The host virus coexistence is completely dependent
The host-virus coexistence is completely dependent on the balance between a strong immune response inhibiting virus replication and immune evasion and survival of the virus with periodic shedding to enable transmission to new hosts. In the process of ensuring this balance, the virus manipulates 7TM receptors and their ligands.58, 59, 60 Thus, like many other herpesviruses, EBV encodes a 7TM receptor and in addition regulates the expression of both 7TM receptors and ligands in the host. In the following parts of the review, we will give an overview of the 7TM receptor exploitation and regulation of EBV along with the potential druggability of these receptors.
EBV-BILF1—A Virus-Encoded 7TM Receptor with Immune Evasive Functions The EBV-encoded BILF1 receptor (EBV-BILF1) is thought to be implicated in the immune evasion strategy of EBV.56, 61, 62 This orphan 7TM receptor is expressed at significant levels during the early lytic phase of the virus infection, intermediate levels in LCLs and nasopharyngeal carcinoma derived C666-1 line and at low levels during the viral latent phase.63, 64 Several studies have shown that the pivotal role in immune evasion played by EBV-BILF1 occurs during the lytic replication rather than the latent phase.56, 61, 62, 63, 64 In addition to EBV, the BILF1 gene is present in the two so far characterized nonhuman primate LCVs, Old World rhesus LCV-1 (RhLCV-1), and New World callitrichine herpesvirus-3 (CalHV-3).62, 65 Furthermore, ungulate gammaherpesviruses belonging to the genera Macavirus (Porcine lymphotropic herpesviruses 1–3, Alcelaphine herpesvirus 1, and Ovine herpesvirus 2) and Percavirus (Equine herpesvirus 2) encode putative 7TM receptors at the homologous genomic position. Although these BILF1 receptor homologs remain uncharacterized, the strong conservation reflects a significance of this gene in the viral pathogenesis.
EBI2: An Endogenous 7TM Receptor Manipulated by EBV EBI2 was identified in 1993, when Kieff and colleagues used subtractive hybridization of DNA from Burkitt\'s lymphoma Calpain Inhibitor II, ALLM to screen for upregulated genes in EBV-infected cells. They found, being more than 200-fold upregulated (hence the name: EBV-induced gene 2). Since 1993, this finding has been confirmed in four different studies describing EBI2 upregulation in both lytic and latent settings29, 88, 89, 90 (see Table 2). The name of EBI2 suggests that EBV directly induces expression of the receptor, but the fact is that we, after more than two decades, still do not know if EBI2 is induced by EBV or if it is induced as part of the immune response to the virus infection. As described in detail below, EBI2 has moved from being an orphan receptor with no known biological function to an oxysterol-induced receptor with important functions in the immune system within a few years; in addition, the molecular basis for activation and inhibition of EBI2 has been studied extensively.
Manipulation of the Host Immune System 7TM Receptors and Ligands by EBV—The Chemokine System Chemokines induce chemotaxis of leukocytes through interactions with 7TM chemokine receptors. Approximately, 40 chemokines and 18 functional chemokine receptors have been identified in humans. Based on the pattern of conserved cysteine residues in the N-terminal region they are classified into four subfamilies: CC, CXC, C, and CX3C. By controlling leukocyte migration, the chemokine system has important functions in coordinating the immune system, leukocyte homeostasis, lymphocyte activation, and the host immune response to infectious pathogens. It is therefore not surprising that many viruses have been shown to modulate the chemokine system, several of them by encoding chemokine receptors or ligands.60, 120 EBV has not yet been shown to encode either chemokine receptors or ligands, but the system is being markedly manipulated during EBV infection, as some chemokines and chemokine receptors are upregulated, while others are downregulated (Fig. 3). Hence, the chemokine system may play an important role in the tissue localization of EBV-infected B cells and thereby contribute to the pathogenesis of EBV-associated diseases.