Epstein-Barr virus (EBV), also known as Human Herpes Virus 4, is the etiologic agent for infectious mononucleosis, an illness often colloquially called "mono." Although "mono" is notorious among adolescents, Epstein-Barr virus itself is frequently overshadowed by its viral relatives HSV-1 and HSV-2 when it comes to research and public interest. To combat these issues, this paper will provide specific information about EBV, including data on its structure, classification, pathogenesis, replication cycle, epidemiology, and the treatment and prevention of infectious mononucleosis and other EBV-related illnesses.
Structure and Classification
EBV is a linear, double stranded DNA virus with a Baltimore classification of Class I (1,16). Belonging to the family herpesviridae and the subfamily Gammaherpesvirinae, the virus can also be categorized as a human B-lymphotropic gamma herpesvirus (1,9,12). EBV has an icosadeltahedral capsid consisting of 162 capsomeres, and the virus is significantly large, with a diameter of 150 nm (12). Like all herpes viruses, the virus is surrounded by an envelope containing glycoproteins that play various roles in assisting in its proliferation (9,12). Glycoproteins B, H, and L, for example, assist in the virus's entry into its target cells, which include B cells as well as epithelial cells (9). Glycoproteins H and L aggregate together to form a heterodimeric structure on the surface of the virus (9). Subsequent folding of these proteins results in a 4-domained structure with a conceivable but as of yet unconfirmed movable portion that may play a further role in the fusion between the host cell and the virus (9).
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EBV's genome consists of 175 kilobase pairs, and within its DNA are numerous tandem repeats (1). Although the exact number of tandem repeats differs depending upon the strain, researchers have found that there are standard terminal repeats, called TRs, at both ends of the DNA strand, and approximately between six to twelve repeats of an area in the genome termed IR1 (1,16). EBV exhibits two lifecycles: the latent lifecycle and the lytic lifecycle (12). Once the virus infects its target cell, the viral genome is maintained as an episome, specifically a plasmid, during the latent lifecycle of the virus (1). The previously linear DNA forms its circular shape by covalent interactions between these aforementioned terminal repeats (16).
The Epstein-Barr viral genome encodes for six important structural proteins that aid in the construction of its capsid. Three of these proteins are encoded from the late genes BFRF3, BcLF1, and BdRF1. In order for EBV to successfully complete its lifecycle, BFRF3, the small capsid protein, must be present and functioning correctly. BdRF1, a scaffolding protein, and BcLF1, the major capsid protein, are required to be present with the small capsid protein as the capsid self-assembles. Other proteins encoded for during this period include a protease, rising from the BVRF2 gene, which cuts the scaffolding protein and allows for EBV's maturation (8).
Pathogenesis and Immunity
EBV infects B lymphocytes as well as epithelial cells (12). When EBV infects epithelial nasopharyngeal carcinoma cell lines, the virus induces these cells to not only become round in appearance, but to also transform into large, multinucleated entities (15). Furthermore, syncytia as well as nuclear and cytoplasmic inclusion bodies begin to develop as the virus actively replicates (15). Despite these physical alterations, cells infected with EBV face other aspects of irregularity (12). EBV causes a lifelong infection in the cells it infects, and when it infects B cells, it exploits the stages of B cell growth in order to launch its infection (12). EBV contains certain attributes that allow it to thrive within the body of an infected person quite successfully; for example, the virus uses proteins to disallow for apoptosis and to allow for B lymphocytes to continuously divide, thus rendering these cells an everlasting production facility for the virus (12). Once an individual is infected, one B cell per milliliter of blood within the individual's body carries EBV (12).
When EBV is actively replicating within B cells or the oropharynx's epithelial cells, the virus is shed within the saliva, and thus contact such as kissing is its mode of transmission. As a result, infectious mononucleosis, the disease that is caused by EBV, is often coined the "kissing disease." Once the virus is contracted, EBV invades the blood in order to effectively attack a plethora of B cells. During this initial infection, EBV manufactures certain proteins which are the first to be targeted by the immune system. These proteins include the viral capsid antigen, the membrane antigen, and the early antigen. The immune system builds antibodies to pursue and destroy these surface and cytoplasmic antigens, before building more antibodies to target the nuclear antigens of EBV. In conjunction with these antibodies, T cells help to control the replication of B cells as the EBV attempts to stimulate it. Nevertheless, EBV does employ mechanisms to fend off the immune system's attack. For example, EBV produces a molecule that resembles interleukin-10. This molecule competitively inhibits the TH1 CD4+ T-cell receptor and disallows for the regulation of B cell proliferation, thus leading to a surge in B cell replication (12).
