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Virology of Epstein-Barr virus

Virology of Epstein-Barr virus
Literature review current through: Jan 2024.
This topic last updated: Sep 19, 2023.

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 [1].

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 [2].

Similar to HSV-1, the major EBV capsid proteins range in size from 28 to 160 KDa [3]. 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 [6]. 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 [10], EBNA-3A, -3B, and -3C [11] and in the small, nonpolyadenylated RNAs EBERs 1 and 2 [12]. 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 [16].

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 [6]. 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 [19]. Limited genomic divergence between various EBV-1 isolates has also been documented [20].

Genome structure — The EBV genome consists of a linear, 172-kilobase-pair, double-stranded DNA molecule [21], and was completely sequenced in the early 1980s [22]. 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 [7].

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 [19].

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 [23]. 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 [26], 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 [27].

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 [28]. Related oncogenic herpesviruses have been detected in Old-World primate species and more recently in New-World primates [29]. 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) [30]. The following observations have confirmed this association:

Purified CD21 binds to EBV [31]

Virus infection is blocked by anti-CD21 antibodies [32]

Expression of CD21 on heterologous cells also allows these cells to bind EBV [33]. 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 [34]. 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 [35].

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 [38].

CD21 or related structures are also present on cells of the T lineage [39]. 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 [40]. 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 [42]. 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 [43]. Depletion of this protein abolishes fusion with EBV receptor-bearing cells [44]. 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 [45].

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 [48], 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 [49].

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 [50]. Current evidence suggests that the epithelium surrounding Waldeyer's ring provides a source of infectious virus in the saliva following lytic infection with EBV [51]. B cell-epithelial cell interactions may facilitate the infection of epithelial cells [52], 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 [58]. It persists as multiple, extrachromosomal double-stranded EBV episomes, which are organized into nucleosomes similar to chromosomal DNA [59].

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:

Viral persistence

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 [58]. 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) [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 [67].

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 [48]. 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 [73]; there is also less or no transactivation of LMP-1 [74]. 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 [77]. By 32 hours after infection, all of the EBNA proteins and LMP-1 can be detected using appropriate antisera [48]. 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 [68]) are also transcribed during lytic infection. The majority of EBERs are localized within the cell nucleus but their functions remain unclear [80]. EBV recombinants carrying EBER mutations do not affect in vitro replication and transformation of B-lymphocytes [81].

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 [82]. 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 [83]. EBV-infected resting (ie, nondividing) B cells growing in vivo express only EBNA-1 [84]. 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 [85]. Work has demonstrated that EBNA-1 targets adenosine deaminase and purine metabolism during the immortalization of B cells [86].

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 [73]. 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 [87]. 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 [76].

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 [88], which is abundantly expressed on EBV-transformed and antigen-primed B lymphocytes [89]. EBNA-2 also upregulates expression of the cellular genes CD21 (the EBV receptor) [90] and c-fgr [91], and the EBV latent genes LMP-1 [92,93] and LMP-2 [94]. 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 [1].

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 [99], or upregulate expression of autocrine factors critical to B-cell growth [100].

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 [92]. 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 [105]. 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 [108].

Transfer of the LMP-1 gene into continuous rodent fibroblast lines produces multiple transforming effects [109]. 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 [111]. 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 [116]. 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 [118].

LMP-2 — LMP-2 is an integral membrane protein that co-localizes with LMP-1 in the plasma membrane of EBV-infected lymphocytes [119]. 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 [122].

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 [125]. 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 [68]. The construction of EBV recombinants carrying EBER mutations has demonstrated that neither EBER is required for the in vitro growth transformation of B cells [81]. 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 [126]. Viral replication occurs in response to normal physiologic signals that drive B cell differentiation to a plasma cell [127]. 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 [117].

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 [136]. 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 [140]. 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 [141]. 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 [51].

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 [145]. One study suggests that polymorphisms in the BZLF1 promoter may distinguish subtypes of EBV that are not associated with malignancy [146]. In addition to lytic proteins, miRNAs are produced in all phases of the EBV life cycle [147].

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 [148]. Surprisingly, EBV DNA polymerase is not required for viral DNA replication associated with episome establishment [149].

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 [150].

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.

