Determinants in the envelope E protein and viral RNA helicase NS3 that influence the induction of apoptosis in response to infection with dengue type1 virus

One mechanism by which dengue (DEN) virus may cause cell death is apoptosis . In this study, we investigated whether the genetic determinants responsib le for acquisition by DEN type 1 (DEN-1) virus of mouse neurovirulence inte rfere with the induction of apoptosis. Neurovirulent variant FGA/NA did 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 [Despre s, P. Frenkiel, M.-P. Ceccaldi, P.-E. Duarte Dos Santos, C. and Deubel, V. (1998) J. Virol., 72: 823-829]. Genetic determinants possibly responsible f or mouse neurovirulence were studied by sequencing the entire genomes of bo th DEN-1 viruses. Three amino acid differences in the envelope E protein an d 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 did was more pathogenic for mouse neuroblastoma cells and attenuated for human hepatoma cells. Cha nges in virus replicative functions and virus assembly may account, in a la rge part, for the differences in the induction of apoptosis. Our data sugge st that identified amino acid substitutions in the envelope E protein and v iral RNA helicase NS3 may influence DEN-1 virus pathogenicity by altering v iral growth. (C) 2000 Academic Press.