INTRODUCTION — Epstein-Barr virus (EBV) is a widely disseminated herpesvirus (human herpes virus 4), which is spread by intimate contact between susceptible persons and asymptomatic EBV shedders. The majority of primary EBV infections throughout the world are subclinical and unapparent. Antibodies to EBV have been demonstrated in all population groups with a worldwide distribution; approximately 90 to 95 percent of adults are EBV-seropositive.
Like other members of the herpesvirus family, EBV has a latency phase. The host cells for the organism in humans are B lymphocytes, T lymphocytes, epithelial cells and myocytes. Unlike herpes simplex (HSV) or cytomegalovirus (CMV), EBV is capable of transforming B cells and does not routinely display a cytopathic effect in cell culture.
EBV is the primary agent of infectious mononucleosis, persists asymptomatically for life in most adults, and is associated with the development of B cell lymphomas, T cell lymphomas, Hodgkin lymphoma and nasopharyngeal carcinomas in certain patients. Reactivation disease is not a prominent issue with EBV, in contrast to other prominent herpesviruses, but it has been associated with an aggressive lymphoproliferative disorder in transplant recipients. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)
The virology and biology of EBV will be reviewed here. The epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of EBV infections are discussed separately. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)
VIROLOGY — EBV is a member of the gamma herpesvirus family and is the prototype for the lymphocryptovirus genus. In vitro, all gamma herpesviruses replicate in lymphoid cells and some are capable of lytic replication in epithelial cells and fibroblasts. Infection of primate B lymphocytes typically results in latent infection. This is characterized by persistence of the viral genome along with expression of a restricted set of latent gene products, which contribute to the transformation process and help drive cell proliferation .
Composition of virus — Membership in the Herpesviridae family is based upon virion architecture. EBV consists of a toroid-shaped protein core wrapped with linear double-stranded DNA, an icosahedral nucleocapsid containing 162 capsomeres, an amorphous protein tegument surrounding the capsid, and an outer envelope containing glycoprotein spikes .
Similar to HSV-1, the major EBV capsid proteins range in size from 28 to 160 KDa . However, unlike most other herpesviruses, the outer viral envelope of EBV contains only a single predominant glycoprotein known as gp350/220 [4,5].
Type and strain variations — Advances in next-generation whole-genome sequencing (NGS) have provided a greater understanding of strain variation and cellular tropisms . Two types of EBV, referred to as EBV-1 and EBV-2 (formerly EBV-A and EBV-B), have been identified in most human populations [6-9]. This nomenclature parallels the terminology for HSV-1 and HSV-2. However, in contrast to the latter viruses, there is extensive homology and restriction endonuclease site conservation throughout most of the EBV-1 and EBV-2 genomes [6,10]. The major identified differences between the EBV-1 and EBV-2 genomes exist in the latent infection cycle nuclear antigen genes EBNA-2, EBNA-LP , EBNA-3A, -3B, and -3C  and in the small, nonpolyadenylated RNAs EBERs 1 and 2 . EBV derived from cases of nasopharyngeal carcinoma were subjected to NGS and confirmed a previously described polymorphism in the promoter of the lytic transactivator of BZLF 1 associated with increased lytic replication [6,13].
The differences between EBV-1 and EBV-2 EBNA genes are reflected in type-specific and type-common EBNA epitopes. Similarly, the immune recognition of EBV transformed B lymphoblastoid cells by EBV-specific cytotoxic lymphocytes is dependent upon the infecting EBV strain [14,15]. EBV-2 has been shown to latently infect T cells and induce T cell cytokines .
NGS has been used to determine the prevalence and geographic distribution of the two EBV strains. In the United States and Europe, the EBV genomes are 10 times more likely to be EBV-1 than EBV-2; in contrast the two genomes are equally distributed in Africa . The identification of EBV DNA in a 5700-year-old chewed birch pitch demonstrated polymorphisms in EBV strains have present in Europe for thousands of years [17,18].
With respect to homology, the various EBNA gene products share between 50 to 85 percent primary amino acid sequence identity . Limited genomic divergence between various EBV-1 isolates has also been documented .
