Epstein–Barr virus

Virology

Structure and genome

The virus is about 122–180 nm in diameter and is composed of a double helix of deoxyribonucleic acid (DNA) which contains about 172,000 base pairs encoding 85 genes. In July 2020, a team of researchers reported the first complete atomic model of the nucleocapsid of the virus. This "first complete atomic model [includes] the icosahedral capsid, the capsid-associated tegument complex (CATC) and the dodecameric portal—the viral genome translocation apparatus."

Tropism

The term viral tropism refers to which cell types that EBV infects. EBV can infect different cell types, including and epithelial cells.

The viral three-part glycoprotein complexes of mediate B cell membrane fusion; although the two-part complexes of gHgL mediate epithelial cell membrane fusion. EBVs that are made in the B cells have low numbers of gHgLgp42 complexes, because these three-part complexes interact with Human-leukocyte-antigen class II molecules present in B cells 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 normally contain molecules. As a consequence, EBV made from B cells are more infectious to epithelial cells, and EBV made from epithelial cells is more infectious to B cells. Viruses lacking the gp42 portion can bind to human B cells, but are unable to infect.

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). 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.

To enter epithelial cells, viral protein BMRF-2 interacts with cellular β1 integrins. Then, viral protein gH/gL interacts with cellular αvβ6/αvβ8 integrins. This triggers fusion of the viral envelope with the epithelial cell membrane, allowing EBV to enter the epithelial cell. Unlike B-cell entry, epithelial-cell entry is impeded by viral glycoprotein gp42.

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.

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.

Lytic gene products are produced in three consecutive stages: immediate-early, early, and late. 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, EB1, associated with its product gene ZEBRA) and BRLF1 (associated with its product gene Rta). Early lytic gene products have many more functions, such as replication, metabolism, and blockade of antigen processing. Early lytic gene products include BNLF2. Finally, late lytic gene products tend to be proteins with structural roles, such as VCA, which forms the viral capsid. Other late lytic gene products, such as BCRF1, help EBV evade the immune system.

EGCG, a polyphenol in green tea, has shown in a study to inhibit EBV spontaneous lytic infection at the DNA, gene transcription, and protein levels in a time- and dose-dependent manner; the expression of EBV lytic genes* Zta, Rta*, and early antigen complex EA-D (induced by Rta), however, the highly stable EBNA-1 gene found across all stages of EBV infection is unaffected. Specific inhibitors (to the pathways) suggest that Ras/MEK/MAPK pathway contributes to EBV lytic infection though BZLF1 and PI3-K pathway through BRLF1, the latter completely abrogating the ability of a BRLF1 adenovirus vector to induce the lytic form of EBV infection. Additionally, the activation of some genes but not others is being studied to determine just how to induce immune destruction of latently infected B cells by use of either TPA or sodium butyrate.

Latency

Unlike lytic replication, latency does not result in production of virions. Instead, the EBV genome circular DNA resides in the cell nucleus as an episome and is copied by host-cell DNA polymerase. Only a portion of EBV's genes are expressed, which support the latent state of the virus. Latent EBV expresses its genes in one of three patterns, known as latency programs. EBV can latently persist within and epithelial cells, but different latency programs are possible in the two types of cells. Beyond restricted gene expression, episomal EBV can physically hook onto host chromatin, reorganize 3D genome compartments, and rewire enhancer landscapes.

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.

Also, a program is postulated in which all viral protein expression is shut off (Latency 0).

Within B cells, all three latency programs are possible. 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. Upon infecting a resting naïve 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). 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. 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.

Within epithelial cells, only Latency II is possible.

In primary infection, EBV replicates in oropharyngeal 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-cells can result in malignancies, marked by uniform EBV genome presence and gene expression.

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 it is likely reactivation in vivo takes place after latently infected B cells respond to unrelated infections.

Transformation of B lymphocytes

EBV infection of B lymphocytes leads to "immortalization" of these cells, meaning that the virus causes them to continue dividing indefinitely. Normally, cells have a limited lifespan and eventually die, but when EBV infects B lymphocytes, it alters their behavior, making them "immortal" in the sense that they can keep dividing and surviving much longer than usual. This allows the virus to persist in the body for the individual's lifetime.

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, whereas EBNA-LP and the EBERs are not.

Following a natural infection with EBV, the virus is thought to execute 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 numbers of virions 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 and only occasionally reactivates and produces progeny virions. A balance is eventually struck between occasional viral reactivation and host immune surveillance, removing cells that activate viral gene expression. The manipulation of the human body's epigenetics by EBV can alter the genome of the cell to leave oncogenic phenotypes.

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

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

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.

Detection

Serological testing is the first-line approach, employing enzyme-linked immunosorbent assays (ELISA) to detect IgM and IgG antibodies against viral capsid antigen (VCA), early antigen (EA), and Epstein–Barr nuclear antigen (EBNA); the pattern of these antibodies differentiates acute, recent, or past infection stages.