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Infectious mononucleosis is a mild, nonfatal disease. Its symptoms are flu-like and include a painful sore throat, a fever, and swollen lymph organs (20). Those infected with HIV may suffer from hairy oral leukoplakia, a condition where white lesions can be found on and in the mouth, specifically on the tongue (4, 12). Viral DNA can readily be found within these lesions (4). As with most diseases, these symptoms are a result of the immune system attempting to control the infection (12). Once infected with EBV, the body's cellular immunity goes into overdrive in an attempt to control the infection (7). When analyzing the blood of an EBV-infected individual, T cells make up most of the abnormal number of lymphocytes found in circulation (7). Symptoms generally subside within one to two months, and although the healthy individual will be perpetually infected with the virus, having infectious mononucleosis does not result in long-lasting damaging effects (20). However, immunocompromised populations are in danger of developing cancers due to the absence of T cells (20). B cells can then proliferate to the point of causing lymphomas such as Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkin's lymphoma (20). Burkitt's lymphoma is a cancer endemic to Africa that usually affects children (12). Malarial infections compromise the immune system and disallow T cells to control the infection (4, 12). As a result, tumors arise in the face and jaw (12). Unlike Burkitt's lymphoma, nasopharyngeal carcinoma is common in Asia, and the cancer is of epithelial-cell origin, not B cell origin (12). Moreover, all three cancers can occur in HIV/AIDS patients infected with EBV, and is therefore one of the many complications of the disease (4).
EBV, as was previously stated, uses a receptor-mediated approach to gain entry into its target cells, which include B cells and the epithelial cells of the nasopharynx and oropharynx (12). EBV has an affinity for the CD21 receptor that these cells express; CD21 is an important receptor for the complement cascade, and thus only a select few cells display this protein on their surface (12). As a result, EBV has a narrow cell tropism and preferentially attaches to these aforementioned B cells (12). From here, the virus fuses with its target cell by using glycoproteins B, H, and L which are located on the virion's surface (9). These proteins undergo an as of yet unidentified conformational change that aids in fusion (9). From here, how EBV specifically uncoats and enters the nucleus is uncertain; however, its method may be similar to that of other gammaherpesviruses (10). These viruses use microtubules and manipulation of the cell's signaling pathways to direct the virion to the nucleus where it can then inject its genome (10).
Once the viral DNA is inside of the nucleus, the virus can either enter a latent phase or a lytic phase (16). During a lytic infection gene expression occurs, and the host cell's DNA-dependent RNA polymerase is used for circularization of the the linear DNA as well as for transcription (16). EBV undergoes three phases of gene expression: the intermediate-early phase, the early phase, and the late phase (19). The intermediate-early phase controls genes such as BZLF1 and BRLF1, which initiates a productive infection by encoding for the ZEBRA protein (19). An origin binding protein, ZEBRA also activates transcription, thereby initiating gene expression and moving the virus from the latent phase, if it is in one, into the lytic cycle (5,19). In order to perform this function, the protein must bind to specific sequences of DNA called ZEBRA response elements (5). ZEBRA also uses these sequences to initiate viral replication; it is currently unknown how this protein can differentiate between when to initiate transcription and when to initiate viral replication (5).
In all, EBV's genome encodes for six important proteins needed for viral replication, including ZEBRA (11). Early gene BMRF1 encodes for a polymerase processivity factor, and early gene BALF5 encodes for a catalytic subunit; once produced, these proteins interact to form the DNA-dependent DNA polymerase (5,11). Other early genes include BALF2, which encodes for a single-stranded DNA-binding protein, BSLF1, which encodes for a primase, and BBLF4, which encodes for a helicase (11). Furthermore, EBV expresses a protein known as EB2 that exports mRNA from the nucleus to the cytoplasm where translation by host ribosomes can occur (2). Once all of these necessary proteins are synthesized, DNA replication can begin. EBV uses a rolling circle mechanism for the synthesis of new DNA (11). Initiation of replication begins with ZEBRA recognizing a lengthy stretch of DNA termed oriLYt (5). This origin of replication contains seven ZEBRA-binding sites which the protein must recognize for replication to occur (5). The polymerase, helicase, and primase all work in conjunction at the origin of replication to produce progeny DNA in an intermediate concatemer form before being cleaved into several progeny viral genomes (11,19). The method by which this cleavage occurs has yet to be determined (16).
