells are more infectious to B cells.

Replication cycle

The EBV replication cycle

Entry to the cell

EBV can infect both B cells and epithelial cells. The mechanisms for entering these two cells are different.

To enter B cells, viral glycoprotein gp350 binds to cellular receptor CD21 (also known as CR2).[13] Then, viral glycoprotein gp42 interacts with cellular MHC class II molecules. This triggers fusion of the viral envelope with the cell membrane, allowing EBV to enter the B cell.[10]

To enter epithelial cells, viral protein BMRF-2 interacts with cellular β1 integrins. Then, viral protein gH/gL interacts with cellular αvβ6/8 integrins. This triggers fusion of the viral envelope with the epithelial cell membrane, allowing EBV to enter the epithelial cell.[10] Unlike B cell entry, epithelial cell entry is actually impeded by viral glycoprotein gp42.[13]

Once EBV enters the cell, the viral capsid dissolves and the viral genome is transported to the cell nucleus.

Lytic replication

The lytic cycle, or productive infection, results in the production of infectious virions. EBV can undergo lytic replication in both B cells and epithelial cells. In B cells, lytic replication normally only takes place after reactivation from latency. In epithelial cells, lytic replication often directly follows viral entry.[10]

For lytic replication to occur, the viral genome must be linear. The latent EBV genome is circular, so it must linearize in the process of lytic reactivation. During lytic replication, viral DNA polymerase is responsible for copying the viral genome. This contrasts with latency, in which host cell DNA polymerase copies the viral genome.[10]

Lytic gene products are produced in three consecutive stages: immediate-early, early, and late.[10] Immediate-early lytic gene products act as transactivators, enhancing the expression of later lytic genes. Immediate-early lytic gene products include BZLF1 (also known as Zta and ZEBRA) and BRLF1.[10] Early lytic gene products have many more functions, such as replication, metabolism, and blockade of antigen processing. Early lytic gene products include BNLF2.[10] Finally, late lytic gene products tend to be proteins with structural roles, like VCA, which forms the viral capsid. Other late lytic gene products, such as BCRF1, help EBV evade the immune system.[10]

Unlike lytic replication for many other viruses, EBV lytic replication does not inevitably lead to lysis of the host cell because EBV virions are produced by budding from the infected cell. Lytic proteins include gp350 and gp110.[10][14]

Latency

Unlike lytic replication, latency does not result in production of virions.[10] Instead, the EBV genome circularizes, resides in the cell nucleus as an episome, and is copied by cellular DNA polymerase.[10] In latency, only a portion of EBV's genes are expressed.[7] Latent EBV expresses its genes in one of three patterns, known as latency programs. EBV can latently persist within B cells and epithelial cells, but different latency programs are possible in the two types of cell.

EBV can exhibit one of three latency programs: Latency I, Latency II, or Latency III. Each latency program leads to the production of a limited, distinct set of viral proteins and viral RNAs.[15][16]

Gene Expressed EBNA-1 EBNA-2 EBNA-3A EBNA-3B EBNA-3C EBNA-LP LMP-1 LMP-2A LMP-2B EBER
Product Protein Protein Protein Protein Protein Protein Protein Protein Protein ncRNAs
Latency I + – – – – – – – – +
Latency II + – – – – + + + + +
Latency III + + + + + + + + + +

It is also postulated that a program exists in which all viral protein expression is shut off (Latency 0).

Within B cells, all three latency programs are possible.[7] EBV latency within B cells usually progresses from Latency III to Latency II to Latency I. Each stage of latency uniquely influences B cell behavior.[7] Upon infecting a resting naive B cell, EBV enters Latency III. The set of proteins and RNAs produced in Latency III transforms the B cell into a proliferating blast (also known as B cell activation).[7][10] Later, the virus restricts its gene expression and enters Latency II. The more limited set of proteins and RNAs produced in Latency II induces the B cell to differentiate into a memory B cell.[7][10] Finally, EBV restricts gene expression even further and enters Latency I. Expression of EBNA-1 allows the EBV genome to replicate when the memory B cell divides.[7][10]

Within epithelial cells, only Latency II is possible.[citation needed]

In primary infection, EBV replicates in oro-pharyngeal epithelial cells and establishes Latency III, II, and I infections in B-lymphocytes. EBV latent infection of B-lymphocytes is necessary for virus persistence, subsequent replication in epithelial cells, and release of infectious virus into saliva. EBV Latency III and II infections of B-lymphocytes, Latency II infection of oral epithelial cells, and Latency II infection of NK- or T-cell can result in malignancies, marked by uniform EBV genome presence and gene expression.[17]

