Notably, ISG15−/− mice have been shown to have increased susceptibility to influenza A, influenza B, herpes simplex virus 1, murine gamma herpes virus and Sindbis virus (SNV) (Lenschow et al., 2007), while IFN-α receptor−/− (IFNAR−/−) mice can be rescued from SNV infection by expression of ISG15, but not by expression of a mutated ISG15 that cannot be coupled to other proteins, suggesting that the conjugation of ISG15 to its cellular substrates is essential for it to exert its antiviral effect (Lenschow et al., 2005). Here, ISG15 is linked to infection.