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Once viral replication has begun, late genes are expressed (19). These late genes include BLRFR, which encodes for a protein to be packaged in the tegument, BcLF1, which encodes for the major capsid protein, and BFRF3, which encodes for a small capsid element (8). Other important late genes transcribed and subsequently translated include BdRF1, which encodes for the scaffolding protein, and BVRF2, which encodes for a protease used to achieve maturation of the virus (8). Late genes are also expressed to lead to the production of glycoproteins, such as the ones mentioned earlier that aid in fusion (9,19). Again, the expression of these late genes seems to be tied to the ability of ZEBRA to commence the lytic cycle; once replication has occurred, these genes are immediately expressed (5,19). Assembly of the progeny virions occurs in the nucleus of infected cells; therefore structural proteins must make specific associations with each other in order to be moved to this location (8). For example, it is the scaffolding protein's task to transport the major capsid protein into the nucleus, and, subsequently, when these two proteins are associated with each other, the small capsid protein can enter the nucleus as well (8). Once inside, EBV structural proteins self-assemble through physical interactions (8). The small and major capsid proteins and the scaffolding protein form the procapsid; this shell interacts with the DNA packaging complex in the nucleus and is then filled with the progeny DNA (8). Once the genome is inside of the capsid, EBV uses a protease to dispose of the scaffolding protein, and the progeny virion is now mature and ready to exit the cell (8). The mechanism by which EBV obtains its envelope and exits the cell is still uncertain (13). One study, which looks at gammaherpesviruses in general, states that the virus may receive an initial envelope from budding off of the inner nuclear membrane followed by a de-envelopment stage where the virus fuses with the outer nuclear membrane (13). As a result, the naked virus is released into the cytoplasm where it obtains its tegument proteins (13). The virus acquires these proteins while in proximity to the Golgi apparatus; as a result, numerous vesicles are readily available to swallow the virions and carry them to the plasma membrane where egress occurs through exocytosis (13).
Latency is established by the encoding of certain latency-associated genes on the EBV genome. These genes include EBNA1, a latency protein that creates an association between the EBV epsiome and the host DNA. As a result, as the host cells grow and divide, the EBV genome is maintained from generation to generation within the host cell. EBNA2 activates the expression of all other latency-associated proteins, and assists in inhibiting the cellular functions that lead to the inhibition of B-cell differentiation. The bulk of these latent genes work to initiate a false B-cell activation in order for latent infection of these cells to occur. The products of these genes emulate the signals produced from immune system cells such as the products of T-helper cells and antigen-presenting cells. For example, LMP1 functions as a T-helper cell signal. In short, the virus produces proteins to push infected B cells to become differentiated into memory cells. These memory cells will then act as a reservoir for the virus (17).
Treatment and Prevention
Due the ubiquity of EBV and the mild nature of infectious mononucleosis, an intense drug regimen is not necessary nor available (12). For most who fall ill with infectious mononucleosis, rest and avoidance of strenuous activity is recommended because splenic rupture can occur (4). Those with complicated infectious mononucleosis, including individuals with cardiac disease, central nervous system complications, elevated fevers, and those who experience severe symptoms, should be administered glucocorticoids, an anti-inflammatory hormone that also works to suppress the immune system (4,20). While glucocorticoids can assist in reducing severe inflammation of the throat and tonsils, they can also lead to secondary bacterial infections; therefore, glucocorticoids should not be administered to patients who do not suffer from any of the previously listed conditions (4,20).
Like glucocorticoids, prednisone is administered to individuals infected with EBV who already have pre-existing medical conditions such as autoimmune hemolytic anemia or tonsillar hypertrophy (4). Prednisone, also like glucocorticoid, is an anti-inflammatory, immunosuppressive drug (2,20). In addition to these steroids, treatments are also available for complications that arise from an EBV infection or for manifestations of diseases that have a correlation with EBV (4). Acyclovir, an antiviral drug that acts as a nucleoside inhibitor, works well against oral hairy leukoplakia, an ailment that usually develops in those who are coinfected with HIV (4,12). Once introduced into the body, acyclovir is activated by cellular thymidine kinase; it then binds to the viral DNA polymerase after the polymerase falsely identifies the drug as a nucleotide (12). As a result, replication ends prematurely (12). Finally, for those suffering from Burkitt's Lymphoma, chemotherapy has proven to be an effective treatment (3).
The most prominent problem with attempting to find an antiviral remedy for infectious mononucleosis is the fact that most of the symptoms an EBV-infected person experiences are a result from the immune system. This intense immune response, led by an influx of T cells, is the reason why immunosuppressive drugs such as the aforementioned corticosteroids are used, even though clinically they have little to no affect on the symptoms or outcome of infectious mononucleosis. Again, these steroids are mostly employed for their anti-inflammatory effects to prevent or lessen airway obstruction (7).
