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Epstein-Barr Virus (EBV) is an enveloped virus that 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 (7). 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 (7). As a result, EBV has a narrow cell tropism and preferentially attaches to these aforementioned B cells (7). From here, the virus fuses with its target cell by using glycoproteins B, H, and L which are located on the virion's surface (4). These proteins undergo an as of yet unidentified conformational change that aids in fusion (4). From here, how EBV specifically uncoats and enters the nucleus is uncertain; however, its method may be similar to that of other gammaherpesviruses (5). 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 (5).
Once the viral DNA is inside of the nucleus, the virus can either enter a latent phase or a lytic phase (9). 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 (9). EBV undergoes three phases of gene expression: the intermediate-early phase, the early phase, and the late phase (10). The intermediate-early phase controls genes such as BZLF1 and BRLF1, which initiates a productive infection by encoding for the ZEBRA protein (10). 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 (2,10). In order to perform this function, the protein must bind to specific sequences of DNA called ZEBRA response elements (2). 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 (2).
In all, EBV's genome encodes for six important proteins needed for viral replication, including ZEBRA (6). 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 (2,6). 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 (6). Furthermore, EBV expresses a protein known as EB2 that exports mRNA from the nucleus to the cytoplasm where translation by host ribosomes can occur (1). Once all of these necessary proteins are synthesized, DNA replication can begin. EBV uses a rolling circle mechanism for the synthesis of new DNA (6). Initiation of replication begins with ZEBRA recognizing a lengthy stretch of DNA termed oriLYt (2). This origin of replication contains seven ZEBRA-binding sites which the protein must recognize for replication to occur (2). 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 (6,10). The method by which this cleavage occurs has yet to be determined (9).
Once viral replication has begun, late genes are expressed (10). 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 (3). 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 (3). Late genes are also expressed to lead to the production of glycoproteins, such as the ones mentioned earlier that aid in fusion (4,10). 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 (2,10). 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 (3). 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 (3). Once inside, EBV structural proteins self-assemble through physical interactions (3). 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 (3). 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 (3). The mechanism by which EBV obtains its envelope and exits the cell is still uncertain (8). 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 (8). As a result, the naked virus is released into the cytoplasm where it obtains its tegument proteins (8). 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 (8).