title: Interaction between mouse adenovirus type 1 and cell surface heparan sulfate proteoglycans.
abstract: Application of human adenovirus type 5 (Ad5) derived vectors for cancer gene therapy has been limited by the poor cell surface expression, on some tumor cell types, of the primary Ad5 receptor, the coxsackie-adenovirus-receptor (CAR), as well as the accumulation of Ad5 in the liver following interaction with blood coagulation factor X (FX) and subsequent tethering of the FX-Ad5 complex to heparan sulfate proteoglycan (HSPG) on liver cells. As an alternative vector, mouse adenovirus type 1 (MAV-1) is particularly attractive, since this non-human adenovirus displays pronounced endothelial cell tropism and does not use CAR as a cellular attachment receptor. We here demonstrate that MAV-1 uses cell surface heparan sulfate proteoglycans (HSPGs) as primary cellular attachment receptor. Direct binding of MAV-1 to heparan sulfate-coated plates proved to be markedly more efficient compared to that of Ad5. Experiments with modified heparins revealed that the interaction of MAV-1 to HSPGs depends on their N-sulfation and, to a lesser extent, 6-O-sulfation rate. Whereas the interaction between Ad5 and HSPGs was enhanced by FX, this was not the case for MAV-1. A slot blot assay demonstrated the ability of MAV-1 to directly interact with FX, although the amount of FX complexed to MAV-1 was much lower than observed for Ad5. Analysis of the binding of MAV-1 and Ad5 to the NCI-60 panel of different human tumor cell lines revealed the preference of MAV-1 for ovarian carcinoma cells. Together, the data presented here enlarge our insight into the HSPG receptor usage of MAV-1 and support the development of an MAV-1-derived gene vector for human cancer therapy.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Lenaerts
authors.forename: Wim
authors.initials: W
authors.lastname: van Dam
authors.forename: Leentje
authors.initials: L
authors.lastname: Persoons
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
mesh_terms: D000256:Adenoviridae / Q000378:metabolism*; D000818:Animals; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D005822:Genetic Vectors; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011485:Protein Binding; D011991:Receptors, Virus
chemical_list: D019496:Cancer Vaccines; D019812:Heparan Sulfate Proteoglycans; D011991:Receptors, Virus; C085301:adenovirus receptor