Abstract
Epstein–Barr virus (EBV) was first discovered in cells from a patient with Burkitt lymphoma (BL), and is now known to be a contributory factor in 1–2% of all cancers, for which there are as yet, no EBV-targeted therapies available. Like other herpesviruses, EBV adopts a persistent latent infection in vivo and only rarely reactivates into replicative lytic cycle. Although latency is associated with restricted patterns of gene expression, genes are never expressed in isolation; always in groups. Here, we discuss (1) the ways in which the latent genes of EBV are known to modulate cell death, (2) how these mechanisms relate to growth transformation and lymphomagenesis, and (3) how EBV genes cooperate to coordinately regulate key cell death pathways in BL and lymphoblastoid cell lines (LCLs). Since manipulation of the cell death machinery is critical in EBV pathogenesis, understanding the mechanisms that underpin EBV regulation of apoptosis therefore provides opportunities for novel therapeutic interventions.
Highlights
All viruses possess methods to negotiate and subvert the cell death pathways of their hosts, but for viruses such as influenza that lead to acute infections, the battle for host cell survival is lost when the host clears the virus
Latency III is the most extensive form of latent infection, involving the expression of ten Epstein–Barr virus (EBV)-encoded proteins and a variety of non-coding RNAs. These are the Epstein–Barr Nuclear Antigens (EBNA-1, EBNA-2, EBNAs-3A, -3B, -3C and EBNA-LP), Latent Membrane Proteins (LMP1, LMP2A and LMP2B), and the viral BCL-2 homologue, BHRF1; as well as two non-coding RNAs (EBER1 and EBER2), and two families of microRNAs encoded within the BamHI A rightward transcripts (BARTs) and the BHRF1 locus (BHRF1 miRNAs), respectively (Figure 1) [18,19,20,21,22,23,24]
BALF1 transcripts can be detected at low levels in lymphoblastoid cell lines (LCLs) [33], it is not known whether these arise from a small number of lytically infected cells or, like BHRF1, are expressed during latency
Summary
All viruses possess methods to negotiate and subvert the cell death pathways of their hosts, but for viruses such as influenza that lead to acute infections, the battle for host cell survival is lost when the host clears the virus. These are the Epstein–Barr Nuclear Antigens (EBNA-1, EBNA-2, EBNAs-3A, -3B, -3C and EBNA-LP), Latent Membrane Proteins (LMP1, LMP2A and LMP2B), and the viral BCL-2 homologue, BHRF1; as well as two non-coding RNAs (EBER1 and EBER2), and two families of microRNAs encoded within the BamHI A rightward transcripts (BARTs) and the BHRF1 locus (BHRF1 miRNAs), respectively (Figure 1) [18,19,20,21,22,23,24] These EBV latent gene products are expressed at different time points post-infection of B cells, leading to growth transformation. Truncated due to a genomic deletion and is denoted as t-EBNA-LP
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