Epstein-Barr virus

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

Epstein-Barr virus, frequently referred to as EBV, is a distinct member of the herpesvirus family (Herpesviridae) of DNA viruses and one of the most common viruses in humans. Most people become infected with EBV, which is often asymptomatic but commonly is associated with acute infectious mononucleosis, as well as certain types of cancer, such as nasopharyngeal carcinoma and Burkitt's lymphoma. It is also known as Human herpesvirus 4 (HHV-4).

EBV is so ubiquitous among humans worldwide that it is difficult to tell if it is the causal agent of the various associated diseases or simply present. Most people become infected with EBV sometime during their lives. In the United States, as many as 95 percent of adults between 35 and 40 years of age have been infected. Infants become susceptible to EBV as soon as maternal antibody protection (present at birth) 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 in other developed countries, many persons are not infected with EBV in their childhood years. When infection with EBV occurs during adolescence or young adulthood, it is associated with infectious mononucleosis about thirty-five to fifty percent of the time. In these cases, the transmission of EBV typically requires intimate contact with the saliva (found in the mouth) of an infected person, and thus a monogamous lifestyle decreases the chances of transmission, as with some other viruses of the Herpesviridae family.

Overview

The Epstein-Barr virus is a member of the Herpesviridae, a large family of DNA viruses that cause diseases in animals, including humans (Ryan and Ray 2004; Mettenleiter et al. 2008; Sandri-Goldin 2006). Herpesviridae can cause latent or lytic infections. All herpes viruses are composed of relatively large double-stranded, linear DNA genomes encoding 100-200 genes encased within an icosahedral protein cage called the capsid, which is itself wrapped in a lipid bilayer membrane called the envelope. This particle is known as the virion. All herpes viruses are nuclear-replicating—the viral DNA is transcribed to RNA within the infected cell's nucleus. There are eight distinct viruses in this family known to be associated with disease in humans, including herpes simplex virus (HSV-1, HSV-2)(cold sores and genital herpes), varicella zoster virus (cause of chickenpox and shingles), and Epstein-Barr virus (Whitley 1996). In addition to the Herpes viruses considered endemic in humans, some viruses associated primarily with animals may infect humans.

EBV is found in all regions of the world and is very common. The Centers for Disease Control (CDC) estimates that 95 percent of all adult Americans between the ages of 35 and 40 years have been infected, and is more prevalent in adults than children and adolescents (Longe 2006). In Africa, however, most children have been infected by EBV by the age of three years old (Longe 2005). Once EBV infects a person, it remains in the human body for life (Longe 2006).

The Epstein-Barr virus test involves a blood test or a group of tests to ascertain the presence or absence of antibodies in the blood that are active against the proteins of the Epstein-Barr virus (Lutwick 2004).

EBV is named after Michael Epstein and Yvonne Barr, who, together with Bert Achong, discovered the virus in 1964, in cells cultured from the tumor specimens sent to them from Mulago Hospital in Kampala, Uganda by Denis Burkitt (Epstein et al. 1964). Burkitt and Epstein had met three years earlier in London during a talk by Burkitt on his findings regarding children's cancers in tropical Africa. In the talk, Burkitt postulated that there may be an infectious component to what he referred to as "African lymphoma." After the presentation, the two men met and Burkitt agreed to send Epstein frozen specimens for him to analyze (Coakley 2006).

Virology

Epstein-Barr virus and its sister virus KSHV (Kaposi's sarcoma-associated herpesvirus) 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.

It has been discovered that EBV can directly alter white blood cells associated with the immune system, altering B lymphocytes (Longe 2006). On infecting the B lymphocyte, the linear virus genome circularizes and the virus subsequently persists within the cell as an episome.

The virus can execute many distinct programs of gene expression, which can be broadly categorized as being lytic cycle or latent cycle.

The lytic cycle, or productive infection, results in staged expression of several viral proteins with the ultimate result of producing infectious virions. Formally, this phase of infection does not inevitably lead to lysis of the host cell as EBV virions are produced by budding from the infected cell.

The latent cycle (lysogenic) programs are those that do not result in production of virions. A very limited, distinct set of viral proteins are produced during latent cycle infection. These include Epstein-Barr nuclear antigen (EBNA)-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA-leader protein (EBNA-LP) and latent membrane proteins (LMP)-1, LMP-2A and LMP-2B and the Epstein-Barr encoded RNAs (EBERs). In addition, EBV codes for at least twenty microRNAs, which are expressed in latently infected cells. (The nomenclature used here is that of the Kieff lab. Other laboratories use different nomenclatures.)

