Regulation of HSV glycoprotein induced cascade of events governing cell-cell fusion.

Cell-cell fusion mediated by HSV glycoproteins requires gD, gH/gL, gB and a gD receptor. Here, we show that fusion by wild type HSV-2 glycoproteins occurs twice as fast as that achieved by HSV-1 glycoproteins. By sequentially swapping each glycoprotein between the two serotypes, we found that the fusion process was controlled by gH/gL. Restrictions imposed on the gB structure by mutations could be overcome by gH/gL, enhancing their activity. Using low pH or deregulated forms of gD and gH/gL the fusogenic potential of gB could only be increased in the absence of receptor, underlining the exquisite regulation that occurs in the presence of receptor. Our data highlight the complexity of the fusion machinery, the impact of the activation state of each glycoprotein on the fusion process and the critical role of gH/gL in regulating HSV induced fusion.