Epstein-Barr Virus 

Epstein–Barr virus (EBV) is a ubiquitous human herpesvirus that is the causative agent of infectious mononucleosis and associated with several malignancies, such as Burkitt's lymphoma (BL), nasopharyngeal carcinoma (NPC), some cases of peripheral T-cell lymphoma and gastric carcinoma, and B-cell lymphoma of acquired immune deficiency syndrome (AIDS ) and transplant patients. EBV has the ability to immortalize human B-lymphocytes in vitro.

 The EBV genome is double-stranded linear DNA with an approximate length of 175 kbp and a G+C content of 59%. Reiterated direct repeat sequences at both termini (TR) and within the genome (IR( separate the EBV genome into five unique regions. The EBV genome circularizes after entry into cells, and it is maintained stably as a plasmid .

 Although the entire EBV genome is maintained in immortalized lymphocytes, virus replication usually does not occur in these cells. During a latent infection, six nuclear antigens (EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C, and EBNA-LP), three membrane proteins (LMP1, LMP2A, and LMP2B), and two small nuclear RNAs (EBER1 and EBER2) are expressed. EBNA-LP, 2, 3A, and 3C and LMP1 are essential or critical for primary B-lymphocyte growth transformation. EBNA3B, LMP2A, LMP2B, and EBERs are dispensable for immortalization.

EBNA1 from a typical EBV strain B95-8 consists of 641 amino acid residues. A long hydrophilic domain of residues 459 to 607 has a DNA-binding activity that is nucleotide sequence-specific. The specific EBNA1 binding sequence is located at oriP, which is the origin of EBV plasmid replication. Replication from oriP requires both the cis-acting elements (the family of repeats and the dyad symmetry elements) and the viral protein EBNA1. EBNA1 binding to oriP is also required for efficient EBNA transcription, where oriP serves as an enhancer. EBNA2 induces expression of viral genes LMP1 and LMP2 and cellular genes CD21, CD23, and c-fgr. EBNA2 responsive elements have been defined in the upstream promoter regions of these genes. Interaction of EBNA2 with its response element is mediated by a cell protein Jk, which recognizes a GTGGGAA sequence present in all known EBNA2 response elements. EBNA3A, EBNA3B, and EBNA3C are encoded by three genes that are tandemly placed in the EBV genome and are likely to have been derived a common origin. EBNA-LP is encoded by the leader of each of the EBNA messenger RNAs and is translated from these mRNAs when the first and second exons are spliced, so as to create the EBNA-LP initiation codon. Deletion of the EBNA-LP gene reduces greatly the efficiency of B-lymphocyte immortalization by EBV.

LMP1 consists of an amino-terminal cytoplasmic domain, six membrane-spanning hydrophobic domains separated by short reverse turns, and a carboxy-terminal cytoplasmic domain. LMP1 has the ability to transform rodent fibroblasts, and it blocks differentiation in human keratinocytes. In transgenic mice, LMP1 expression causes epithelial hyperplasia. In BL cells, LMP1 induces villous projections, growth in tight clumps, NFkB activity, and expression of activation markers (CD23 and CD40), cell adhesion molecules (ICAM-1, LFA-1, and LFA-3), IL-10, and the Bcl-2 proto-oncogene. There are two NFkB-activating regions in the carboxy-terminal cytoplasmic domain. One of these regions associates with members of the tumor necrosis factor receptor-associated factor) TRAF) family of proteins. CD40 is a well-known mediator of growth of B lymphocytes. LMP1, through direct interaction with TRAFs, may constitutively activate CD40 signal transduction and promote cell growth. LMP2A is a substrate for B lymphocyte src family tyrosine kinases. LMP2A expression blocks calcium mobilization in B lymphocytes. There is no known function for LMP2B.

 EBERs are RNAs that are not polyadenylated, and they have extensive primary sequence similarity to adenovirus VA1 and VA2 and cellular U6 small RNAs.

In contrast to the EBV gene expression in immortalized lymphocytes, more limited numbers of EBV genes are expressed in EBV-associated tumor cells. BL and gastric carcinoma cells express EBNA1, but do not express other EBNAs and LMPs. NPC and T-cell lymphoma cells express EBNA1 and LMPs, but do not express other EBNAs. It is known that EBNAs other than EBNA1 become targets of cytotoxic T lymphocytes. Therefore, it is important for tumor cells not to express these antigens so as to survive under normal immunity.

EBNA2 and LMP1 are particularly important for the immortalization of primary lymphocytes. These proteins, however, are not expressed in most EBV-associated malignancies, although there is a report suggesting that malignant phenotypes are dependent on the presence of EBV genomes. These observations may be extended to the pathogenic role of EBV in other EBV-associated malignancies.

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