  1. Kieff E, Rickinson AB. Epstein-Barr virus and its replication. In: Fields Virology, 5th ed, Knipe DM, Howley PM (Eds), Lippincott Williams and Wilkins, Philadelphia 2005. p.2603.
  2. Liebowitz D, Kieff E. Epstein-Barr virus. In: The Human Herpesviruses, Roizman B, Whitley R, Lopez C (Eds), Raven Press, New York 1993. p.107.
  3. Dolyniuk M, Wolff E, Kieff E. Proteins of Epstein-Barr Virus. II. Electrophoretic analysis of the polypeptides of the nucleocapsid and the glucosamine- and polysaccharide-containing components of enveloped virus. J Virol 1976; 18:289.
  4. Dolyniuk M, Pritchett R, Kieff E. Proteins of Epstein-Barr virus. I. Analysis of the polypeptides of purified enveloped Epstein-Barr virus. J Virol 1976; 17:935.
  5. Thorley-Lawson DA, Edson CM. Polypeptides of the Epstein-Barr virus membrane antigen complex. J Virol 1979; 32:458.
  6. Correia S, Bridges R, Wegner F, et al. Sequence Variation of Epstein-Barr Virus: Viral Types, Geography, Codon Usage, and Diseases. J Virol 2018; 92.
  7. Bornkamm GW, Delius H, Zimber U, et al. Comparison of Epstein-Barr virus strains of different origin by analysis of the viral DNAs. J Virol 1980; 35:603.
  8. Sample J, Young L, Martin B, et al. Epstein-Barr virus types 1 and 2 differ in their EBNA-3A, EBNA-3B, and EBNA-3C genes. J Virol 1990; 64:4084.
  9. Zimber U, Adldinger HK, Lenoir GM, et al. Geographical prevalence of two types of Epstein-Barr virus. Virology 1986; 154:56.
  10. Dambaugh T, Hennessy K, Chamnankit L, Kieff E. U2 region of Epstein-Barr virus DNA may encode Epstein-Barr nuclear antigen 2. Proc Natl Acad Sci U S A 1984; 81:7632.
  11. Rowe M, Young LS, Cadwallader K, et al. Distinction between Epstein-Barr virus type A (EBNA 2A) and type B (EBNA 2B) isolates extends to the EBNA 3 family of nuclear proteins. J Virol 1989; 63:1031.
  12. Arrand JR, Young LS, Tugwood JD. Two families of sequences in the small RNA-encoding region of Epstein-Barr virus (EBV) correlate with EBV types A and B. J Virol 1989; 63:983.
  13. Tsai MH, Raykova A, Klinke O, et al. Spontaneous lytic replication and epitheliotropism define an Epstein-Barr virus strain found in carcinomas. Cell Rep 2013; 5:458.
  14. Moss DJ, Misko IS, Burrows SR, et al. Cytotoxic T-cell clones discriminate between A- and B-type Epstein-Barr virus transformants. Nature 1988; 331:719.
  15. Misko IS, Schmidt C, Moss DJ, et al. Cytotoxic T lymphocyte discrimination between type A Epstein-Barr virus transformants is mapped to an immunodominant epitope in EBNA 3. J Gen Virol 1991; 72 ( Pt 2):405.
  16. Coleman CB, Wohlford EM, Smith NA, et al. Epstein-Barr virus type 2 latently infects T cells, inducing an atypical activation characterized by expression of lymphotactic cytokines. J Virol 2015; 89:2301.
  17. Jensen TZT, Niemann J, Iversen KH, et al. A 5700 year-old human genome and oral microbiome from chewed birch pitch. Nat Commun 2019; 10:5520.
  18. Telford M, Hughes DA, Juan D, et al. Expanding the Geographic Characterisation of Epstein-Barr Virus Variation through Gene-Based Approaches. Microorganisms 2020; 8.
  19. Raab-Traub N, Flynn K. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell 1986; 47:883.
  20. Hatfull G, Bankier AT, Barrell BG, Farrell PJ. Sequence analysis of Raji Epstein-Barr virus DNA. Virology 1988; 164:334.
  21. Pritchett RF, Hayward SD, Kieff ED. DNA of Epstein-Barr virus. I. Comparative studies of the DNA of Epstein-Barr virus from HR-1 and B95-8 cells: size, structure, and relatedness. J Virol 1975; 15:556.
  22. Baer R, Bankier AT, Biggin MD, et al. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature 1984; 310:207.