Reactivation

Latent EBV in B cells can be reactivated to switch to lytic replication. This is known to happen in vivo, but what triggers it is not known precisely. In vitro, latent EBV in B cells can be reactivated by stimulating the B cell receptor, so reactivation in vivo probably takes place when latently infected B cells respond to unrelated infections.[10] In vitro, latent EBV in B cells can also be reactivated by treating the cells with sodium butyrate or TPA.[citation needed]

Transformation of B-lymphocytes

When EBV infects B cells in vitro, lymphoblastoid cell lines eventually emerge that are capable of indefinite growth. The growth transformation of these cell lines is the consequence of viral protein expression.

EBNA-2, EBNA-3C and LMP-1 are essential for transformation, while EBNA-LP and the EBERs are not.[18]

It is postulated that following natural infection with EBV, the virus executes some or all of its repertoire of gene expression programs to establish a persistent infection. Given the initial absence of host immunity, the lytic cycle produces large amounts of virus to infect other (presumably) B-lymphocytes within the host.

The latent programs reprogram and subvert infected B-lymphocytes to proliferate and bring infected cells to the sites at which the virus presumably persists. Eventually, when host immunity develops, the virus persists by turning off most (or possibly all) of its genes, only occasionally reactivating to produce fresh virions. A balance is eventually struck between occasional viral reactivation and host immune surveillance removing cells that activate viral gene expression.

The site of persistence of EBV may be bone marrow. EBV-positive patients who have had their own bone marrow replaced with bone marrow from an EBV-negative donor are found to be EBV-negative after transplantation.[19]

Latent antigens

All EBV nuclear proteins are produced by alternative splicing of a transcript starting at either the Cp or Wp promoters at the left end of the genome (in the conventional nomenclature). The genes are ordered EBNA-LP/EBNA-2/EBNA-3A/EBNA-3B/EBNA-3C/EBNA-1 within the genome.

The initiation codon of the EBNA-LP coding region is created by an alternate splice of the nuclear protein transcript. In the absence of this initiation codon, EBNA-2/EBNA-3A/EBNA-3B/EBNA-3C/EBNA-1 will be expressed depending on which of these genes is alternatively spliced into the transcript.

Protein/genes

Protein/gene/antigen Stage Description
EBNA-1 latent+lytic EBNA-1 protein binds to a replication origin (oriP) within the viral genome and mediates replication and partitioning of the episome during division of the host cell. It is the only viral protein expressed during group I latency.
EBNA-2 latent+lytic EBNA-2 is the main viral transactivator.
EBNA-3 latent+lytic These genes also bind the host RBP-Jκ protein.
LMP-1 latent LMP-1 is a six-span transmembrane protein that is also essential for EBV-mediated growth transformation.
LMP-2 latent LMP-2A/LMP-2B are transmembrane proteins that act to block tyrosine kinase signaling.
EBER latent EBER-1/EBER-2 are small nuclear RNAs, which bind to certain nucleoprotein particles, enabling binding to PKR (dsRNA dependent serin/threonin protein kinase) thus inhibiting its function. EBER-particles also induce the production of IL-10 which enhances growth and inhibits cytotoxic T-cells.
miRNAs latent EBV microRNAs are encoded by two transcripts, one set in the BART gene and one set near the BHRF1 cluster. The three BHRF1 miRNAS are expressed during type III latency while the large cluster of BART miRNAs (up to 20 miRNAs) are expressed during type II latency. The functions of these miRNAs are currently unknown.
EBV-EA lytic early antigen
EBV-MA lytic membrane antigen
EBV-VCA lytic viral capsid antigen
EBV-AN lytic alkaline nuclease[20][21]

Subtypes of EBV

EBV can be divided into two major types, EBV type 1 and EBV type 2. These two subtypes have different EBNA-3 genes. As a result, the two subtypes differ in their transforming capabilities and reactivation ability. Type 1 is dominant throughout most of the world, but the two types are equally prevalent in Africa. One can distinguish EBV type 1 from EBV type 2 by cutting the viral genome with a restriction enzyme and comparing the resulting digestion patterns by gel electrophoresis.[10]

Role in disease

EBV has been implicated in several diseases that include infectious mononucleosis, Burkitt's lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma and multiple sclerosis.[6]