Genome structure — The EBV genome consists of a linear, 172-kilobase-pair, double-stranded DNA molecule , and was completely sequenced in the early 1980s . Genetic studies have been particularly important in determining the biology of this virus (see below). The characteristic features of the EBV genome include a single overall format and gene arrangement and variable tandem repeats. These DNA repeat elements are important landmarks on the EBV genome, which allow the EBV strains to be distinguished .
Although EBV DNA is linear in the virus particle, the terminal repeats mediate circularization in infected cells; each infected cell contains 1 to 20 copies of the EBV episomes in the nucleus. The characteristic DNA repeat elements serve as important landmarks on the EBV genome, which allow one to distinguish between EBV strains. While various EBV isolates differ in their tandem repeat frequency, individual EBV isolates tend to contain a constant number of repeats even through serial passage. This is exemplified each time EBV establishes latent infection where the virus persists as an episome containing a set number of tandem terminal repeats. This principle is extremely useful in determining whether or not latently infected cells, such as Burkitt's lymphoma, arise from a single progenitor .
There is general conservation of the genetic organization between herpesvirus saimiri, a primate gamma herpesvirus, and Epstein-Barr virus; however, there are unique EBV DNA segments which function in latent B cell infection . Antigenic cross-reactivity between EBV and other herpesviruses is rare, even among the proteins encoded by the more conserved genes. The EBV genes expressed in latent infection, as well as certain lytic cycle genes, have no detectable homology to other herpesvirus genes and may have arisen in part from cellular DNA [24,25].
Examples of EBV lytic cycle genes with significant homology to the human genome, but little homology to other herpesviruses, including BHRF1 and BCRF1 [26,27]. BHRF1 is an EBV early gene with significant homology to the human B cell leukemia/lymphoma 2 (bcl-2) gene , thought to be involved in preventing B cells and other cells from undergoing apoptosis. BCRF1 is an EBV late gene with nearly identical primary amino acid sequence homology and biological activity to human IL-10 .
BIOLOGY — Much of the function of EBV has been determined from genetic studies of the virus. Various components of EBV and the cells that the virus infects contribute to the pathogenesis of infection including the virus receptor, penetration and uncoating, virus expression in latent infection, and cell transformation with the production of latent proteins.
Virus receptor — The host range of Epstein-Barr virus is restricted to humans and certain sub-human primates including squirrel monkeys and cotton top marmosets . Related oncogenic herpesviruses have been detected in Old-World primate species and more recently in New-World primates . The EBV receptor on human cells is the B cell surface molecule CD21, which is the receptor for the C3d component of complement (also called CR2, complement receptor type 2) . The following observations have confirmed this association:
●Purified CD21 binds to EBV 
●Virus infection is blocked by anti-CD21 antibodies 
●Expression of CD21 on heterologous cells also allows these cells to bind EBV . Currently, gp350 is believed to bind exclusively to the CD21 molecule.
Infection is initiated by the interaction of the major EBV outer envelope glycoprotein gp350/220 with CD21 . gp350/220 is believed to bind exclusively to the CD21 molecule. Comparison of the primary amino acid sequences of gp350/220 and C3d has revealed a shared nonapeptide, which probably explains their common binding properties with CD21 .
The majority of primary EBV infections in humans are thought to originate in the oropharynx. Oropharyngeal epithelial cells, unlike B lymphocytes, are permissive for viral replication [36,37]. EBV binds much less efficiently to epithelial cells than B cells. Although most anti-CD21 antibodies do not bind to epithelial cells, small amounts of CD21 mRNA indistinguishable in size from that expressed in B cells have been identified by northern blot hybridization in these cells. Cloning and sequencing of epithelial cell derived RNA has shown it to be identical to B cell derived CD21 .
CD21 or related structures are also present on cells of the T lineage . As an example, both thymocytes and peripheral T cells express CD21 or CD21-like molecules; however, their reactivity with anti-CD21 antibodies differs from that of B cells, suggesting there may be structural differences between T cell and B cell CD21 molecules.