  23. Nicholas J, Cameron KR, Coleman H, et al. Analysis of nucleotide sequence of the rightmost 43 kbp of herpesvirus saimiri (HVS) L-DNA: general conservation of genetic organization between HVS and Epstein-Barr virus. Virology 1992; 188:296.
  24. Heller M, Henderson A, Kieff E. Repeat array in Epstein-Barr virus DNA is related to cell DNA sequences interspersed on human chromosomes. Proc Natl Acad Sci U S A 1982; 79:5916.
  25. Heller M, Flemington E, Kieff E, Deininger P. Repeat arrays in cellular DNA related to the Epstein-Barr virus IR3 repeat. Mol Cell Biol 1985; 5:457.
  26. Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 1986; 47:19.
  27. Hsu DH, de Waal Malefyt R, Fiorentino DF, et al. Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1. Science 1990; 250:830.
  28. Miller, G., T. Shope, H. Lisco, D. Stitt, and M. Lipman. 1972. Epstein-Barr virus: transformation, cytopathic changes, and viral antigens in squirrel monkey and marmoset leukocytes. Proc. Natl. Acad. Sci. U S A. 69:383-387.
  29. Cho Y, Ramer J, Rivailler P, et al. An Epstein-Barr-related herpesvirus from marmoset lymphomas. Proc Natl Acad Sci U S A 2001; 98:1224.
  30. Cooper NR, Moore MD, Nemerow GR. Immunobiology of CR2, the B lymphocyte receptor for Epstein-Barr virus and the C3d complement fragment. Annu Rev Immunol 1988; 6:85.
  31. Nemerow GR, Siaw MF, Cooper NR. Purification of the Epstein-Barr virus/C3d complement receptor of human B lymphocytes: antigenic and functional properties of the purified protein. J Virol 1986; 58:709.
  32. Nemerow GR, Mold C, Schwend VK, et al. Identification of gp350 as the viral glycoprotein mediating attachment of Epstein-Barr virus (EBV) to the EBV/C3d receptor of B cells: sequence homology of gp350 and C3 complement fragment C3d. J Virol 1987; 61:1416.
  33. Ahearn JM, Hayward SD, Hickey JC, Fearon DT. Epstein-Barr virus (EBV) infection of murine L cells expressing recombinant human EBV/C3d receptor. Proc Natl Acad Sci U S A 1988; 85:9307.
  34. Tanner J, Weis J, Fearon D, et al. Epstein-Barr virus gp350/220 binding to the B lymphocyte C3d receptor mediates adsorption, capping, and endocytosis. Cell 1987; 50:203.
  35. Lambris JD, Ganu VS, Hirani S, Müller-Eberhard HJ. Mapping of the C3d receptor (CR2)-binding site and a neoantigenic site in the C3d domain of the third component of complement. Proc Natl Acad Sci U S A 1985; 82:4235.
  36. Sixbey JW, Vesterinen EH, Nedrud JG, et al. Replication of Epstein-Barr virus in human epithelial cells infected in vitro. Nature 1983; 306:480.
  37. Li QX, Young LS, Niedobitek G, et al. Epstein-Barr virus infection and replication in a human epithelial cell system. Nature 1992; 356:347.
  38. Birkenbach M, Tong X, Bradbury LE, et al. Characterization of an Epstein-Barr virus receptor on human epithelial cells. J Exp Med 1992; 176:1405.
  39. Tsoukas CD, Lambris JD. Expression of EBV/C3d receptors on T cells: biological significance. Immunol Today 1993; 14:56.
  40. Savard M, Bélanger C, Tardif M, et al. Infection of primary human monocytes by Epstein-Barr virus. J Virol 2000; 74:2612.
  41. Wells A, Koide N, Klein G. Two large virion envelope glycoproteins mediate Epstein-Barr virus binding to receptor-positive cells. J Virol 1982; 41:286.
  42. Hislop AD. Early virological and immunological events in Epstein-Barr virus infection. Curr Opin Virol 2015; 15:75.
  43. Miller N, Hutt-Fletcher LM. A monoclonal antibody to glycoprotein gp85 inhibits fusion but not attachment of Epstein-Barr virus. J Virol 1988; 62:2366.
  44. Haddad RS, Hutt-Fletcher LM. Depletion of glycoprotein gp85 from virosomes made with Epstein-Barr virus proteins abolishes their ability to fuse with virus receptor-bearing cells. J Virol 1989; 63:4998.
