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Determinants in the Envelope E Protein and Viral RNA Helicase NS3 That Influence the Induction of Apoptosis in Response to Infection with Dengue Type 1 Virus

2000; Elsevier BV; Volume: 274; Issue: 2 Linguagem: Inglês

10.1006/viro.2000.0457

1096-0341

Claudia Nunes Duarte dos Santos, Marie‐Pascale Frenkiel, Marie-Pierre Courageot, Carlos Fernando S. Rocha, M Vazeille-Falcoz, Michelle W. Wien, F.A. Rey, Vincent Deubel, Philippe Després,

Viral Infections and Outbreaks Research

One mechanism by which dengue (DEN) virus may cause cell death is apoptosis. In this study, we investigated whether the genetic determinants responsible for acquisition by DEN type 1 (DEN-1) virus of mouse neurovirulence interfere with the induction of apoptosis. Neurovirulent variant FGA/NA d1d was generated during the adaptation of the human isolate of DEN-1 virus strain FGA/89 to grow in newborn mouse brains and mosquito cells in vitro [Desprès, P. Frenkiel, M.-P. Ceccaldi, P.-E. Duarte Dos Santos, C. and Deubel, V. (1998) J. Virol., 72: 823–829]. Genetic determinants possibly responsible for mouse neurovirulence were studied by sequencing the entire genomes of both DEN-1 viruses. Three amino acid differences in the envelope E protein and one in the nonstructural NS3 protein were found. The cytotoxicity of the mouse-neurovirulent DEN-1 variant was studied in different target cells in vitro and compared with the parental strain. FGA/NA d1d was more pathogenic for mouse neuroblastoma cells and attenuated for human hepatoma cells. Changes in virus replicative functions and virus assembly may account, in a large part, for the differences in the induction of apoptosis. Our data suggest that identified amino acid substitutions in the envelope E protein and viral RNA helicase NS3 may influence DEN-1 virus pathogenicity by altering viral growth.