Primary EBV infection usually occurs through the oropharynx, where mucosal epithelial cells and/or B cells become infected (Fig. 1). Infection of B cells by EBV is initiated by binding of the dominant viral glycoprotein gp350/220 to CD21, the C3d complement receptor; subsequent cell entry is mediated by a complex of three viral glycoproteins, gH, gL, and gp42. Gp42 binds to human leukocyte antigen (HLA) class II, which functions as a coreceptor, and gH is most likely involved in virus-cell fusion. The entry of EBV into epithelial cells may occur through multiple mechanisms because the majority of epithelial cells are CD21 negative. After viral entry, the capsid is dissolved and the EBV genome is transported into the nucleus, where it circularizes. Infection of epithelial cells results in lytic or abortive infection. In contrast, B-cell infection results predominantly in latency; however, lytic infection also occurs, resulting in the release of infectious virus into the saliva and other secretions. During primary infection, EBV establishes lifelong latency in B cells, and it is estimated that 1 to 50 cells per 1 × 106 B cells in the peripheral circulation are infected with EBV. The number of latently infected B cells within a person remains stable over years; however, intermittent reactivation of EBV in B cells into the lytic cycle at mucosal sites is probably responsible for the observed shedding of infectious virus into the saliva of asymptomatic carriers (see Fig. 1).
Fig1. INFECTIOUS LIFE CYCLE OF EPSTEIN-BARR VIRUS. EBV, Epstein-Barr virus; EBNA, Epstein-Barr nuclear antigen; LMP, latent mem brane protein.
Although EBV can infect any B cell and express the full spectrum of latency proteins, typically only infection of naïve B cells results in persistent infection (see Fig. 1). EBV infection pushes the naïve B cell into a memory state independent of an antigen-dependent germinal center (GC) reaction by upregulation of cytosine deaminase, which induces both class switching and somatic hypermutation. The former also requires the expression of EBV-encoded LMP1, a constitutively activated CD40 molecule, or CD40 ligation, most likely provided by GC T helper (Th)3 cells that can provide T-cell help for B-cell differentiation by provision of CD40 ligand, interleukin (IL) 4, and IL-10 while preventing antigen-dependent effector T cell mediated B-cell elimination by expression of transforming growth factor (TGF)-β. This reaction occurs within the lymph node and also involves downregulation of latency proteins and expression of latency type II. On exit from the lymph node, expression of latency proteins is completely inhibited. In this way, infected B cells can evade immune elimination. By contrast, primarily infected memory B cells enter and remain in latency type III and are rapidly eliminated by effector T cells and therefore do not contribute to virus persistence.