  45. Wang X, Hutt-Fletcher LM. Epstein-Barr virus lacking glycoprotein gp42 can bind to B cells but is not able to infect. J Virol 1998; 72:158.
  46. Adams A, Lindahl T. Epstein-Barr virus genomes with properties of circular DNA molecules in carrier cells. Proc Natl Acad Sci U S A 1975; 72:1477.
  47. Lindahl T, Adams A, Bjursell G, et al. Covalently closed circular duplex DNA of Epstein-Barr virus in a human lymphoid cell line. J Mol Biol 1976; 102:511.
  48. Alfieri C, Birkenbach M, Kieff E. Early events in Epstein-Barr virus infection of human B lymphocytes. Virology 1991; 181:595.
  49. Bell A, Skinner J, Kirby H, Rickinson A. Characterisation of regulatory sequences at the Epstein-Barr virus BamHI W promoter. Virology 1998; 252:149.
  50. Hutt-Fletcher L. EBV entry and epithelial infection. In: Epstein-Barr Virus, Robertson ES (Ed), Caister Academic Press, Norfolk 2005. p.359.
  51. Thorley-Lawson DA, Duca KA, Shapiro M. Epstein-Barr virus: a paradigm for persistent infection - for real and in virtual reality. Trends Immunol 2008; 29:195.
  52. Shannon-Lowe CD, Neuhierl B, Baldwin G, et al. Resting B cells as a transfer vehicle for Epstein-Barr virus infection of epithelial cells. Proc Natl Acad Sci U S A 2006; 103:7065.
  53. Jiang R, Gu X, Nathan CO, Hutt-Fletcher L. Laser-capture microdissection of oropharyngeal epithelium indicates restriction of Epstein-Barr virus receptor/CD21 mRNA to tonsil epithelial cells. J Oral Pathol Med 2008; 37:626.
  54. Chen J, Sathiyamoorthy K, Zhang X, et al. Ephrin receptor A2 is a functional entry receptor for Epstein-Barr virus. Nat Microbiol 2018; 3:172.
  55. Zhang H, Li Y, Wang HB, et al. Ephrin receptor A2 is an epithelial cell receptor for Epstein-Barr virus entry. Nat Microbiol 2018; 3:1.
  56. Albanese M, Tagawa T, Bouvet M, et al. Epstein-Barr virus microRNAs reduce immune surveillance by virus-specific CD8+ T cells. Proc Natl Acad Sci U S A 2016; 113:E6467.
  57. Tagawa T, Albanese M, Bouvet M, et al. Epstein-Barr viral miRNAs inhibit antiviral CD4+ T cell responses targeting IL-12 and peptide processing. J Exp Med 2016; 213:2065.
  58. Adams A. Replication of latent Epstein-Barr virus genomes in Raji cells. J Virol 1987; 61:1743.
  59. Dyson PJ, Farrell PJ. Chromatin structure of Epstein-Barr virus. J Gen Virol 1985; 66 ( Pt 9):1931.
  60. Thorley-Lawson DA. Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol 2001; 1:75.
  61. Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 2004; 350:1328.
  62. Yates J, Warren N, Reisman D, Sugden B. A cis-acting element from the Epstein-Barr viral genome that permits stable replication of recombinant plasmids in latently infected cells. Proc Natl Acad Sci U S A 1984; 81:3806.
  63. Yates JL, Warren N, Sugden B. Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature 1985; 313:812.
  64. Kirchmaier AL, Sugden B. Rep*: a viral element that can partially replace the origin of plasmid DNA synthesis of Epstein-Barr virus. J Virol 1998; 72:4657.
  65. Packham G, Economou A, Rooney CM, et al. Structure and function of the Epstein-Barr virus BZLF1 protein. J Virol 1990; 64:2110.
  66. Flemington E, Speck SH. Epstein-Barr virus BZLF1 trans activator induces the promoter of a cellular cognate gene, c-fos. J Virol 1990; 64:4549.
  67. Adamson AL, Kenney SC. Rescue of the Epstein-Barr virus BZLF1 mutant, Z(S186A), early gene activation defect by the BRLF1 gene product. Virology 1998; 251:187.
  68. Howe JG, Shu MD. Epstein-Barr virus small RNA (EBER) genes: unique transcription units that combine RNA polymerase II and III promoter elements. Cell 1989; 57:825.
