title: Intracellular trafficking of a fiber-modified adenovirus using lipid raft/caveolae endocytosis.
abstract: Most adenoviral vectors (HAdvs) elaborated for gene therapy are derived from serotype 5 viruses that use clathrin-coated vesicle endocytosis for cell entry. However, it appears that adenoviral vectors are able to take advantage of lipid raft/caveolae endocytosis to infect cells. In vivo targeting of a therapeutic gene to specific cells by vector engineering has become a major focus of gene therapy research. Yet, modification of adenoviral tropism, especially fiber gene engineering, can induce deficient intracellular trafficking of the viral particle, with a shift in subcellular localization resulting in extensive exocytosis. In this study we demonstrate that uptake of a fiber-modified adenovirus using lipid raft/caveolae endocytosis leads to non-altered intracellular trafficking without endosomal retention. Moreover, activation of lipid raft structures by this vector leads to the formation of "mega-caveosomes". These results demonstrate that, by forcing adenoviruses to take advantage of a non-clathrin, non-classical endocytic pathway, it is possible to compensate for the deficiency in endosomolysis that is associated with the use of some of the fiber-modified adenoviral constructs. Moreover, it renders such vectors ideal candidates for infecting human coxsackie and adenoviruses receptor (hCAR) negative cells.
authors: Institut National de la Santé et de la Recherche Médicale U837, Lille, France.
authors: Sophie
authors: S
authors: Rogée
authors: Elodie
authors: E
authors: Grellier
authors: Claudine
authors: C
authors: Bernard
authors: Anne
authors: A
authors: Loyens
authors: Jean-Claude
authors: JC
authors: Beauvillain
authors: Jean-Claude
authors: JC
authors: D'halluin
authors: Morvane
authors: M
authors: Colin
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D021941:Caveolae / Q000378:metabolism*; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D016253:Microscopy, Immunoelectron; D014771:Virion / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D002966:Clathrin