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Unformatted text preview: The EMBO Journal Vol.17 No.14 pp.3899–3908, 1998 A matrix-less measles virus is infectious and elicits extensive cell fusion: consequences for propagation in the brain Toni Cathomen 1 , Branka Mrkic, Danie ` le Spehner 2 , Robert Drillien 2 , Roland Naef 3 , Jovan Pavlovic 4 , Adriano Aguzzi 5 , Martin A.Billeter and Roberto Cattaneo 6 Institut fu ¨r Molekularbiologie, Abt. I, Universita ¨t Zu ¨rich, Ho ¨nggerberg, 8093 Zu ¨rich, 3 Institute of Cell Biology, Swiss Federal Institute of Technology, Zu ¨rich, 4 Institut fu ¨r Medizinische Virologie, 5 Institut fu ¨r Neuropathologie, Universita ¨t Zu ¨rich, Zu ¨rich, Switzerland and 2 Etablissement de Transfusion Sanguine de Strasbourg, Strasbourg, France 1 Present address: Laboratory of Genetics, The Salk Institute, San Diego, CA, USA 6 Corresponding author e-mail: [email protected] Measles viruses (MV) can be isolated from the brains of deceased subacute sclerosing panencephalitis patients only in a cell-associated form. These viruses are often defective in the matrix (M) protein and always seem to have an altered fusion protein cytoplasmic tail. We reconstituted a cell-free, infectious M-less MV (MV- ∆ M) from cDNA. In comparison with standard MV, MV- ∆ M was considerably more efficient at inducing cell-to-cell fusion but virus titres were reduced ~250- fold. In MV- ∆ M-induced syncytia the ribonucleo- capsids and glycoproteins largely lost co-localization, confirming the role of M protein as the virus assembly organizer. Genetically modified mice were inoculated with MV- ∆ M or with another highly fusogenic virus bearing glycoproteins with shortened cytoplasmic tails (MV- ∆ tails ). MV- ∆ M and MV- ∆ tails lost acute patho- genicity but penetrated more deeply into the brain parenchyma than standard MV. We suggest that enhanced cell fusion may also favour the propagation of mutated, assembly-defective MV in human brains. Keywords : cell-to-cell fusion/envelope protein cytoplasmic tail/matrix protein/subacute sclerosing panencephalitis/virus assembly Introduction Subacute sclerosing panencephalitis (SSPE) is one of the most thoroughly studied neurodegenerative diseases caused by persistent viral infection of the human central nervous system (CNS), and serves as a model for the analysis of persistent viral infections causing other human syndromes (Kristensson and Norrby, 1986). SSPE gener- ally develops 5–10 years after acute measles virus (MV) infection, starting with subtle intellectual and psycholo- gical dysfunction and progressing to motor and sensory deterioration, cerebral degeneration and death within months or years (ter Meulen et al ., 1983). MV is a non- © Oxford University Press 3899 integrating negative-strand RNA virus which consists of a replicative unit, the ribonucleocapsid and an envelope....
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- RNA, measles virus, standard MV, MV-∆M, standard MV infections