This report shows that deletion of a single cytoplasmic protein that blocks NF-κB activation and IFN-β induction can alter both virus virulence and the primary immune response to infection, promoting a Th1 (type 1 T-helper cell)-skewed response, despite the presence of other VACV inhibitors of NF-κB and IRF3. This evidence concerns the gene NFKB1 and infection.