Demonstration of the Burkitt's lymphoma Epstein-Barr virus phenotype in dividing latently infected memory cellsin vivo

Abstract

Epstein-Barr virus (EBV) is a herpesvirus that establishes a lifelong, persistent infection.It was first discovered in the tumor Burkitt's lymphoma (BL). Despite intensive study, the role of EBV in BL remains enigmatic. One striking feature of the tumor is the unique pattern of viral latent protein expression, which is restricted to EBV-encoded nuclear antigen (EBNA) 1. EBNA1 is required to maintain the viral genome but is not recognized by cytotoxic T cells. Consequently, it was proposed that this expression pattern was used by latently infected B cells in vivo. This would be the site of long-term, persistent infection by the virus and, by implication, the progenitor of BL. We now know that EBV persists in memory B cells in the peripheral blood and that BL is a tumor of memory cells. However, a normal B cell expressing EBNA1 alone has been elusive. Here we show that most infected cells in the blood express no detectable latent mRNA or proteins. The exception is that when infected cells divide they express EBNA1 only. This is the first detection of the BL viral phenotype in a normal, infected B cell in vivo. It suggests that BL may be a tumor of a latently infected memory B cell that is stuck proliferating because it is a tumor and, therefore, constitutively expressing only EBNA1.

Animal models of Epstein Barr virus infection

“…EBV infection in humans has lytic and latent infection stages. Lytic infection produces infectious virus for transmission to other susceptible host cells within the infected individual, mainly epithelial and B cells, or to uninfected individuals during transmission via saliva exchange (Young and Rickinson, 2004 (Babcock et al, 1998;Babcock et al, 2000;Hochberg et al, 2004). Infected plasma B cell differentiation reactivates EBV into lytic replication 6 (Laichalk and Thorley-Lawson, 2005).…”

Epstein-Barr virus–associated lymphoproliferative disorders

“…This theory is based upon the highly restricted pattern of the EBV-latent proteins, similar to that seen in memory B cells in healthy carriers [13]. However, this theory is heavily negated by the phenotype of the Burkitt lymphoma cells, which is more consistent with a GC origin.…”

“…According to the WHO classification, they are divided into early lesions (reactive plasmacytic hyperplasia and mononucleosis-like syndrome), polymorphic lesions, monomorphic lesions, and Hodgkin-like lesions [48]. A GC or a post-GC origin has been recognized for PTLD because of the detection of somatic mutations in a considerable percentage of cases [13].…”

“…The infected GC cells then differentiate into memory B cells, which function as the long-term reservoir for EBV. Most of the infected memory B cells in the periphery seem not to express any of the viral antigens (considered by some as type 0 latency); but some only express EBNA-1, which has been referred to as type I latency [12,13]. The EBV latency patterns in different EBVassociated diseases are summarized in Table 2.…”

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

“…Therefore, immunosuppressive therapy [13], hereditary immunodeficiencies [14] or immunocompromising HIV-infection [15] may lead to uncontrolled EBV reactivation and disease. EBV nuclear antigen 1 (EBNA-1) is a latent antigen that is invariably expressed in all EBV-infected proliferating cells [16] and associated malignancies [17], being crucial for viral persistence by acting as replication and transcription factor [18], without viral particle formation. EBNA-1 is an immunodominant latent target of EBVspecific CD4 1 T cells [19,20].…”