Inhibition of IFN-γ Signaling by an Epstein-Barr Virus Immediate-Early Protein

Viruses have evolved elaborate mechanisms to target many aspects of the host's immune response. The cytokine IFN-γ plays a central role in resistance of the host to infection via direct antiviral effects as well as modulation of the immune response. In this study, we demonstrate that the Epstein-Barr virus (EBV) immediate-early protein, BZLF1, inhibits the IFN-γ signaling pathway. BZLF1 decreases the ability of IFN-γ to activate a variety of important downstream target genes, such as IRF-1, p48, and CIITA, and prevents IFN-γ-induced class II MHC surface expression. Additionally, BZLF1 inhibits IFN-γ-induced STAT1 tyrosine phosphorylation and nuclear translocation. Finally, we demonstrate that BZLF1 decreases expression of the IFN-γ receptor, suggesting a mechanism by which EBV may escape antiviral immune responses during primary infection.