Molecular Properties and Therapeutic Targeting of the EBV-Encoded Receptor BILF1

Abstract

The γ-herpesvirus Epstein–Barr Virus (EBV) establishes lifelong infections in approximately 90% of adults worldwide. Up to 1,000,000 people yearly are estimated to suffer from health conditions attributed to the infection with this virus, such as nasopharyngeal and gastric carcinomas as well as several forms of B, T and NK cell lymphoma. To date, no EBV-specific therapeutic option has reached the market, greatly reducing the survival prognoses of affected patients. Similar to other herpesviruses, EBV encodes for a G protein–coupled receptor (GPCR), BILF1, affecting a multitude of cellular signaling pathways. BILF1 has been identified to promote immune evasion and tumorigenesis, effectively ensuring a life-long persistence of EBV in, and driving detrimental health conditions to its host. This review summarizes the epidemiology of EBV-associated malignancies, their current standard-of-care, EBV-specific therapeutics in development, GPCRs and their druggability, and most importantly consolidates the findings of over 15 years of research on BILF1 in the context of EBV-specific drug development. Taken together, BILF1 constitutes a promising target for the development of novel EBV-specific therapeutics.

Role of the VEGF in virus‐associated cancers

“…To confirm the relation between EBV and VEGF, Early antigen antibody (EA‐IgA) and viral capsid antigen IgA were analysed by ELISA, and significant correlation between them was found 46 . In contrast to the articles mention above, 10–49 the data of one article did not find VEGF in EBER positive cells (peripheral T‐cell lymphomas and Hodgkin's disease) 47,48 . (Figure 1).…”

“…35 BILF1 as a lytic protein of EBV also can regulate G protein-coupled receptor, and it may lead to VEGF secretion and malignant transformation. 33,36 It was interesting as the BZLF1 promoter through the PI3K-p38 MAPK-NF-κB signalling pathway can be activated to induce VEGF by knocking-down IL-10 in EBV positive cells. 37 With regards to chemokines ligand, CCL5 can be observed after EBV infections which contribute angiogenesis.…”

Viral G Protein–Coupled Receptors Encoded by β- and γ-Herpesviruses

“…Here, the gene expression is limited to a number of (or no) latent genes depending on the exact latency program (0, I, II, III), in order to evade the immune system and persist in the host ( 6 ). EBV was initially identified in Burkitt’s lymphoma tissue ( 92 ) but is now associated with multiple cancers ( 93 ). While predominantly being involved in various lymphomas in immunocompetent and immunosuppressed persons, EBV-associated carcinomas, such as nasopharyngeal carcinoma among others, are the cause of the majority of EBV-associated malignancies ( 93 ).…”

“…EBV was initially identified in Burkitt’s lymphoma tissue ( 92 ) but is now associated with multiple cancers ( 93 ). While predominantly being involved in various lymphomas in immunocompetent and immunosuppressed persons, EBV-associated carcinomas, such as nasopharyngeal carcinoma among others, are the cause of the majority of EBV-associated malignancies ( 93 ).…”

Whole genome sequence analysis of equid gammaherpesvirus -2 field isolates reveals high levels of genomic diversity and recombination

“…High levels of genomic variability have been detected in the gB and gH genes [83,91] and in ORFs E1, 74 and E6 [75,87]. The latter three are homologues of cellular seven-transmembrane receptors (7TMR), which in other gammaherpesviruses can act as functional G protein-coupled receptors (GPCR) [16,22,45,60].…”