Analysis of molecular bases determining tropism of negative strand viruses

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The P gene of measles virus (MV) encodes the P protein and three accessory proteins (C,V and R). However, the role of these accessory proteins in the natural course of MV infection remains unclear. Here, we generated a recombinant wild-type MV lacking the C protein, wtMV(C-), using a reverse genetics system (Takeda et al., J.Virol.74:6643-6647). When 293 cells expressing the MV receptor SLAM (293/hSLAM) were infected with wtMV(C-) or parental wtMV, growth of wtMV(C-) was restricted, particularly in late stages. Consistently, EGFP-expressing wtMV(C-) induced late-stage cell rounding and cell death in the presence of the fusion-inhibiting peptide, suggesting that the C protein can prevent cell death and is required for long-term MV infection. Neutralizing antibodies against interferon-α/β did not restore the growth restriction of wtMV(C-) in the 293/hSLAM cells. When cynomolgus monkeys were infected with wtMV(C-) or wtMV, the number of MV-infected cells in the thymus was more than 1,000-fold lower for wtMV(C-) than wtMV. Immunohistochemical analyses showed strong expression of a MV antigen in the spleen, lymph nodes, tonsils and larynx of cynomolgus monkey infected with wtMV, but dramatically reduced expression in those tissues in cynomolgus monkey infected with wtMV(C-). These data indicate that the MV C protein is necessary for efficient MV replication both in vitro and in cynomolgus monkeys.