  69. Arrand JR, Rymo L. Characterization of the major Epstein-Barr virus-specific RNA in Burkitt lymphoma-derived cells. J Virol 1982; 41:376.
  70. Bornkamm GW, Hudewentz J, Freese UK, Zimber U. Deletion of the nontransforming Epstein-Barr virus strain P3HR-1 causes fusion of the large internal repeat to the DSL region. J Virol 1982; 43:952.
  71. Jones MD, Foster L, Sheedy T, Griffin BE. The EB virus genome in Daudi Burkitt's lymphoma cells has a deletion similar to that observed in a non-transforming strain (P3HR-1) of the virus. EMBO J 1984; 3:813.
  72. Miller G, Robinson J, Heston L, Lipman M. Differences between laboratory strains of Epstein-Barr virus based on immortalization, abortive infection, and interference. Proc Natl Acad Sci U S A 1974; 71:4006.
  73. Rooney C, Howe JG, Speck SH, Miller G. Influence of Burkitt's lymphoma and primary B cells on latent gene expression by the nonimmortalizing P3J-HR-1 strain of Epstein-Barr virus. J Virol 1989; 63:1531.
  74. Cohen JI, Wang F, Kieff E. Epstein-Barr virus nuclear protein 2 mutations define essential domains for transformation and transactivation. J Virol 1991; 65:2545.
  75. Skare J, Farley J, Strominger JL, et al. Transformation by Epstein-Barr virus requires DNA sequences in the region of BamHI fragments Y and H. J Virol 1985; 55:286.
  76. Cohen JI, Wang F, Mannick J, Kieff E. Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation. Proc Natl Acad Sci U S A 1989; 86:9558.
  77. Woisetschlaeger M, Jin XW, Yandava CN, et al. Role for the Epstein-Barr virus nuclear antigen 2 in viral promoter switching during initial stages of infection. Proc Natl Acad Sci U S A 1991; 88:3942.
  78. Allday MJ, Crawford DH, Griffin BE. Epstein-Barr virus latent gene expression during the initiation of B cell immortalization. J Gen Virol 1989; 70 ( Pt 7):1755.
  79. Moss DJ, Rickinson AB, Wallace LE, Epstein MA. Sequential appearance of Epstein-Barr virus nuclear and lymphocyte-detected membrane antigens in B cell transformation. Nature 1981; 291:664.
  80. Howe JG, Steitz JA. Localization of Epstein-Barr virus-encoded small RNAs by in situ hybridization. Proc Natl Acad Sci U S A 1986; 83:9006.
  81. Swaminathan S, Tomkinson B, Kieff E. Recombinant Epstein-Barr virus with small RNA (EBER) genes deleted transforms lymphocytes and replicates in vitro. Proc Natl Acad Sci U S A 1991; 88:1546.
  82. Gahn TA, Schildkraut CL. The Epstein-Barr virus origin of plasmid replication, oriP, contains both the initiation and termination sites of DNA replication. Cell 1989; 58:527.
  83. Dheekollu J, Wiedmer A, Ayyanathan K, et al. Cell-cycle-dependent EBNA1-DNA crosslinking promotes replication termination at oriP and viral episome maintenance. Cell 2021; 184:643.
  84. Miyashita EM, Yang B, Lam KM, et al. A novel form of Epstein-Barr virus latency in normal B cells in vivo. Cell 1995; 80:593.
  85. Li JSZ, Abbasi A, Kim DH, et al. Chromosomal fragile site breakage by EBV-encoded EBNA1 at clustered repeats. Nature 2023; 616:504.
  86. Lamontagne RJ, Soldan SS, Su C, et al. A multi-omics approach to Epstein-Barr virus immortalization of B-cells reveals EBNA1 chromatin pioneering activities targeting nucleotide metabolism. PLoS Pathog 2021; 17:e1009208.
  87. Rickinson AB, Young LS, Rowe M. Influence of the Epstein-Barr virus nuclear antigen EBNA 2 on the growth phenotype of virus-transformed B cells. J Virol 1987; 61:1310.
  88. Wang F, Gregory CD, Rowe M, et al. Epstein-Barr virus nuclear antigen 2 specifically induces expression of the B-cell activation antigen CD23. Proc Natl Acad Sci U S A 1987; 84:3452.