EBV has also been demonstrated to enter and replicate within monocytes in vitro . Once infected, these monocytes displayed decreased phagocytic activity. These cells may serve as another potential early site for viral replication and for a blunted immune response to the virus.
Adsorption, penetration, and uncoating — As noted above, virus binding to CD21 and the initial phase of penetration are mediated through the major viral coat glycoprotein gp350/220 [34,41]. Virus adsorption on the surface of B cell results in capping of CD21, followed by endocytosis of EBV into smooth membrane vesicles . A second EBV envelope glycoprotein (gp85) then mediates fusion of the virus with the vesicle membrane, causing release of the nucleocapsid into the B cell cytoplasm . Depletion of this protein abolishes fusion with EBV receptor-bearing cells . A third membrane glycoprotein, gp42, also appears to be essential for penetration of B cells by binding to HLA class II on the cell surface .
Dissolution of the viral nucleocapsid and transport of the genome to the B cell nucleus are less well understood. Once inside the nucleus, the linear EBV genome circularizes [46,47]. This event precedes or at least coincides with the earliest gene expression , directed by Wp, an important viral promoter. Wp has been shown to be 11- to 190-fold more active in B cells than other cells and to contain three regions which act as transcriptional binding sites; one of these regions appears to be most active in B cells .
While EBV can also infect epithelial cells in vitro and in vivo, the precise role of the epithelium in EBV replication and persistence has been somewhat controversial . Current evidence suggests that the epithelium surrounding Waldeyer's ring provides a source of infectious virus in the saliva following lytic infection with EBV . B cell-epithelial cell interactions may facilitate the infection of epithelial cells , tonsillar epithelial cells express CD21 and studies have shown ephrin A2 as an EBV receptor on epithelial cells [53-55].
EBV encodes numerous microRNAs (miRNAs). The function of these miRNAs is poorly understood, but studies have shown they play a role in disrupting antigen presentation on major histocompatibility complex molecules [56,57].
The EBV genome is replicated by cellular DNA polymerases during the cell cycle S phase . It persists as multiple, extrachromosomal double-stranded EBV episomes, which are organized into nucleosomes similar to chromosomal DNA .
Virus expression in latent infection — The hallmark of B lymphocyte infection with EBV is the establishment of latency. The viral genes and products have been studied in detail, but the triggers for the shift from latency to lytic replication are not clearly defined.
Latency is characterized by three distinct processes:
●Restricted virus expression which alters cell growth and proliferation
●Retained potential for reactivation to lytic replication
Persistent EBV infection likely results from a dynamic interplay between viral evasion strategies and host immune responses. Potent T-cell activation occurs and high levels of EBV-specific CD4+ and CD8+ responses are generated during acute EBV infection. How and why EBV persists despite these broad and vigorous immune responses is unclear, but recent studies have provided insight into potential EBV immune evasion strategies:
●EBV exploits normal pathways of B cell differentiation to allow it to persist in a transcriptionally quiescent state in memory B cells and thus minimize immune recognition [60,61]. Two genes (LMP-1 and LMP-2) encoded by the virus allow an EBV-infected B blast to become a resting memory cell, where EBV persists in a transcriptionally quiescent state. (See 'Transformation and latent proteins' below.)
●EBV can infect resting naive B cells that traffic to germinal centers within lymphoid follicles; these cells escape immune surveillance by turning off production of certain viral proteins (EBNA 2).
Intracellular persistence of the entire viral genome is achieved through circularization of the linear EBV genome, and maintenance of multiple copies of this covalently closed episomal DNA . The episomes are replicated semiconservatively during cell cycle S-phase by cellular DNA polymerases, and equal partitioning of episomes to daughter cells is mediated by interactions between the latent origin of plasmid replication (OriP) and EBV nuclear protein-1 (EBNA-1) [62-64].
The 172 Kbp EBV genome encodes approximately 100 genes, ten of which are expressed during latency and are thought to be involved in establishing and maintaining the "immortalized" state. Included in this group are six nuclear proteins (EBNAs 1, 2, 3A, 3B, 3C, and LP), two latent membrane proteins (LMP-1 and 2), and two EBERS = EBV encoded RNA's (EBERs 1, 2) .
Latency can be disrupted by a variety of cellular activators, resulting in the expression of BZLF1 (Z), which induces the switch from viral latency to lytic replication [65,66]. During lytic replication, the virus reproduces with associated destruction of the host cell. A mutation in Z results in inhibition of the ability to induce lytic replication, but addition of a second factor BRLF1 (R) partially restores this activity .
Although only about 10 percent of the genes encoded by EBV are expressed in latently infected B cells, the transcribed regions encompass a major portion of the viral genome. The most abundantly transcribed EBV genes in latently infected cells are the EBERs (107 copies/cell), distantly followed by LMP-1, which is significantly more abundant than the EBNAs and LMP-2 [68,69].
EBNA-LP and EBNA-2 are the first EBV proteins expressed during latent infection of B cells, reaching their steady state levels within 24 to 32 hours . EBNA-2 is essential to the immortalization process since viruses with deletions encompassing EBNA 2 are immortalization incompetent [70-72]. Infection of primary B cells with such EBNA-2 mutants results in failure of expression of EBNA-2 and of genes that have not been deleted such as EBNA-1 and EBNA-3 ; there is also less or no transactivation of LMP-1 . Restoration of the deleted DNA in defective EBV produces progeny virus with the ability to transform primary human B lymphocytes [75,76].
EBNA-2 is also required for expression of other EBV latent genes, for the transactivation of both EBV genes and cellular genes (see 'Transformation and latent proteins' below), and probably for promoter switching during the initial stages of latent B cell infection . By 32 hours after infection, all of the EBNA proteins and LMP-1 can be detected using appropriate antisera . Concomitant with LMP-1 expression is a further increase in the level of CD23 and the onset of cell DNA synthesis. Expression of the EBNA proteins reaches a steady state level within 48 hours of primary B cell infection [78,79].
Unlike the other EBV genes expressed during latent infection, the EBERs (the most abundantly expressed EBV RNAs in latently infected cells ) are also transcribed during lytic infection. The majority of EBERs are localized within the cell nucleus but their functions remain unclear . EBV recombinants carrying EBER mutations do not affect in vitro replication and transformation of B-lymphocytes .
Transformation and latent proteins — Many of the proteins described above are involved in cellular transformation including the EBNAs (1, 2, and 3) and the LMPs (1 and 2).
EBNA-1 — EBNA-1 is required for episome replication and maintenance of the viral genome once the cell has been immortalized . EBNA-1 tyrosine 518 (Y518) forms DNA protein crosslinks and promotes replication termination at the EBV origin of plasmid replication OriP and viral episome maintenance . EBV-infected resting (ie, nondividing) B cells growing in vivo express only EBNA-1 . EBNA-1, the only EBV protein expressed in all EBV-associated malignancies, binds to a specific palindromic DNA sequence on chromosome 11 resulting in breaks and genome instability . Work has demonstrated that EBNA-1 targets adenosine deaminase and purine metabolism during the immortalization of B cells .
EBNA-2 — As mentioned above, EBNA-2 mutants have demonstrated that EBNA-2 is essential to the process of B lymphocyte immortalization [70-72] and for the expression of EBNA-1 and EBNA-3 . Variations in the EBNA-2 protein impart the most significant biologic difference between the two major EBV types, EBV-1 and EBV-2. In general, EBV-1 transforms normal human B lymphocytes much more efficiently than EBV-2 . Confirmation of the critical role played by the type of EBNA-2 in the transformation process was made by inserting cloned type 1 EBNA-2 DNA into EBV-2; the recombinant EBV-2 displayed a highly efficient transformation phenotype identical to that of EBV-1 .
The first biochemical evidence for a role of EBNA-2 in B cell growth-transformation came from the demonstration that EBNA-2 specifically transactivates expression of the B lymphocyte activation marker CD23 , which is abundantly expressed on EBV-transformed and antigen-primed B lymphocytes . EBNA-2 also upregulates expression of the cellular genes CD21 (the EBV receptor)  and c-fgr , and the EBV latent genes LMP-1 [92,93] and LMP-2 . Thus, most of the effect of EBNA-2 in B lymphocyte transformation comes from its ability to transactivate cellular and EBV genes.