Then in situ hybridization using EBER-ISH targets the highly abundant EBV-encoded small RNAs within infected cells, enabling precise localization of latent infection in tissue biopsies and serving as the diagnostic gold standard in pathology.

Then, nucleic acid detection via polymerase chain reaction (PCR) assays allows rapid, sensitive detection of EBV DNA in blood or tissue, although it cannot distinguish latent from active infection and shows poor correlation with clinical symptoms.

Additional methods such as immunofluorescence assays (IFA) offer high specificity and staging capability in specialized laboratories, and chemiluminescence immunoassays (CLIA) show promise in distinguishing primary from past infections pending further validation.

Role in disease

:See also Infectious mononucleosis, diseases associated with EBV infection and the other diseases listed in this section

EBV causes infectious mononucleosis. Children infected with EBV have few symptoms or can appear asymptomatic, but when infection is delayed to adolescence or adulthood, it can cause fatigue, fever, inflamed throat, swollen lymph nodes in the neck, enlarged spleen, swollen liver, or rash. Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome has also been associated with EBV infection.

EBV has also been implicated in several other diseases, including Burkitt's lymphoma, hemophagocytic lymphohistiocytosis, Hodgkin's lymphoma, stomach cancer, nasopharyngeal carcinoma, multiple sclerosis, and lymphomatoid granulomatosis.

EBV-infected B cells have been shown to reside within the brain lesions of multiple sclerosis patients,

Additional diseases that have been linked to EBV include Gianotti–Crosti syndrome, erythema multiforme, acute genital ulcers, and oral hairy leukoplakia. The viral infection is also associated with, and often contributes to the development of, a wide range of non-malignant lymphoproliferative diseases such as severe hypersensitivity mosquito bite allergy reactions, Epstein–Barr virus-positive mucocutaneous ulcers, and hydroa vacciniforme as well as malignant lymphoproliferative diseases such as Epstein–Barr virus-positive Burkitt lymphoma, Epstein–Barr virus-positive Hodgkin lymphoma, and primary effusion lymphoma.

The Epstein–Barr virus has been implicated in disorders related to alpha-synuclein aggregation (e.g., Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy).

It has been found that EBNA1 may induce chromosomal breakage in the 11th chromosome, specifically in the 11q23 region between the FAM55D gene and FAM55B, which EBNA-1 appears to have a high affinity for due to its DNA-binding domain having an interest in a specific palindromic repeat in this section of the genome. While the cause and exact mechanism for this is unknown, the byproduct results in errors and breakage of the chromosomal structure as cells stemming from the line of the tainted genome undergo mitosis. Since genes in this area have been implicated in leukemia and is home to a tumor suppressor gene that is modified or not present in most tumor gene expression, it's been hypothesized that breakage in this area is the main culprit behind the cancers that EBV increases the chance of. The breakage is also dose-dependent; a person with a latent infection will have less breakage than a person with a novel or reactivated infection, since EBNA1 levels in the nucleus and nucleolus are higher during active attack of the body because of the constant replication and takeover of cells in the body.

The complexities of Epstein–Barr virus (EBV) persistence and its integration into host genomes have been explored. Research involving tissue samples from individuals with various conditions revealed that viral sequences were highly conserved, indicating long-term persistence from dominant strains. Notably, EBV was found to integrate into the host genome in cases of malignancies, including mantle cell lymphoma, where a significant integration event was observed involving the EBV LMP-1 gene and chromosome 17. This integration likely occurred via microhomology-mediated end joining, suggesting a potential mechanism through which EBV may influence tumorigenesis. Moreover, instances of high viral loads and accompanying genetic diversity were noted in patients with active disease, underscoring the virus's dynamic nature within the host and its possible contribution to the progression of EBV-associated cancers.

History

The Epstein–Barr virus was named after M. A. Epstein and Yvonne Barr, who discovered the virus together with Bert Achong. 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" by D. P. Burkitt, a surgeon practicing in Uganda, in which Burkitt described the "endemic variant" (pediatric form) of the disease that now 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, Achong, and Barr. In 1968, they discovered that EBV can directly immortalize B cells after infection, mimicking some forms of EBV-related infections, and confirmed the link between the virus and infectious mononucleosis.

Research

As 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. Epstein–Barr virus can be maintained and manipulated in the laboratory in continual latency (a property shared with Kaposi's sarcoma-associated herpesvirus, another of the eight human herpesviruses). Although many viruses are assumed to have this property during infection of their natural hosts, there is no 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.

Although under active research, an Epstein–Barr virus vaccine is not yet available. The development of an effective vaccine could prevent up to 200,000 cancers globally per year.

It is possible, in theory, that a prolonged use of valaciclovir, an antiviral drug approved to treat herpes simplex or herpes zoster, might lead to Epstein–Barr eradication, but such a theory was not confirmed by any study. Antiviral agents act by inhibiting viral DNA replication, but there is little evidence that they are effective against Epstein–Barr virus. Moreover, they are expensive, risk causing resistance to antiviral agents, and (in 1% to 10% of cases) can cause unpleasant side effects.

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