  89. Hurley EA, Thorley-Lawson DA. B cell activation and the establishment of Epstein-Barr virus latency. J Exp Med 1988; 168:2059.
  90. Wang F, Gregory C, Sample C, et al. Epstein-Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23. J Virol 1990; 64:2309.
  91. Knutson JC. The level of c-fgr RNA is increased by EBNA-2, an Epstein-Barr virus gene required for B-cell immortalization. J Virol 1990; 64:2530.
  92. Abbot SD, Rowe M, Cadwallader K, et al. Epstein-Barr virus nuclear antigen 2 induces expression of the virus-encoded latent membrane protein. J Virol 1990; 64:2126.
  93. Sjöblom A, Yang W, Palmqvist L, et al. An ATF/CRE element mediates both EBNA2-dependent and EBNA2-independent activation of the Epstein-Barr virus LMP1 gene promoter. J Virol 1998; 72:1365.
  94. Zimber-Strobl U, Suentzenich KO, Laux G, et al. Epstein-Barr virus nuclear antigen 2 activates transcription of the terminal protein gene. J Virol 1991; 65:415.
  95. Hennessy K, Fennewald S, Kieff E. A third viral nuclear protein in lymphoblasts immortalized by Epstein-Barr virus. Proc Natl Acad Sci U S A 1985; 82:5944.
  96. Hennessy K, Wang F, Bushman EW, Kieff E. Definitive identification of a member of the Epstein-Barr virus nuclear protein 3 family. Proc Natl Acad Sci U S A 1986; 83:5693.
  97. Petti L, Kieff E. A sixth Epstein-Barr virus nuclear protein (EBNA3B) is expressed in latently infected growth-transformed lymphocytes. J Virol 1988; 62:2173.
  98. Petti L, Sample J, Wang F, Kieff E. A fifth Epstein-Barr virus nuclear protein (EBNA3C) is expressed in latently infected growth-transformed lymphocytes. J Virol 1988; 62:1330.
  99. Jiang WQ, Szekely L, Wendel-Hansen V, et al. Co-localization of the retinoblastoma protein and the Epstein-Barr virus-encoded nuclear antigen EBNA-5. Exp Cell Res 1991; 197:314.
  100. Mannick JB, Cohen JI, Birkenbach M, et al. The Epstein-Barr virus nuclear protein encoded by the leader of the EBNA RNAs is important in B-lymphocyte transformation. J Virol 1991; 65:6826.
  101. Fennewald S, van Santen V, Kieff E. Nucleotide sequence of an mRNA transcribed in latent growth-transforming virus infection indicates that it may encode a membrane protein. J Virol 1984; 51:411.
  102. Hennessy K, Fennewald S, Hummel M, et al. A membrane protein encoded by Epstein-Barr virus in latent growth-transforming infection. Proc Natl Acad Sci U S A 1984; 81:7207.
  103. Contreras-Salazar B, Ehlin-Henriksson B, Klein G, Masucci MG. Up regulation of the Epstein-Barr virus (EBV)-encoded membrane protein LMP in the Burkitt's lymphoma line Daudi after exposure to n-butyrate and after EBV superinfection. J Virol 1990; 64:5441.
  104. Brooks L, Yao QY, Rickinson AB, Young LS. Epstein-Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J Virol 1992; 66:2689.
  105. Schechter Y, Hernaez L, Schlessinger J, Cuatrecasas P. Local aggregation of hormone-receptor complexes is required for activation by epidermal growth factor. Nature 1979; 278:835.
  106. Kaye KM, Izumi KM, Kieff E. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci U S A 1993; 90:9150.
  107. Kaye KM, Izumi KM, Mosialos G, Kieff E. The Epstein-Barr virus LMP1 cytoplasmic carboxy terminus is essential for B-lymphocyte transformation; fibroblast cocultivation complements a critical function within the terminal 155 residues. J Virol 1995; 69:675.
  108. Rowe M, Peng-Pilon M, Huen DS, et al. Upregulation of bcl-2 by the Epstein-Barr virus latent membrane protein LMP1: a B-cell-specific response that is delayed relative to NF-kappa B activation and to induction of cell surface markers. J Virol 1994; 68:5602.
