Urabe AM9 mumps virus vaccine causes post-vaccination meningitis. Two variants of Urabe AM9 virus differ in their replication efficiency in human nerve cells, HN-A(1081) variant being more neurotropic than HN-G(1081). The effect of interferon (IFN) on viral replication and transcription was analyzed. Priming of nerve cells with IFN reduced more significantly the replication of HN-G(1081) variant (from 10(2.5) to 10(1.3) TCID(50)) than that of HN-A(1081) (from 10(3.5) to 10(2.6) TCID(50)). IFN-priming also reduced the transcription of HN-G(1081) genes, but not of HN-A(1081). The effect of viral infection on the transcription of cellular IFN responsive genes was analyzed. HN-A(1081) virus reduced the transcription of STAT1, STAT2, p48 and MxA in both unprimed and IFN-primed cells; whereas HN-G(1081) virus just reduced MxA transcription. Since rubulavirus V protein inhibits IFN signaling, the V mRNA was cloned and sequenced, finding that HN-G(1081) but not HN-A(1081) presented three extra G in the P/V edition site, producing the insertion of Gly156 in the V protein. Our results suggest that the replication efficiency of Urabe AM9 mumps virus variants is influenced by their sensitivity to interferon and their capacity to reduce the antiviral response.