History

Epstein–Barr virus is named after Michael Anthony Epstein, Professor Emeritus at the University of Bristol and Yvonne Barr (born 1932 in London), graduated from the University of London in 1966 with a Ph.D, who discovered and documented the virus.[22] In 1961, Epstein, a pathologist and expert electron microscopist, attended a lecture on "The Commonest Children's Cancer in Tropical Africa—A Hitherto Unrecognised Syndrome." This lecture, by Denis Parsons Burkitt, a surgeon practicing in Uganda, was the description of the "endemic variant" (pediatric form) of the disease that bears his name. In 1963, a specimen was sent from Uganda to Middlesex Hospital to be cultured. Virus particles were identified in the cultured cells, and the results were published in The Lancet in 1964 by Epstein, Bert Achong, and Barr. Cell lines were sent to Werner and Gertrude Henle at the Children's Hospital of Philadelphia who developed serological markers. In 1967, a technician in their laboratory developed mononucleosis and they were able to compare a stored serum sample, showing that antibodies to the virus developed.[23][24][25] In 1968, they discovered that EBV can directly immortalize B cells after infection, mimicking some forms of EBV-related infections,[26] and confirmed the link between the virus and infectious mononucleosis.[27]

Research

A relatively complex virus, EBV is not yet fully understood. Laboratories around the world continue to study the virus and develop new ways to treat the diseases it causes. One popular way of studying EBV in vitro is to use bacterial artificial chromosomes.[28] Epstein–Barr virus and its sister virus KSHV can be maintained and manipulated in the laboratory in continual latency. While many viruses are assumed to have this property during infection of their natural host, they do not have an easily managed system for studying this part of the viral lifecycle. Genomic studies of EBV have been able to explore lytic reactivation and regulation of the latent viral episome.[12]

References

  1. ^ Maeda E, Akahane M, Kiryu S; et al. (2009). "Spectrum of Epstein–Barr virus-related diseases: a pictorial review". Jpn J Radiol. 27 (1): 4–19. doi:10.1007/s11604-008-0291-2. PMID 19373526. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Cherry-Peppers, G (2003 Feb). "Oral manifestations in the era of HAART" (PDF). Journal of the National Medical Association. 95 (2 Suppl 2): 21S–32S. PMC 2568277. PMID 12656429. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. ^ Toussirot E, Roudier J (2008). "Epstein–Barr virus in autoimmune diseases". Best Practice & Research. Clinical Rheumatology. 22 (5): 883–96. doi:10.1016/j.berh.2008.09.007. PMID 19028369. {{cite journal}}: Unknown parameter |month= ignored (help)
  4. ^ Dreyfus DH (2011). "Autoimmune disease: A role for new anti-viral therapies?". Autoimmunity Reviews. 11 (2): 88–97. doi:10.1016/j.autrev.2011.08.005. PMID 21871974. {{cite journal}}: Unknown parameter |month= ignored (help)
  5. ^ Pender MP (2012). "CD8+ T-Cell Deficiency, Epstein–Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis". Autoimmune Diseases. 2012: 189096. doi:10.1155/2012/189096. PMC 3270541. PMID 22312480.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ a b Ascherio A, Munger KL (2010). "Epstein–Barr virus infection and multiple sclerosis: a review". Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology. 5 (3): 271–7. doi:10.1007/s11481-010-9201-3. PMID 20369303. {{cite journal}}: Unknown parameter |month= ignored (help) Cite error: The named reference "pmid20369303" was defined multiple times with different content (see the help page).
  7. ^ a b c d e f g h i Amon (2004). "Reactivation of Epstein–Barr virus from latency". Reviews in Medical Virology. doi:10.1002/rmv.456. Retrieved 28 May 2012. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  8. ^ In the United States, as many as 95% of adults between 35 and 40 years of age have been infected. National Center for Infectious Diseases
  9. ^ CDC. "Epstein–Barr Virus and Infectious Mononucleosis". CDC. Retrieved 2011-12-29.
  10. ^ a b c d e f g h i j k l m n o p q r Odumade (2011). "Progress and Problems in Understanding and Managing Primary Epstein–Barr Virus Infections". American Society for Microbiology. doi:10.1128/CMR.00044-10. Retrieved 30 May 2012. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  11. ^ Quaia M, Zancai P, Cariati R, Rizzo S, Boiocchi M, Dolcetti R (2000). "Glucocorticoids promote the proliferation and antagonize the retinoic acid-mediated growth suppression of Epstein–Barr virus-immortalized B lymphocytes". Blood. 96 (2): 711–8. PMID 10887139. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ a b Arvey A, Tempera I, Tsai K, Chen HS, Tikhmyanova N, Klichinsky M, Leslie C, Lieberman PM (2012). "An atlas of the Epstein–Barr virus transcriptome and epigenome reveals host-virus regulatory interactions". Cell Host Microbe. 12 (2): 233–245. doi:10.1016/j.chom.2012.06.008. PMID 22901543. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ a b "Entrez Gene: CR2 complement component (3d/Epstein Barr virus) receptor 2".
  14. ^ Lockey TD, Zhan X, Surman S, Sample CE, Hurwitz JL (2008). "Epstein–Barr virus vaccine development: a lytic and latent protein cocktail". Front. Biosci. 13 (13): 5916–27. doi:10.2741/3126. PMID 18508632.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Calderwood MA, Venkatesan K, Xing L, Chase MR, Vazquez A, Holthaus AM, Ewence AE, Li N, Hirozane-Kishikawa T, Hill DE, Vidal M, Kieff E, Johannsen E (2007). "Epstein–Barr virus and virus human protein interaction maps". Proceedings of the National Academy of Sciences of the United States of America. 104 (18): 7606–11. doi:10.1073/pnas.0702332104. PMC 1863443. PMID 17446270. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) The nomenclature used here is that of Kieff. Other laboratories use different nomenclatures.
  16. ^ Hutzinger R, Feederle R, Mrazek J, Schiefermeier N, Balwierz PJ, Zavolan M, Polacek N, Delecluse H, Hüttenhofer A (August 14, 2009). Cullen, Bryan R. (ed.). "Expression and Processing of a Small Nucleolar RNA from the Epstein–Barr Virus Genome". PLoS Pathogens. 5 (8): e1000547. doi:10.1371/journal.ppat.1000547. PMC 2718842. PMID 19680535.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  17. ^ Robertson, ES (editor) (2010). Epstein–Barr Virus: Latency and Transformation. Caister Academic Press. ISBN 978-1-904455-62-2. {{cite book}}: |author= has generic name (help)
  18. ^ Yates JL, Warren N, Sugden B (1985). "Stable replication of plasmids derived from Epstein–Barr virus in various mammalian cells". Nature. 313 (6005): 812–5. doi:10.1038/313812a0. PMID 2983224.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Gratama JW, Oosterveer MA, Zwaan FE, Lepoutre J, Klein G, Ernberg I (1988). "Eradication of Epstein–Barr virus by allogeneic bone marrow transplantation: implications for sites of viral latency". Proc. Natl. Acad. Sci. U.S.A. 85 (22): 8693–6. doi:10.1073/pnas.85.22.8693. PMC 282526. PMID 2847171.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Buisson M, Géoui T, Flot D, Tarbouriech N, Ressing ME, Wiertz EJ, Burmeister WP (2009). "A bridge crosses the active-site canyon of the Epstein–Barr virus nuclease with DNase and RNase activities". J Mol. Biol. 319 (4): 717–28. doi:10.1016/j.jmb.2009.06.034. PMID 19538972.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.jmb.2009.06.034, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.jmb.2009.06.034 instead.
  22. ^ M. A. Epstein, B. G. Achong, and Y. M. Barr: Virus particles in cultured lymphoblasts from Burkitt's lymphoma. The Lancet, March 28, 1964, 1: 702–703
  23. ^ Epstein, M. Anthony (2005). "1. The origins of EBV research: discovery and characterization of the virus". In Robertson, Earl S. (ed.). Epstein–Barr Virus. Trowbridge: Cromwell Press. pp. 1–14. ISBN 1-904455-03-4. Retrieved September 18, 2010.
  24. ^ Erle S. Robertson (2005). Epstein-Barr Virus. Horizon Scientific Press. p. 18. ISBN 978-1-904455-03-5. Retrieved 3 June 2012.
  25. ^ Miller, George (December 21, 2006). "Book Review: Epstein–Barr Virus". New England Journal of Medicine. 355 (25): 2708–2709. doi:10.1056/NEJMbkrev39523. Retrieved September 18, 2010.
  26. ^ Henle W, Henle G (1980). "Epidemiologic aspects of Epstein–Barr virus (EBV)-associated diseases". Annals of the New York Academy of Sciences. 354: 326–31. PMID 6261650.
  27. ^ Young, LS (2009). Desk Encyclopedia of Human and Medical Virology. Boston: Academic Press. pp. 532–533.
  28. ^ Delecluse HJ, Feederle R, Behrends U, Mautner J (2008). "Contribution of viral recombinants to the study of the immune response against the Epstein–Barr virus". Seminars in Cancer Biology. 18 (6): 409–15. doi:10.1016/j.semcancer.2008.09.001. PMID 18938248. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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