From studies of EBV gene expression in cultured Burkitt's lymphoma cell lines, at least three programs exist:

  • EBNA1 only (group I)
  • EBNA1 + EBNA2 (group II)
  • Latent cycle proteins (group III)

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

When EBV infects B lymphocytes 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. The EBNA-1 protein is essential for maintenance of the virus genome (Yates et al. 1985).

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 (Gratama et al. 1988).

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.

  • EBNA-1

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-1 possesses a glycine-alanine repeat that impairs antigen processing and MHC class I-restricted antigen presentation thereby inhibiting the CD8-restricted cytotoxic T-cell response against virus infected cells (levitskaya et al. 1995).

EBNA-1 was initially identified as the target antigen of sera from rheumatoid arthritis patients (rheumatoid arthritis-associated nuclear antigen; RANA).

  • EBNA-2

EBNA-2 is the main viral transactivator, switching transcription from the Wp promoters used during initially after infection to the Cp promoter. Together with EBNA-3C, it also activates the LMP-1 promoter. It is known to bind the host RBP-Jκ protein that is a key player in the Notch pathway. EBNA-2 is essential for EBV-mediated growth transformation.

  • EBNA-3A/EBNA-3B/EBNA-3C

These genes also bind the host RBP-Jκ protein.

  • EBNA-3C

EBNA-3C can recruit a ubiquitin-ligase and has been shown to target cell cycle regulators like pRb (Knight et al. 2005a; Knight et al. 2005b).

  • LMP-1

LMP-1 is a six-span transmembrane protein that is also essential for EBV-mediated growth transformation. LMP-1 mediates signaling through the Tumor necrosis factor-alpha/CD40 pathway.

  • LMP-2A/LMP-2B

LMP-2A/LMP-2B are transmembrane proteins that act to block tyrosine kinase signaling. it is believed that they act to inhibit activation of the viral lytic cycle. It is unknown whether LMP-2B is required for EBV-mediated growth transformation, while different groups have reported that LMP-2A alternatively is, or is not needed for transformation.

  • EBER-1/EBER-2

EBER-1/EBER-2 are small nuclear RNAs of an unknown role. They are not required for EBV-mediated growth transformation.

  • miRNAs

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.

Surface receptors

The Epstein-Barr virus surface glycoprotein H (gH) is essential for penetration of B cells but also plays a role in attachment of virus to epithelial cells (Molesworth et al. 2000).

In laboratory and animal trials reported 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 (Quaia et al. 2000).

Pathology

Infectious mononucleosis

Epstein-Barr is associated with and considered as the predominant cause of infectious mononucleosis, also known as "glandular fever," "mono," and "Pfeiffer's disease." It is thought to be predominantly caused by the Epstein-Barr virus (EBV) infecting B cells (B-lymphocytes), producing a reactive lymphocytosis predominantly consisting of atypical lymphocytes, a specific type of T-cell that gives the disease its name. The name "kissing disease" is often applied to mono in casual speech, as in developed countries it is most common at the same age when adolescents and young adults are initiating romantic behavior. This co-occurrence is not apparent in undeveloped countries, where poor sanitation and close living arrangements cause the causative virus to be spread at a much earlier age, when the disease is mild and seldom diagnosed. Both males and females are susceptible to mononucleosis.

Infectious mononucleosis is predominantly found in the developing world, and most children in the developing world are found to have already been infected by around 18 months of age. EBV antibody tests turn up almost universally positive. In the United States roughly half of five-year-olds have been infected (Bennett 2008), with higher percentages in adults.

EBV-associated malignancies

EBV establishes a lifelong dormant infection in some cells of the body's immune system. A late event in a very few carriers of this virus is the emergence of Burkitt's lymphoma and nasopharyngeal carcinoma, two rare cancers. EBV appears to play an important role in these malignancies, but is probably not the sole cause of disease.

The strongest evidence linking EBV and cancer formation is found in Burkitt's lymphoma and nasopharyngeal carcinoma. It has been postulated to be a trigger for a subset of chronic fatigue syndrome patients (Lerner et al. 2004), as well as multiple sclerosis and other autoimmune diseases (Lünemann and Münz 2007).

Burkitt's lymphoma is a type of Non-Hodgkin's lymphoma and is most common in equatorial Africa and is co-existent with the presence of malaria (dugdale and Mason 2008). Malaria infection causes reduced immune surveillance of B cells immortalized by EBV, resulting in an excessive number of B cells and an increased likelihood of an unchecked mutation. Repeated mutations can lead to loss of cell-cycle control, causing excessive proliferation observed as Burkitt's lymphoma. Burkitt's lymphoma commonly affects the jaw bone, forming a huge tumor mass. It responds quickly to chemotherapy treatment, namely cyclophosphamide, but recurrence is common.

