A putative model of the steps involved in entry of virus into a B lymphocyte. (1) The virus binds to CR2 via gp350, possibly initiating signaling events and triggering endocytosis. (2) CR2 may now bind to gp220 rather than gp350, and this, combined with the potential flexibility of CR2, may allow the virus to approach closer to the cell membrane, where gp42 can interact with HLA class II. (3) Interaction of gp42 with HLA class II triggers the interaction of the core fusion machinery, gHgL and gB, with the endosomal membrane and may also initiate further signaling events. (4) The virus and endosomal membranes fuse, allowing entry of the tegumented capsid into the cytoplasm. Modified from reference 18, with permission.

Glycoprotein gp42 as a switch of cell tropism. (a) B-cell infection requires an interaction between gHgLgp42 and HLA class II, whereas epithelial cell infection requires an interaction between gHgL and gHgLR. Complexes lacking gp42 cannot bind to HLA class II, and complexes containing gp42 cannot bind to gHgLR. (b) gHgLgp42 complexes can interact with HLA class II in the endoplasmic reticulum of a B cell. They may then be targeted to endosomal vesicles rich in proteases, where incoming proteins are digested into peptides for loading into the peptide binding groove of HLA class II before continuing on to the cell surface. The result is a loss of gHgLgp42 complexes to degradation and a relative decrease in gHgLgp42 complexes in viruses produced from B cells or plasmablasts (B-EBV). Complexes in epithelial cells are not lost to this degradative pathway, and viruses produced from epithelial cells (E-EBV) are richer in gp42. Epithelial cells high in gp42 are better able to infect B cells, and B cells low in gp42 are better able to infect epithelial cells. Modified from reference 18, with permission.

Putative models of the steps involved in entry of virus into epithelial cells after attachment via different cell proteins. (a) Entry via CR2 and gHgLR. (1) The virus binds to CR2 via gp350; signaling may occur, but endocytosis is not triggered. (2) A switch to interaction with gp220, combined with the potential flexibility of CR2, may allow the virus to approach closer to the cell membrane, where gHgL can interact with gHgLR. (3) Interaction of gHgL with gHgLR triggers the interaction of the core fusion machinery, gHgL and gB, with the cell membrane. (b) Entry via gHgLR alone (which is less efficient). (1) There is no separate attachment event. (2) gHgL interacts directly with gHgLR. (3) Interaction of gHgL with gHgLR triggers the interaction of the core fusion machinery, gHgL and gB, with the cell membrane. (c) Entry via integrins and gHgLR. (1) BMRF2 interacts with α5β1 integrins, possibly initiating signaling events. (2) gHgL interacts with gHgLR. (3) Interaction of gHgL with gHgLR triggers the interaction of the core fusion machinery, gHgL and gB, with the cell membrane. Step 4 is the same for all routes: the virus and cell membrane fuse, allowing entry of the tegumented capsid into the cytoplasm. Modified from reference 18, with permission.