Fibroblasts from individuals bearing the P554S variant displayed impaired NF-κB and IRF3 activation and cytokine responsiveness to the TLR3 ligand polyinosine-polycytidylic acid (poly(I:C)), as well as defective IFN-dependent control of viral replication and enhanced cell mortality upon infection with HSV-1. Here, IFNA1 is linked to infection.