Canine distemper virus (CDV) causes in dogs a severe systemic infection, with a high frequency of demyelinating encephalitis. Among the six genes transcribed by CDV, the P gene encodes the polymerase cofactor protein (P) as well as two additional nonstructural proteins, C and V; of these V was shown to act as a virulence factor. We investigated the molecular mechanisms by which the P gene products of the neurovirulent CDV A75/17 strain disrupt type I interferon ( Virulent canine distemper virus (CDV) causes a severe systemic infection in dogs that is characterized by high fever, diarrhea, and pneumonia. Large-scale immunosuppression is a hallmark of infection, and some virus strains additionally invade the central nervous system to cause chronic demyelinating encephalitis. The molecular mechanisms differentiating virulent from attenuated strains are poorly understood. However, the fact that dogs can be protected from infection with virulent CDV by vaccination with attenuated strains suggests that reliable induction of adaptive immunity is possible, provided that the critical early stage of infection is successfully mastered by the host. During the early stage of infection, host defense depends on the innate immune system, which is also responsible for generating signals that activate the adaptive immune response (27). The interferons of type I (IFN-I, e.g., IFN-␣/␤) are a critical element of the innate immune defense against viruses (13,36,41). Virtually all nucleated cells are capable of sensing viral infection by receptors such as Rig-I, MDA-5, or Toll-like receptor-3 (16). Activation of these receptors initiates a signal cascade that results in transcription, translation, and release from the cells of IFN-␣/␤. This part of the IFN defense is referred to as the induction stage. IFN action is initiated by the binding of IFN to type I IFN receptors that activates the receptor-associated tyrosine kinases JAK1 and Tyk2, which, in turn, phosphorylate the signal transducers and activators of transcription (STATs) (21, 41). Subsequently, the activated STAT1 and STAT2 together with IFN regulatory factor 9 (IRF9) form a complex, the IFN-stimulated gene factor 3 (ISGF3), which, once translocated to the nucleus, binds the IFN-stimulated response element (ISRE) sequence (39,45). This initiates the expression of well over 100 proteins which are responsible for the antiviral effect of IFN (36). In recent years, gene products targeting specific steps of IFN induction or action have been found in virtually all viruses studied, indicating the crucial role of IFN evasion in any successful interaction of viruses with their hosts.CDV, a Morbillivirus of the Paramyxoviridae, contains a nonsegmented, single-stranded, negative-sense RNA genome. The genome consists of six genes expressing the structural nucleocapsid (N), matrix (M), fusion (F), hemagglutinin (H), and large (L) proteins and the phospho-protein (P) (20). The P and the L proteins together form the RNA polymerase. In addition to the P protein, the nonstructural C and V p...