EBNA-3 — EBNA-3 consists of a family of three high molecular weight gene products (EBNA-3A, 3B, 3C) [8,95-98]. The EBNA 3 genes are located in tandem on the EBV genome. Much like EBNA-2, the EBNA-3 genes are polymorphic and differ according to EBV type. Unlike the difference in transformation phenotype imparted by the EBNA-2 type, the type specificity of the EBNA-3 genes (types 1 or 2) does not affect the ability of the virus to initiate growth transformation, episome maintenance, or lytic replication. Systematic analysis of the transformation capability of EBV recombinants having specific mutations in each of the EBNA 3 genes demonstrated that while EBNA-3B is dispensable for B-lymphocyte growth transformation, mutations in either EBNA-3A or -3C renders the virus transformation incompetent .
EBNA-LP — EBNA-LP, or leader protein, is a set of highly polymorphic protein. Although the function of EBNA-LP remains unclear, it may play a role in RNA processing, associate with some nuclear regulatory protein , or upregulate expression of autocrine factors critical to B-cell growth .
LMP-1 — The second most abundant EBV mRNA species (the EBERs are first, see below) in latently infected B cells (60 copies/cell) is highly stable and encodes an integral membrane protein LMP-1 [101,102]. The LMP-1 promoter contains an EBNA-2 response element which upregulates LMP-1 expression . However, LMP-1 can be expressed in the absence of EBNA-2 during lytic cycle activation in BL cells, and in nasopharyngeal carcinoma (NPC) tumors [103,104].
The majority of LMP-1 is associated into discrete patches within the plasma membrane, which are often further assembled into a single cap-like structure, a behavior characteristic of many activated receptors . This characteristic plasma membrane patching of LMP-1 prompted an exploration of its role in B-lymphocyte growth transformation. The following observations illustrate its role in this setting:
●In vitro, LMP-1 is essential for EBV-induced transformation of B cells into immortalized lymphoblastoid cells [106,107], and induces many of the activation markers associated with EBV infection of B lymphocytes .
●Transfer of the LMP-1 gene into continuous rodent fibroblast lines produces multiple transforming effects . Importantly, some of these cells, which are not normally tumorigenic in nude mice, become uniformly tumorigenic when expressing LMP-1; mice expressing the transgene develop B cell lymphomas [109,110].
●Expression of LMP-1 in EBV-negative Burkitt lymphoma lines induces many of the changes typically associated with EBV infection or antigen activation of primary B lymphocytes [90,111,112]. LMP-expressing cells grow in tight clumps due to increased expression of the cellular adhesion molecules LFA-1 and ICAM-1 . LMP-1 induction of the adhesion molecules LFA-1, LFA-3 and ICAM-1 promotes an interaction between B and T lymphocytes via the LFA-3/CD2 and LFA-1/ICAM-1 pathways. These heterotypic adhesions are important since the in vivo elimination of EBV-transformed B lymphocytes is dependent upon conjugate formation with cytotoxic T cells. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)
●LMP-1 protects EBV-infected B cells from programmed cell death (apoptosis), in part via induction of the cellular oncogene bcl-2 [113,114].
The transforming action of LMP-1 appears to involve the engagement of signaling proteins from the tumor necrosis factor receptor-associated factors (TRAF) [115-117]. LMP-1 mutations that eliminate the association with TRAF prevent B cell growth transformation . A second LMP-1 site required for lymphoblastoid cell outgrowth also has been identified which interacts with the tumor necrosis factor receptor-associated death domain protein .
LMP-2 — LMP-2 is an integral membrane protein that co-localizes with LMP-1 in the plasma membrane of EBV-infected lymphocytes . Among the transformation-associated EBV proteins, EBNA-1, LMP-1, and LMP-2 are present most consistently in nasopharyngeal carcinomas and EBV-related malignancies [104,120,121]. Since both LMP-1 and LMP-2 contain T cell epitopes, their persistent expression in vivo suggests an important role in the persistence of EBV in the human host .