  109. Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 1985; 43:831.
  110. Kulwichit W, Edwards RH, Davenport EM, et al. Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. Proc Natl Acad Sci U S A 1998; 95:11963.
  111. Wang D, Liebowitz D, Wang F, et al. Epstein-Barr virus latent infection membrane protein alters the human B-lymphocyte phenotype: deletion of the amino terminus abolishes activity. J Virol 1988; 62:4173.
  112. Liebowitz D, Mannick J, Takada K, Kieff E. Phenotypes of Epstein-Barr virus LMP1 deletion mutants indicate transmembrane and amino-terminal cytoplasmic domains necessary for effects in B-lymphoma cells. J Virol 1992; 66:4612.
  113. Gregory CD, Dive C, Henderson S, et al. Activation of Epstein-Barr virus latent genes protects human B cells from death by apoptosis. Nature 1991; 349:612.
  114. Henderson S, Rowe M, Gregory C, et al. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell 1991; 65:1107.
  115. Mosialos G, Birkenbach M, Yalamanchili R, et al. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 1995; 80:389.
  116. Izumi KM, Kaye KM, Kieff ED. The Epstein-Barr virus LMP1 amino acid sequence that engages tumor necrosis factor receptor associated factors is critical for primary B lymphocyte growth transformation. Proc Natl Acad Sci U S A 1997; 94:1447.
  117. Liebowitz D. Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients. N Engl J Med 1998; 338:1413.
  118. Izumi KM, Kieff ED. The Epstein-Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF-kappaB. Proc Natl Acad Sci U S A 1997; 94:12592.
  119. Longnecker R, Kieff E. A second Epstein-Barr virus membrane protein (LMP2) is expressed in latent infection and colocalizes with LMP1. J Virol 1990; 64:2319.
  120. Young L, Alfieri C, Hennessy K, et al. Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med 1989; 321:1080.
  121. Busson P, McCoy R, Sadler R, et al. Consistent transcription of the Epstein-Barr virus LMP2 gene in nasopharyngeal carcinoma. J Virol 1992; 66:3257.
  122. Murray RJ, Kurilla MG, Brooks JM, et al. Identification of target antigens for the human cytotoxic T cell response to Epstein-Barr virus (EBV): implications for the immune control of EBV-positive malignancies. J Exp Med 1992; 176:157.
  123. Longnecker R, Druker B, Roberts TM, Kieff E. An Epstein-Barr virus protein associated with cell growth transformation interacts with a tyrosine kinase. J Virol 1991; 65:3681.
  124. Burkhardt AL, Bolen JB, Kieff E, Longnecker R. An Epstein-Barr virus transformation-associated membrane protein interacts with src family tyrosine kinases. J Virol 1992; 66:5161.
  125. Longnecker R, Miller CL, Miao XQ, et al. The only domain which distinguishes Epstein-Barr virus latent membrane protein 2A (LMP2A) from LMP2B is dispensable for lymphocyte infection and growth transformation in vitro; LMP2A is therefore nonessential. J Virol 1992; 66:6461.
  126. Tosato G, Blaese RM. Epstein-Barr virus infection and immunoregulation in man. Adv Immunol 1985; 37:99.
  127. Laichalk LL, Thorley-Lawson DA. Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. J Virol 2005; 79:1296.
  128. Heller M, Dambaugh T, Kieff E. Epstein-Barr virus DNA. IX. Variation among viral DNAs from producer and nonproducer infected cells. J Virol 1981; 38:632.
  129. Matsuo T, Heller M, Petti L, et al. Persistence of the entire Epstein-Barr virus genome integrated into human lymphocyte DNA. Science 1984; 226:1322.
  130. Hurley EA, Agger S, McNeil JA, et al. When Epstein-Barr virus persistently infects B-cell lines, it frequently integrates. J Virol 1991; 65:1245.
