Regulation of Epstein–Barr virus reactivation from latency

Abstract

The Epstein-Barr virus (EBV) is a human gamma-herpesvirus that is implicated in various types of proliferative diseases. Upon infection, it predominantly establishes latency in B cells and cannot ever be eradicated; it persists for the host's lifetime. Reactivation of the virus from latency depends on expression of the viral immediate-early gene, BamHI Z fragment leftward open reading frame 1 (BZLF1). The BZLF1 promoter normally exhibits only low basal activity but is activated in response to chemical or biological inducers, such as 12-O-tetradecanoylphorbol-13-acetate, calcium ionophore, histone deacetylase inhibitor, or anti-Ig. Transcription from the BZLF1 promoter is activated by myocyte enhancer factor 2, specificity protein 1, b-Zip type transcription factors and mediating epigenetic modifications of the promoter, such as histone acetylation and H3K4me3. In contrast, repression of the promoter is mediated by transcriptional suppressors, such as ZEB, ZIIR-BP, and jun dimerization protein 2, causing suppressive histone modifications like histone H3K27me3, H3K9me2/3 and H4K20me3. Interestingly, there is little CpG DNA methylation of the promoter, indicating that DNA methylation is not crucial for suppression of BZLF1. This review will focus on the molecular mechanisms by which the EBV lytic switch is controlled and discuss the physiological significance of this switching for its survival and oncogenesis.

Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase

“…Phosphorylation of p38 also plays a key role in reactivation of EBV from latency (27). Since BGLF2 activated AP-1 and AP-1 regulates BZLF1 (25,28,40), we postulated that BGLF2 may be important for EBV reactivation. To test this hypothesis, we transduced EBV-positive Akata and Raji cells with lentiviruses expressing BGLF2, an shRNA against BGLF2, or GFP and measured BZLF1 expression as an indicator of EBV reactivation.…”

“…BRLF1, another EBV immediate early protein, activates the AP-1 pathway by increasing the levels of phosphorylated p38, JNK, and ERK (22,23) and induces phosphorylation of Akt through the PI3K pathway (24). Activation of Akt, ERK, and p38 signaling is required for EBV reactivation from latency (25)(26)(27)(28).…”

Epstein-Barr virus lytic reactivation regulation and its pathogenic role in carcinogenesis

“…Cellular transcription factors and their binding motifs within Zp and Rp have been well-studied 17,18. However, activation of both IE promoters is not sufficient for induction of EBV reactivation.…”

(-)-Epigallocatechin‑3‑gallate inhibition of Epstein‑Barr virus spontaneous lytic infection involves downregulation of latent membrane protein 1

“…In the majority of asymptomatic carriers, the lytic cycle of EBV in the host cells is periodically reactivated (7). Previous studies have focused on the effects of EBV latent infection (2,20).…”

“…EBV, as all other herpes viruses, may establish a latent or lytic infection in host cells (6). Notably, studies suggest that EBV reactivation into a lytic cycle may contribute to the pathogenesis of malignancies (7,8). EBV lytic infection in vivo has been identified by elevated antibody titers against EBV lytic antigens and by increased viral DNA load in the serum/plasma, and these observations correspond with advanced cancer stages, poor prognosis or tumor recurrence following therapy (9,10).…”