BamHI‐A rightward frame 1, an Epstein–Barr virus‐encoded oncogene and immune modulator

Abstract

Epstein–Barr virus (EBV) causes several benign and malignant disorders of lymphoid and epithelial origin. EBV-related tumors display distinct patterns of viral latent gene expression, of which the BamHI-A rightward frame 1 (BARF1) is selectively expressed in carcinomas, regulated by cellular differentiation factors including ΔNp63α. BARF1 functions as a viral oncogene, immortalizing and transforming epithelial cells of different origin by acting as a mitogenic growth factor, inducing cyclin-D expression, and up-regulating antiapoptotic Bcl-2, stimulating host cell growth and survival. In addition, secreted hexameric BARF1 has immune evasive properties, functionally corrupting macrophage colony stimulating factor, as supported by recent functional and structural data. Therefore, BARF1, an intracellular and secreted protein, not only has multiple pathogenic functions but also can function as a target for immune responses. Deciphering the role of BARF1 in EBV biology will contribute to novel diagnostic and treatment options for EBV-driven carcinomas. Herein, we discuss recent insights on the regulation of BARF1 expression and aspects of structure-function relating to its oncogenic and immune suppressive properties. © 2013 The Authors. Reviews in Medical Virology published by John Wiley & Sons, Ltd.

Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells

“…The activation effect seems to be mediated by the N-terminal 1-20 AA domain of BARF1, which remains intracellular [18]. This idea is supported by the fact that NFκB and miR-146a levels decreased dramatically following BARF1-specific siRNA transfection in the present study.…”

“…Unfortunately, the BARF1-induced NFκB /miR-146a /SMAD4 axis observed in cell line was not clearly recapitulated in tissues. BARF1 protein is expressed within EBV-positive tumor cells, after that, almost completely secreted out of tumor cells [18, 21, 22], and this was attested in the present study using a secretion blocker in cell lines. Accordingly, it is challenging to directly detect BARF1 protein in tissue sample.…”

Prognostic role of tumour-associated macrophages and regulatory T cells in EBV-positive and EBV-negative nasopharyngeal carcinoma

“…Thus, the higher CD68 count in EBV-positive NPCs with no increase in M2 phenotypic markers leads us to believe that EBV-negative NPC contains higher numbers of anti-inflammatory macrophages, or that M1 phenotypic macrophages may be more prominent in EBV-positive NPCs. The lack of M2 differentiation in EBV-positive NPC is possibly due to the production of BamHI-A rightward frame 1 (BARF1), a viral protein, which has been shown to inhibit macrophage colony stimulating factor, and thus M2 differentiation of macrophages 52. But, it has also been shown that TAMs correlate with EBV infection titres in NPC,53 and in a recent study CD163 was found to correlate with EBV positivity and worse survival in a patient population in China,54 and these findings might indicate patient population differences regarding (epi)genetics, viral (epi)genotypes or environmental factors which could influence the tumour microenvironment.…”

Epstein-Barr Virus-Specific Humoral Immune Responses in Health and Disease

“…If detectable, the human antibody response seems to target intracellular cytoplasmic repeat or aggregation domains of LMP1 and LMP2, and particularly antibody responses to epitopes located in the putative extracellular membrane loops seem absent. Antibodies to BARF1 could possibly interfere with its function as scavenger of CSF-1 (M-CSF), but also these are barely detectable even in NPC patients with high VCA and EBNA1 antibody responses (Hoebe et al 2011(Hoebe et al , 2013Paramita et al 2011). This apparent void in the anti-EBV humoral immune repertoire may open options for de novo immunisation with peptides derived from these extracellular domains, in order to fill this immunological gap and to create therapeutic antibody responses that potentially can eliminate EBV-driven tumours expressing LMP1 and LMP2.…”