Here, we determined that HSV-1 UL31, which is associated with nuclear matrix and is essential for the formation of viral nuclear egress complex, could inhibit retinoic acid-inducible gene I (RIG-I)-like receptor pathway-mediated interferon beta (IFN-β)–luciferase (Luc) and (PRDIII-I)4-Luc (an expression plasmid of IFN-β positive regulatory elements III and I) promoter activation, as well as the mRNA transcription of IFN-β and downstream interferon-stimulated genes (ISGs), such as ISG15, ISG54, ISG56, etc., to promote viral infection. This evidence concerns the gene IFIT2 and viral infectious disease.