Functionally, LMP-2 is a substrate for the B lymphocyte src family tyrosine kinases, and associates with a 70 kDa tyrosine phosphorylated cellular protein [123,124]. In view of the prominent role of tyrosine kinases in growth factor receptor-mediated transmembrane signaling, the association of LMP-2 with a tyrosine kinase had been thought to reflect an important role in the effect of LMP-2 on cell growth.
However, more recent studies are in conflict with this hypothesis. EBV recombinants carrying LMP-2A mutations, which do not express LMP-2A protein, are capable of initiating and maintaining B lymphocyte growth transformation in vitro . Furthermore, lymphoblastoid cell lines derived from the LMP-2A mutants are identical to wild type EBV-transformed cells with regard to growth characteristics and virus replication. Surprisingly, expression of EBNA-1, EBNA-2 and LMP-1 is unaffected by these mutations.
EBER-1 and EBER-2 — The most abundant EBV RNAs in latently infected B cells are the EBV-encoded, small, nonpolyadenylated RNAs named EBER-1 and EBER-2 . The construction of EBV recombinants carrying EBER mutations has demonstrated that neither EBER is required for the in vitro growth transformation of B cells . These EBER deletion mutants transform B cells into lymphoblastoid cell lines which are phenotypically identical to those induced by wild-type virus in terms of growth characteristics and ability to undergo lytic virus replication.
EBV DNA persistence in latency — During convalescence, low levels of virus are thought to be maintained by sporadic replication in the epithelial cells lining the oropharynx and in 1 in 10(5) to 10(6) infected memory B cells . Viral replication occurs in response to normal physiologic signals that drive B cell differentiation to a plasma cell . Latently infected B cells typically contain between one and ten complete EBV episomes per cell [46,128] and all latently-infected cells express a minimum of the EBNA-1 protein, which is required for episome maintenance and probably for episome amplification.
Although most EBV DNA persists in latently infected cells in an episomal form, the EBV genome also integrates into chromosomal DNA [129,130]. This integration is neither site specific nor a regular feature of EBV-mediated growth transformation. Furthermore, since LMP-2 is the only EBV latent gene disrupted by linearization of the genome, the integrated form of EBV still retains the potential to transform B cells into permanently growing lymphoblastoid cells. However, the integrated form of EBV DNA is limited in its ability to infect new cells, since episomal DNA is probably necessary for lytic cycle EBV replication, which has not been reported in cells containing only the integrated form of EBV.
While lymphoblastoid B cell lines grown in vitro express a restricted set of EBV latent genes (EBNAs 1, 2, 3A, 3B, 3C and LP, LMP-1 and 2, and EBER-1 and 2). Following acute infection, EBV resides in small resting B cells, which express a minimal number of B-cell activation markers or adhesion molecules and, primarily for this reason, escape immune surveillance in the normal host. (See "Pathogenesis of Hodgkin lymphoma".)
Thus, EBV-infected latent B cells should be considered oncogenically transformed since they will proliferate indefinitely when cultured in vitro [131-133]. These cells can also give rise to lymphoproliferative disorders including lymphoma in individuals with congenital (severe combined immunodeficiency; ataxia telangiectasia) or acquired (allograft recipients and AIDS) immunodeficiencies [117,134,135]. LMP-1-mediated signaling through the TRAF system may have a role in the pathogenesis of EBV-positive lymphomas in such patients .
Elevated EBV loads constitute a risk factor for the development of EBV-related malignancies in patients with AIDS. Higher levels of viremia may be related to loss of immune control or as a result of aberrant cellular tropism. In a study of 54 HIV-infected children and adolescents and 88 controls, EBV DNA levels were comparable to those seen in acutely EBV-infected HIV-seronegative children . Levels of EBV DNA did not correlate with HIV RNA or CD4 cell counts. However, in the HIV-infected patients, EBV DNA was found not only in B cells, but also in CD4+ and CD8+ T cell populations.