Other B cell lymphomas arise in immunocompromized patients such as those with AIDS or who have undergone organ transplantation with associated immunosuppression (Post-Transplant Lymphoproliferative Disorder (PTLPD)). Smooth muscle tumors are also associated with the virus in malignant patients (Weiss 2002).

Nasopharyngeal carcinoma is a cancer found in the upper respiratory tract, most commonly in the nasopharynx, and is linked to the EBV virus. It is found predominantly in Southern China and Africa, due to both genetic and environmental factors. It is much more common in people of Chinese ancestry (genetic), but is also linked to the Chinese diet of a high amount of smoked fish, which contain nitrosamines, well known carcinogens (environmental) (Sinha and Gajra 2021).

Clinical symptoms and treatment of infectious mononucleosis

Clinical symptoms

Typical symptoms of infection with EBV include fever, malaise, swollen glands, sore throat, and sometimes swollen spleen and/or liver, and last for one to two months (Longe 2006).

Symptoms of infectious mononucleosis are fever, sore throat, and swollen lymph glands. Sometimes, a swollen spleen or liver involvement may develop. Heart problems or involvement of the central nervous system occurs only rarely, and infectious mononucleosis is almost never fatal. There are no known associations between active EBV infection and problems during pregnancy, such as miscarriages or birth defects (Fleisher and Bolognese 1983; CDC 2008). Although the symptoms of infectious mononucleosis usually resolve in 1 or 2 months, EBV remains dormant or latent in a few cells in the throat and blood for the rest of the person's life. Periodically, the virus can reactivate and is commonly found in the saliva of infected persons. Reactivated and post-latent virus may pass the placental barrier in (also seropositive) pregnant women via macrophages and therefore can infect the fetus. Also re-infection of prior seropositive individuals may occur. In contrast reactivation in adults usually occurs without symptoms of illness.

Most individuals exposed to people with infectious mononucleosis have previously been infected with EBV and are not at risk for infectious mononucleosis. In addition, transmission of EBV typically, but not exclusively, requires intimate contact with the saliva (found in the mouth) of an infected person. Transmission of this virus through the air or blood does not normally occur. The incubation period, or the time from infection to appearance of symptoms, ranges from 4 to 6 weeks. Persons with infectious mononucleosis may be able to spread the infection to others for a period of weeks. However, no special precautions or isolation procedures are recommended, since the virus is also found frequently in the saliva of healthy people. In fact, many healthy people can carry and spread the virus intermittently for life. These people are usually the primary reservoir for person-to-person transmission. For this reason, transmission of the virus is almost impossible to prevent.

The clinical diagnosis of infectious mononucleosis is suggested on the basis of the symptoms of fever, sore throat, swollen lymph glands, and the age of the patient. Usually, laboratory tests are needed for confirmation. Serologic results for persons with infectious mononucleosis include an elevated white blood cell count, an increased percentage of certain atypical white blood cells, and a positive reaction to a "mono spot" test.

Treatment

There is no specific treatment for infectious mononucleosis, other than treating the symptoms. No antiviral drugs or vaccines are available. Some physicians have prescribed a 5-day course of steroids to control the swelling of the throat and tonsils. The use of steroids has also been reported to decrease the overall length and severity of illness, but these reports have not been published.

It is important to note that symptoms related to infectious mononucleosis caused by EBV infection seldom last for more than 4 months. When such an illness lasts more than 6 months, it is frequently called chronic EBV infection. However, valid laboratory evidence for continued active EBV infection is seldom found in these patients. The illness should be investigated further to determine if it meets the criteria for chronic fatigue syndrome, or CFS. This process includes ruling out other causes of chronic illness or fatigue.

EBV-associated diseases

  • Infectious mononucleosis
  • Several Non-Hodgkin's lymphomas, including Burkitt's lymphoma and primary cerebral lymphoma
  • Hodgkin's disease
  • Stevens-Johnson syndrome
  • Hepatitis
  • Alice in Wonderland syndrome
  • Post-transplant lymphoproliferative disorder
  • Herpangina
  • Multiple Sclerosis (higher risk in patients infected as teenagers than as children)
  • Hairy leukoplakia
  • Common variable immunodeficiency (CVID)
  • Kikuchi's disease
  • Nasopharyngeal cancer
  • Subepithelial Infiltrates
  • Smooth muscle tumors (Deyrup et al. 2006)

In the late 1980s and early 1990s, EBV became the favored explanation for chronic fatigue syndrome. It was noted that people with chronic exhaustion had EBV, although it was also noted EBV was present in almost everyone. In a four year study, the Centers for Disease Control and Prevention found that the virus did not adhere to Koch's Postulates and, therefore, had no definitive association between CFS and EBV but it is still being studied by researchers.

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