Analysis of events leading to neuronal death after infection with E1-deficient adenoviral vectors.
Although recombinant adenoviral vectors are being widely used to target genes to the nervous system, the cellular and genetic effects of recombinant adenoviral infection on neuronal function have not been well characterized. Using sympathetic neuronal cultures, we analyzed the effect of adenoviral infection on viral and neuronal gene expression and on neuronal function and viability. While a delayed cytotoxicity occurred 5 days after infection, numerous biochemical and genetic perturbations occurred within the infected cell prior to this time. This study demonstrates that numerous cellular alterations were produced by recombinant adenoviral vectors and, therefore, emphasizes the need for an analysis of the effects of these viral vectors on neuronal function in the interpretation of data regarding transgene expression induced by these vectors in neurons. It also suggests that continued improvements made to the viral vectors themselves might decrease this direct cytotoxicity and lead to improved safety and function of recombinant adenovirus in vivo.
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110-1031, USA.
R M
RM
Easton
E M
EM
Johnson
D J
DJ
Creedon
D000256:Adenoviridae; D000257:Adenoviridae Infections / Q000503:physiopathology*; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D015967:Gene Expression Regulation, Viral; D005814:Genes, Viral / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000821:virology*; D011247:Pregnancy; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000633:toxicity; D013564:Sympathetic Nervous System / Q000166:cytology
D004279:DNA, Viral; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins