br EBV Infection Epstein Barr virus EBV
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. It belongs to the lymphocryptovirus (LCV) genus of the gammaherpesvirus subfamily (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 glycoprotein-coated viral envelope. The glycoproteins are important for virus tropism, host selectivity, and infection.
Immune Response and Immune Evasion Up to 10% of the host TCS 359 receptor are infected with EBV during acute infectious mononucleosis. 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 replication is initiated. The number of infected B cells in the persisting infection is around 1–50 per 106 B cell. The host uses both the innate and adaptive immune response to eliminate infected B cells. The innate immune response relies heavily on virus recognition by Toll-like receptors (TLR) followed by interferon (IFN)-γ secretion and activation of natural killer (NK) cells. In particular, TLR3 expressed in classical dendritic cells (DCs) recognizes double-stranded RNA such as EBV EBERs and induces secretion of IFN-γ, antiviral cytokines, and NK cell activation. TLR9 expressed in plasmacytoid DCs recognizes unmethylated CpG motifs in the epigenetically naïve viral DNA and induces IFN-γ secretion and NK cell activation. The importance of NK cells is suggested by the finding that the levels of NK cells are significantly increased in patients with infectious mononucleosis. In addition, recent in vivo studies of infectious mononucleosis in mice with reconstituted human immune components showed that depletion of NK cells led to loss of immune control and enhanced symptoms. The innate immune system ensures virus inhibition until the adaptive immune system is ready to launch a much more comprehensive antiviral response, which mainly consists of cytotoxic CD8 T cells and antibody production induced by CD4+ T cells to a minor degree. Initially, cytotoxic T cells (CTL) are directed against lytic epitopes such as the immediate-early gene BZLF1. Later in the infection, the CTL are directed against latent epitopes, in particular. In contrast to the CD8+ T cell response, the CD4+ T cell response is very modest and seems to be directed against a different set of early and late lytic epitopes as compared to the CD8+ T cell response. The important role of the immune response and especially the adaptive immune response in the inhibition of EBV infection can be illustrated by the fact that a large number of patients with EBV-associated diseases have immunodeficiencies related to either genetic, iatrogenic (PTLD), or other diseases (like HIV). Like other herpesviruses, EBV has adapted to the immune system for instance by expressing many genes with immune evasive properties. Among these, LMP1 and BGL5 downregulate TLR9 in the latent and lytic phases, respectively.50, 51 Also, the late lytic function as a deubiquitinase in the TLR signaling pathway and thereby inhibits TLR signaling. The CD8+ T cell cytotoxic response is inhibited by the downregulation of viral epitope presentation on MHC class I molecule on the cell surface by LMP1, BILF1, BGL5, viral IL-10 homolog BCRF1, and BNLF2a.15, 53, 54, 55, 56 BCRF1 has also been shown to have broad inhibitory effects on the immune system by impairing NK cell-mediated killing of infected B cells, interference with CD4+ T cell activity and modulation of cytokine responses. Finally, the CD4+ T cell response is inhibited by binding of the viral glycoprotein gp42 to MHC class II and the ensuing lowered recognition of CD4+ cells.