title: Matrix protein mutations contribute to inefficient induction of apoptosis leading to persistent infection of human neural cells by vesicular stomatitis virus.
abstract: In a model system to study factors involved in the establishment of a persistent viral infection that may lead to neurodegenerative diseases, Indiana and New Jersey variants of vesicular stomatitis virus (VSV) with different capacities to infect and persist in human neural cells were studied. Indiana matrix (M) protein mutants and the wild-type New Jersey strain persisted in the human neural cell line H4 for at least 120 days. The Indiana wild-type virus (HR) and a non-M mutant (TP6), both unable to persist, induced apoptosis more strongly than all the other variants tested, as indicated by higher levels of DNA fragmentation and caspase-3-like activity. Transfection of H4 cells with mRNA coding for the VSV M protein confirmed the importance of this protein in the induction of apoptosis. Furthermore, the pan-caspase inhibitor ZVAD-fmk maintained cell survival to about 80%, whereas inhibition of caspase-8, caspase-9, or both only partially protected the cells against death, consistent with the fact that anti-apoptotic molecules from the Bcl-2 family also protect cells from death only partially. These results suggest that VSV activates many pathways of cell death and that an inefficient induction of caspase-3-related apoptosis participates in the establishment of a persistent infection of human neural cells by less virulent VSV variants.
authors.affiliation: Department of Biological Sciences, Université du Québec à Montréal, Montréal, Québec, H3C 3P8, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Desforges
authors.forename: Geneviève
authors.initials: G
authors.lastname: Despars
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bérard
authors.forename: Myriam
authors.initials: M
authors.lastname: Gosselin
authors.forename: Margie O
authors.initials: MO
authors.lastname: McKenzie
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Lyles
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Talbot
authors.forename: Laurent
authors.initials: L
authors.lastname: Poliquin
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D009154:Mutation; D018696:Neuroprotective Agents / Q000494:pharmacology; D014162:Transfection; D014721:Vesicular stomatitis Indiana virus / Q000472:pathogenicity*; D018116:Vesiculovirus; D014763:Viral Matrix Proteins / Q000235:genetics*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; C094460:M protein, Vesicular stomatitis virus; D018696:Neuroprotective Agents; D014763:Viral Matrix Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone