During latent infection, EBV persists episomally in resting memory B cells. Initially, it was thought that EBNA1 and LMP2 were expressed in memory B cells; however, more recent studies indicate that the majority of infected cells do not express viral proteins and of the almost 100 viral proteins, only EBNA1 is expressed during memory B-cell division (see Fig. 1). This extremely limited expression of viral proteins allows EBV to persist long term despite a robust cellular EBV-specific immune response.
Fig1. INFECTIOUS LIFE CYCLE OF EPSTEIN-BARR VIRUS. EBV, Epstein-Barr virus; EBNA, Epstein-Barr nuclear antigen; LMP, latent mem brane protein.
Three other distinct types of EBV latency have been characterized in a heterogeneous group of malignancies (Fig. 2). Latency type III, which can be readily produced by infecting B cells in vitro with EBV, is expressed in lymphoblastoid cell lines (LCLs). These cells express the entire array of nine EBV latency proteins: EBNA1, -2, -3A, -3B, and -3C, EBNA leader protein (LP), and the two viral membrane proteins LMP1 and LMP2. This pattern of EBV gene expression characterizes the EBV-associated lymphoproliferative dis orders (EBV-LPDs) that occur in individuals severely immunocompromised by solid organ or hematopoietic stem cell transplantation (SOT, HSCT), congenital immunodeficiency, or human immunodeficiency virus (HIV) infection. Latency type II is the hallmark of EBV-positive Hodgkin lymphoma (HL), various EBV-associated non-Hodgkin lymphomas (NHLs), as well as nasopharyngeal carcinoma (NPC), which express EBNA1, LMP1, and LMP2. In addition, BARF1 is expressed in subsets of latency type II–associated malignancies. In latency type I, classically found in EBV-positive BL, only EBNA1 is expressed. However, variants in which all EBNAs are expressed in the absence of LMP1 have also been described. Latency type I or latency type II is found in EBV-associated gastric adenocarcinoma. Although grouping EBV-associated malignancies according to their dominant gene expression profile provided a useful frame work for understanding EBV-driven oncogenesis, more recent studies using comprehensive gene expression array profiling have demonstrated expression of lytic cycle genes in BL or expression of lytic cycle and latency III genes in NPC.
Fig2. EPSTEIN-BARR VIRUS (EBV)–LATENT GENE EXPRESSION AND IMMUNOGENICITY OF COMMON EBV-ASSOCIATED MALIGNANCIES. EBNA, Epstein-Barr nuclear antigen; LP, leader protein; NK, natural killer. For an explanation of symbols, see Fig. 1. *Not all lymphomas are latency type III. **Gastric adenocarcinoma can also express latency type II genes.
The EBV proteins expressed during type III latency are involved in the transformation and growth of EBV-infected B cells. EBNA1 binds to the origin of replication of the latent viral genome and is responsible for the maintenance of the EBV episome in host B cells. EBNA2 upregulates the expression of the viral proteins LMP1 and LMP2 and cellular proteins that contribute to transformation. EBNA3A and EBNA3C are essential for EBV-induced B-cell trans formation, and although EBNA3B is not essential for transformation, it is highly conserved and therefore must provide a survival function in vivo. EBNA-LP cooperates with EBNA2 in the induction of viral and cellular genes. LMP1, a viral oncogene, behaves like a constitutively activated CD40 molecule and is essential for EBV-mediated B-cell transformation. LMP2 mimics an activated B-cell receptor (BCR), allowing for long-term B-cell survival in the absence of anti gen. In addition, it prevents the reactivation of EBV into the lytic phase of infection.
Besides EBV proteins, small nonpolyadenylated viral RNAs termed EBERs 1 and 2 and the BamHI-A rightward transcripts microRNAs (BART-miRs) are expressed in all forms of latency. In addition, the expression of at least 17 distinct EBV-derived microR NAs has been reported. The EBERs are the most abundant viral RNAs in latently infected cells. They enhance the oncogenic phenotype of EBV-transformed cells but are nonessential for EBV-mediated transformation. The expression pattern of the microRNAs depends on the latency type, and it is therefore likely that they play an important role during the life cycle of the virus.
