Chapter Thirteen - EBV, the Human Host, and the 7TM Receptors: Defense or Offense?

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Abstract

Being present in around 90% of the worldwide population, Epstein–Barr virus (EBV) is an exceptionally prevalent virus. This highly successful virus establishes a latent infection in resting memory B cells and is maintained in a balance between viral homeostasis on one side and antiviral defense of the immune system on the other side. The life cycle of EBV is dependent on many viral proteins, but EBV also regulates a number of endogenous proteins. 7TM receptors and ligands of viral and host origin are examples of such proteins. 7TM receptors are highly druggable and they are among the most popular class of investigational drug targets. The 7TM receptor encoded by EBV-BILF1, is known to downregulate cell surface MHC class I expression as part of the immune evasion strategy of EBV. However, the functional impact of the relationship between EBV and the regulated endogenous 7TM receptors and ligands is still unclear. This is for instance the case for the most upregulated 7TM receptor EBI2 (EBV-induced gene 2 or GPR183). Whereas some regulated genes have been suggested to be involved in the EBV life cycle, others could also be important for the antiviral immune defense. As many of these 7TM receptors and ligands have been shown to be modulated in EBV-associated diseases, targeting these could provide an efficient and specific way to inhibit EBV-associated disease progression. Here, we will review current knowledge on EBV infection, the immune defense against EBV and 7TM receptors and ligands being either encoded or manipulated by EBV.

Section snippets

EBV Infection

Epstein–Barr virus (EBV, human herpesvirus 4) was discovered 50 years ago, when Epstein, Achong, and Barr used electron microscopy to identify viral particles in Burkitt's lymphoma cells.1 It belongs to the lymphocryptovirus (LCV) genus of the gammaherpesvirus subfamily2 (Fig. 1A). The EBV genome, which consists of a linear, double-stranded DNA molecule that encodes close to 100 viral genes, is enclosed in a nuclear capsid surrounded by a protein tegument, which in turn, is surrounded by a

Immune Response and Immune Evasion

Up to 10% of the host B cells are infected with EBV during acute infectious mononucleosis.43 Most of these cells are effectively cleared by the immune system, but some downregulate viral gene expression and differentiate into safety in the resting memory B cell pool. In the persisting infection, the virus and host coexist, so that homeostasis of the infected memory B cell pool is maintained by continuous low-level virus shedding while the immune system ensures that no full blown lytic

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

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 cells to screen for upregulated genes in EBV-infected cells.87 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

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.119 By controlling leukocyte migration, the chemokine system has important functions in coordinating the immune system, leukocyte homeostasis, lymphocyte activation,

EBV-Associated Diseases

Primary EBV infection often occurs in young immunocompetent children and is asymptomatic or present with nonspecific mild symptoms.6 However, given that EBV was originally identified in Burkitt's lymphoma cells and has the unique ability to transform resting B cells into highly proliferating lymphoblasts, it is not surprising that this virus is associated with a number of cancers in both immunocompromised and immunocompetent patients. In addition, EBV has been associated with autoimmune

Drug-Target Potential

7TM receptors and in particular class A receptors to which the 7TM receptors mentioned in this review belong, are highly druggable molecules. Approximately, 35% of all currently marketed drugs target class A 7TM receptors.157 There is no specific antiviral treatment for EBV. Current treatment strategies for EBV-associated lymphomas include B cell antibodies (rituximab, chimeric, and monoclonal antibody against CD20), reducing immunosuppression, EBV-specific CTL infusion, and chemotherapy for

Conclusions

In summary, EBV encodes one 7TM receptor and manipulates endogenous 7TM receptors, some of which are involved in the virus life cycle and some of which may be involved in the antiviral host defense. In the case of EBI2, we are still unclear on whether the upregulation is virus mediated or immune system mediated. Nevertheless, EBI2 is upregulated in EBV-associated PTLD and, together with BILF1 and the chemokine receptors constitute potential drug targets in EBV-mediated diseases. Further studies

Acknowledgment

The authors thank Nick Davis-Poynter and Katja Spiess for critical reading of this manuscript and for helpful comments.

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