Abstract
The human gamma herpes virus Epstein–Barr virus (EBV) exploits multiple routes to evade the cellular immune response. During the EBV lytic replication cycle, viral proteins are expressed that provide excellent targets for recognition by cytotoxic T cells. This is countered by the viral BNLF2a gene. In B cells during latency, where BNLF2a is not expressed, we show that its regulatory region is embedded in repressive chromatin. The expression of BNLF2a mirrors the expression of a viral lytic cycle transcriptional regulator, Zta (BZLF1, EB1, ZEBRA), in B cells and we propose that Zta plays a role in up-regulating BNLF2a. In cells undergoing EBV lytic replication, we identified two distinct regions of interaction of Zta with the chromatin-associated BNLF2a promoter. We identify five potential Zta-response elements (ZREs) in the promoter that are highly conserved between virus isolates. Zta binds to these elements in vitro and activates the expression of the BNLF2a promoter in both epithelial and B cells. We also found redundancy amongst the ZREs. The EBV genome undergoes a biphasic DNA methylation cycle during its infection cycle. One of the ZREs contains an integral CpG motif. We show that this can be DNA methylated during EBV latency and that both Zta binding and promoter activation are enhanced by its methylation. In summary, we find that the BNLF2a promoter is directly targeted by Zta and that DNA methylation within the proximal ZRE aids activation. The implications for regulation of this key viral gene during the reactivation of EBV from latency are discussed.
Highlights
Epstein–Barr virus (EBV) is a human gamma herpes virus that has a lifetime association with the host and can enter into a state of long-term latency in memory B cells [1]
BNLF2a is an important component of the programme used by EBV to evade the host immune response during the EBV lytic cycle and immediately following infection of B cells [22, 38, 39]
Within LCLs undergoing the spontaneous lytic cycle, it was recently shown that knockdown of the expression of BGLF5 plays only a minor role in preventing antigen recognition by CD8+ cells, while in contrast knockdown of the expression of either BNLF2a or BILF1 prevents antigen recognition [46]
Summary
Epstein–Barr virus (EBV) is a human gamma herpes virus that has a lifetime association with the host and can enter into a state of long-term latency in memory B cells [1]. Most of the EBV lytic replication cycle genes are transcriptionally silent [2,3,4,5]. A repressive chromatin context is considered to contribute to this, as some EBV lytic replication cycle promoters within the EBV genome have been shown to be associated with heterochromatin, polycomb-associated chromatin or DNA methylation In response to differentiation signals, EBV undergoes the lytic replication cycle in both B cells [13] and epithelial cells [14]. The viral transcription factor Zta (BZLF1, ZEBRA, EB1) is essential for this process [15]. Zta interacts with sequence-specific DNA elements in epigenetically repressed chromatin and drives the activation of certain viral lytic replication cycle genes [16, 17]. Genome-wide mapping of Zta interactions with the viral genome revealed many further genes that are potentially directly regulated by interaction with Zta [18, 19]
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