  131. Henle W, Diehl V, Kohn G, et al. Herpes-type virus and chromosome marker in normal leukocytes after growth with irradiated Burkitt cells. Science 1967; 157:1064.
  132. Pope JH, Horne MK, Scott W. Identification of the filtrable leukocyte-transforming factor of QIMR-WIL cells as herpes-like virus. Int J Cancer 1969; 4:255.
  133. Miller G, Enders JF, Lisco H, Kohn HI. Establishment of lines from normal human blood leukocytes by co-cultivation with a leukocyte line derived from a leukemic child. Proc Soc Exp Biol Med 1969; 132:247.
  134. Randhawa PS, Jaffe R, Demetris AJ, et al. Expression of Epstein-Barr virus-encoded small RNA (by the EBER-1 gene) in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease. N Engl J Med 1992; 327:1710.
  135. Cohen JI. Epstein-Barr virus lymphoproliferative disease associated with acquired immunodeficiency. Medicine (Baltimore) 1991; 70:137.
  136. Bekker V, Scherpbier H, Beld M, et al. Epstein-Barr virus infects B and non-B lymphocytes in HIV-1-infected children and adolescents. J Infect Dis 2006; 194:1323.
  137. Luka J, Kallin B, Klein G. Induction of the Epstein-Barr virus (EBV) cycle in latently infected cells by n-butyrate. Virology 1979; 94:228.
  138. Takada K, Ono Y. Synchronous and sequential activation of latently infected Epstein-Barr virus genomes. J Virol 1989; 63:445.
  139. Sinclair AJ, Brimmell M, Shanahan F, Farrell PJ. Pathways of activation of the Epstein-Barr virus productive cycle. J Virol 1991; 65:2237.
  140. Rosemarie Q, Sugden B. Epstein-Barr Virus: How Its Lytic Phase Contributes to Oncogenesis. Microorganisms 2020; 8.
  141. Takagi S, Takada K, Sairenji T. Formation of intranuclear replication compartments of Epstein-Barr virus with redistribution of BZLF1 and BMRF1 gene products. Virology 1991; 185:309.
  142. Tan LC, Gudgeon N, Annels NE, et al. A re-evaluation of the frequency of CD8+ T cells specific for EBV in healthy virus carriers. J Immunol 1999; 162:1827.
  143. Prang NS, Hornef MW, Jäger M, et al. Lytic replication of Epstein-Barr virus in the peripheral blood: analysis of viral gene expression in B lymphocytes during infectious mononucleosis and in the normal carrier state. Blood 1997; 89:1665.
  144. Jenson HB, Miller G. Polymorphisms of the region of the Epstein-Barr virus genome which disrupts latency. Virology 1988; 165:549.
  145. Takada K, Shimizu N, Sakuma S, Ono Y. trans activation of the latent Epstein-Barr virus (EBV) genome after transfection of the EBV DNA fragment. J Virol 1986; 57:1016.
  146. Gutiérrez MI, Ibrahim MM, Dale JK, et al. Discrete alterations in the BZLF1 promoter in tumor and non-tumor-associated Epstein-Barr virus. J Natl Cancer Inst 2002; 94:1757.
  147. Hartung A, Makarewicz O, Egerer R, et al. EBV miRNA expression profiles in different infection stages: A prospective cohort study. PLoS One 2019; 14:e0212027.
  148. Shaw JE. The circular intracellular form of Epstein-Barr virus DNA is amplified by the virus-associated DNA polymerase. J Virol 1985; 53:1012.
  149. Sixbey JW, Pagano JS. Epstein-Barr virus transformation of human B lymphocytes despite inhibition of viral polymerase. J Virol 1985; 53:299.
  150. Gong M, Kieff E. Intracellular trafficking of two major Epstein-Barr virus glycoproteins, gp350/220 and gp110. J Virol 1990; 64:1507.
  151. Beisel C, Tanner J, Matsuo T, et al. Two major outer envelope glycoproteins of Epstein-Barr virus are encoded by the same gene. J Virol 1985; 54:665.
  152. Heineman T, Gong M, Sample J, Kieff E. Identification of the Epstein-Barr virus gp85 gene. J Virol 1988; 62:1101.
Topic 8276 Version 20.0

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