It adds complexity to recent work describing ISG15 as an antiviral effector during HCMV infection that is antagonized by IE1, pUL50, pUL26 and pUL25 [27,52,53,54], and potentially explains the persistence of ISG15 even in cells treated with high concentrations of the JAK inhibitor pyridone-6 [27]. Here, ISG15 is linked to cytomegalovirus infection.