EBV, also known as human herpesvirus 4 (HHV4), is the prototype of the gamma subfamily of potentially oncogenic herpesviruses.11 EBV was discovered over 35 years ago by electron microscopy of cells cultured from Burkitt's lymphoma tissue by Epstein, Achong, and Barr12; it is ubiquitous and is known to infect over 90% of people and to persist in the body for life.13

Primary EBV infections occurring in early childhood are often asymptomatic. In contrast, primary infections occurring in adolescence and young adulthood often lead to the self-limiting lymphoproliferative disease called infectious mononucleosis (IM), characterized by the triad of fever, lymphadenopathy, and pharyngitis.

EBV, which usually infects humans by entering the oropharynx in saliva, replicates in epithelial cells by coupling of the viral gp 350 glycoprotein with the CD21 receptor on B cells. This leads to host cell infection and subsequent infiltration of oropharyngeal tissue. EBV-infected B cells express a pattern of EBV latent genes known as "latency III" genes. Hence, these cells express multiple viral proteins including the six nuclear proteins known as EBV nuclear antigens (EBNAs) 1, 2, 3a, 3b, 3c, and LP; integral membrane proteins known as latent membrane proteins (LMP) 1, 2a, and 2b; and two untranslated RNAs known as EBERs 1 and 2 (EBV-encoded small RNAs). EBNA1 binds to viral DNA and is responsible for the maintenance of EBV episomes in replicating B cells.14 EBNA2 up-regulate cellular proteins that contribute to the growth and transformation of B cells. LMP1 also functions as a constitutively activated member of the tumor necrosis factor receptor superfamily that activates a number of signaling pathways in a ligand-inde-pendent manner. LMP1 can substitute for CD40 in vivo and leads to the activation of the transcription factor NF-kB (nuclear factor kappa B), which in turn results in cytokine production and B-cell proliferation. Finally, LMP2a alters B-cell receptor (BCR) signaling by mimicking the rescue signal normally delivered by this receptor, thereby enabling nontransformed B cells to survive without appropriate BCR signaling.

Normally, B cells transformed by EBV or containing replicating virus are highly immunogenic and induce an intense cytotoxic T lymphocyte (CTL) and natural killer cell response. These activated T cells, appearing in the peripheral blood as atypical lymphocytes, help control the proliferation of infected B cells. Fortunately, most EBV-infected B cells are eliminated, but some are able to persist because they down-regulate immunogenic EBV proteins, thus allowing the cells to avoid immune recognition. Eventually, the EBV genome forms an episome that remains latent in resting memory B cells. These EBV-infected cells now express only the "latency 0" gene pattern, which consists of LMP2a, the EBERs, and possibly EBNA1.1315 Hence, in the immunocompetent host, an equilibrium is established in which rare EBV-infected cells lacking expression of immunogenic proteins coexist with EBV-specific CTLs. EBV undergoes lytic replication in numerous B cells in the oropharynx of healthy carriers. When people become immunosuppressed after HSCT or SOT, critical T-cell control of B-cell growth is no longer present, leading to unchecked proliferation of EBV-infected cells, which may in turn result in B-cell hyperplasia or frank malignancy.15

The origin of EBV-infected cells in PTLD varies depending on the transplant population being studied. In SOT patients, the PTLD cells are usually of recipient origin. However, most PTLD cells in the HSCT setting are donor derived. It should be noted that primary EBV infection may also result in PTLD; this is usually seen in children.

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