We have previously shown that the vesicular stomatitis virus (VSV) matrix protein plays a key role in viral pathogenesis by inhibiting gene expression from chromosomal DNA and by disrupting the cytoskeleton. Infections with the VSV related measles virus can in some cases lead to persistent infections of the CNS. It has been reported that during persistent infections the measles virus matrix gene has accumulated a high number of U to C transitional mutations. The reason for this is unclear. It may be linked to a potential cytotoxicity of the wild type matrix protein that must be neutralized to establish and maintain a persistent infection. We have obtained a total of three wild type matrix genes and ten mutant measles matrix genes isolated from patients with subacute sclerosing panencephalitis (SSPE) and with measles virus inclusion bodies encephalitis (MIBE). These genes were cloned under control of cytomegalovirus promoter for expression in eukaryotic cells. Experiments are in progress to study the subcellular localization of these proteins as well as any potential cytopathic effects that may explain why these mutant genes are selected during these fatal persistent measles virus infections of the CNS. In collaboration with Dr. Ozato, it was found that VSV infections induce a new nuclear DNA binding factor that binds to the interferon-stimulated response element. This factor is most likely involved in interferon induction. The presence of the factor depends on viral transcription. It can also be induced by transfection of double stranded RNA. VSV is very sensitive to antiviral effects of interferon. In fact, the shutoff of cellular transcription by VSV matrix protein may counteract the effect of interferon. This may in part explain the interferon induction and suppression phenotypes of the virus. These findings have important implications for our understanding of viral pathogenesis and disease progression.