A select few classes of drugs have been used to test for their effectiveness against inhibiting EBV replication. These groups include acyclic nucleoside analogues, acyclic nucleotide analogues, and pyrophosphate analogues, which all have a mechanism of action that works on EBV's DNA polymerase. 4-oxo-dihydroquinolines, maribavir, Î²-L-5-iododioxolane uracil and indolocarbazole NIGC-I are all drugs that also may have an effect on EBV with unknown mechanisms of action. The pyrophosphate analogues, such as fosacarnet and phosphonoacetic acid, bind to an available site on EBV's polymerase, thus preventing its function, while acyclic nucleoside and nucleotide analogues work by blocking elongation of the growing DNA chain and halting replication. For the most part, these drugs are not ideal because they are toxic and can result in the viral mutation. Other drugs, such as TCRB and BDCRB, inhibit a genomic processing step in herpesviruses, but have shown to have no effect on EBV. Maribavir, however, does work against EBV by preventing release of the virus from the nucleus and by impeding the function of EBV's protein kinases. Another drug, indolocarbazoles, has a similar mechanism to maribavir, but it has no effect on EBV, while 4-oxo-dihydroquinolines, like the pyrophosphate analogues and acyclic nucleotide/nucleoside analogues, inhibits the viral DNA polymerase. 4-oxo-dihydroquinolines have been shown to inhibit EBV replication, but in the laboratory only. Therefore, there is still no definitive treatment for infectious mononucleosis (7).
Being that EBV is ever-present in the population and is transmitted from contact with saliva, preventing and controlling the spread of the virus is very problematic, if not impossible (20). However, preventative measures are very important when it comes to recipients of transplants (14). Transplant patients who have been previously infected with EBV or who acquire the virus at the time of their transplant are at risk of contracting lymphoproliferative disease (LPD) (14). The prevention of this disease is very important because its prognosis is bleak (18). Transplant patients at a high risk of contracting the disease, those with 1000 gep/mL of viruses in their plasma, could be administered rituximab, a drug currently used for the treatment of LPD (18). After testing rituximab on patients at a high risk of acquiring of LPD, the study found that none of these patients experienced EBV reactivations; therefore, it can be concluded that rituximab can successfully be used prophylactically (18).
Finally, there are no vaccines in use to prevent EBV; however, a vaccine containing the major EBV glycoprotein is presently in clinical trials (4).
EBV is ubiquitous worldwide (12). The vast majority of people become infected with EBV during the late early stages of their lives, particularly those who are in their adolescent years (12). In the United States, up to 70% of individuals are infected by the time they are thirty years old, and at least 95% of thirty-five to forty year olds are infected with EBV (12,20). For the most part, children who become infected with EBV acquire it by drinking from glasses laden with the virus (12). Fortunately, children do not experience as severe of a disease as those who acquire EBV when they are older, and children are also less likely than adolescents to become infected (20). Children show little to no symptoms and, as a result, often go undiagnosed (20). Adolescents generally become infected with EBV from the swabbing of infected saliva (12,20). The clinical outcome of infectious mononucleosis in adolescents and adults follows the typical presentation of mono with symptoms varying in intensity (20). Becoming infected with EBV, however, does not necessary guarantee that one will have infectious mononucleosis (20). Disease develops only 35% to 50% of the time (20). Because infection with EBV is life-long, a large percentage of individuals become asymptomatic shedders of the virus, thus aiding in its transmission (12, 20).
It is safe to say that everybody is susceptible to becoming infected with EBV (12). The presence of asymptomatic shedders and the nature of human behavior (kissing, sharing glasses with loved ones, etc) facilitate the transmission and circulation of the virus (20). Other factors, found predominately in other countries, may increase the risk of contracting the virus (12). For example, there seems to be a correlation between malaria and EBV in Africa; the presence of parasite (and its subsequent effect of suppressing the immune system) seems to increase the population's susceptibility of acquiring the virus (12). Although not yet confirmed, there also appears to be a correlation between EBV and individuals from certain regions of China (12). Finally, already immunocompromised individuals, such as HIV/AIDS patients and transplant patients taking immunosuppressive drugs, have a severely high chance of contracting EBV and developing LPD (12).
In conclusion, EBV is a multifaceted virus that latently infects a large percentage of the human population. Although the virus only causes a mild illness, infection with EBV can lead to serious complications, especially in at risk populations. While no vaccine or specific treatment exists for the virus, research and growing interest in EBV will hopefully reveal how to protect the vulnerable populations of America from contracting the virus.