VZV manipulates of IFN-gamma activity

During primary infection, varicella zoster virus (VZV) infects epithelial cells in the respiratory lymphoid organs and mucosa. Subsequent infection of lymphocytes allows systemic spread throughout the host. This leads to expression of cytokines, including interferons (IFNs) which partly limit the primary infection. How VZV infects lymphocytes from epithelial cells and evades their antiviral activity has not been established. Here, we show that VZV glycoprotein C (gC), binds IFN ? and modifies its activity, increasing the expression of a small subset of IFN-stimulated genes (ISGs), including intercellular adhesion molecule 1 (ICAM1), as well as several chemokines and immunomodulatory genes. The higher ICAM1 protein levels at the plasma membrane increased lymphocyte function-associated antigen 1 (LFA-1)-dependent T cell adhesion and enhanced VZV spread to peripheral blood mononuclear cells. The mechanism required high affinity interaction between gC and IFN-? and signalling through the IFN-? receptor. This constitutes the discovery of a novel strategy to modulate the activity of IFN-?, inducing the expression of a subset of ISGs leading to enhanced T cell adhesion and virus spread.