Lytic infection/virus replication — The vast majority of latently infected B cells do not undergo lytic cycle replication, but can be induced to do so in vitro [137-139]. Lytic phase induction may contribute to tumorigenesis through the production of virions that infect new cells and affect the regulation of cellular oncogenic pathways by lytic proteins and miRNAs . Following induction, cells undergo cytopathic changes characteristic of lytic herpesvirus infection, including chromatin margination, viral DNA synthesis, nucleocapsid assembly at the nucleus periphery, virus budding through nuclear membrane, and inhibition of host cell protein synthesis . Spontaneous reactivation from latency into a lytic cycle within EBV infected B lymphocytes is a frequent occurrence in vivo [142,143]. Viral replication in plasma cells occurs within Waldeyer's ring and leads to secondary lytic infection of the surrounding epithelial cells .
In lytic EBV infection, immediate-early genes are defined as genes that are transcribed in newly infected cells in the absence of new viral protein synthesis. The key immediate-early transactivators of EBV lytic cycle genes are the 1 kb ZLF1 mRNA and the 2.8 kb RLF1 mRNA [66,144]. Transient expression of the ZLF1 ORF transactivates two major EBV early gene promoters, HLF1 and DR . One study suggests that polymorphisms in the BZLF1 promoter may distinguish subtypes of EBV that are not associated with malignancy . In addition to lytic proteins, miRNAs are produced in all phases of the EBV life cycle .
The induction of EBV lytic cycle replication results in increased episome copy number, which suggests that circular episomal DNA replication is a precursor to subsequent DNA replication . Surprisingly, EBV DNA polymerase is not required for viral DNA replication associated with episome establishment .
The EBV genes expressed during the late stages of lytic infection are mostly structural viral proteins that permit virion maintenance and egress. These proteins are all late genes, which are of potential importance in antibody-mediated immunity to EBV .
Two EBV glycoproteins forming important parts of the virus coat are gp350/220 and gp85 [4,151,152]. As noted above, gp350/220 is the major virus coat glycoprotein and mediates virus binding to the B lymphocyte receptor CD21 [32,34]. Gp85 is a relatively minor virus component that is functionally involved in the fusion between virus and cell membranes [44,152]. The finding that gp350/220 is the most abundant viral protein in lytically infected cell membranes has led to the hypothesis that high levels of gp350/220 may saturate CD21 so that newly released virus can infect uninfected cells rather than being reabsorbed to lytically infected cells.
SUMMARY AND RECOMMENDATIONS
●Lifelong latent infection – Epstein-Barr virus (EBV) is the etiologic agent of infectious mononucleosis. EBV persists as an asymptomatic latent infection for life in most adults, and is associated with the development of B cell lymphoma, T cell lymphoma, Hodgkin lymphoma and nasopharyngeal carcinoma. (See 'Introduction' above.)
●B cell reservoir – Infection of primate B lymphocytes typically results in latent infection. This is characterized by persistence of the viral genome along with expression of a restricted set of latent gene products, which contribute to the transformation process and drive cellular proliferation. (See 'Virology' above.)
●Primary infection in the oropharynx – The majority of primary EBV infections in humans are thought to originate in the oropharynx. Oropharyngeal epithelial cells are permissive for viral replication, unlike B lymphocytes. (See 'Virus receptor' above.)
●Phases of viral latency – Viral latency is characterized by three distinct processes including viral persistence, restricted viral gene expression, and potential to reactivate to lytic replication. (See 'Biology' above.)
●Viral evasion of host immune response – Persistent EBV infection may be the result of viral evasion strategies to host immune responses. (See 'Virus expression in latent infection' above.)
●Oncogenic potential – EBV-infected latent B cells are considered oncogenically transformed since they proliferate indefinitely when cultured in vitro. These cells can also give rise to lymphoproliferative disorders including lymphoma in individuals with congenital or acquired immunodeficiency. (See 'EBV DNA persistence in latency' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Katherine Luzuriaga, MD, who contributed to an earlier version of this topic review.
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