Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors.

Glioblastomas are the most aggressive of the brain tumors occurring in adults and children. Currently available chemotherapy prolongs the median survival time of patients by only 4 months. The low efficiency of current treatments is partly owing to the blood-brain barrier, which restricts the penetration of most drugs into the central nervous system.

A fiber-modified adenoviral vector interacts with immunoevasion molecules of the B7 family at the surface of murine leukemia cells derived from dormant tumors.

Tumor cells can escape the immune system by overexpressing molecules of the B7 family, e.g. B7-H1 (PD-L1 or CD86), which suppresses the anti-tumor T-cell responses through binding to the PD-1 receptor, and similarly for B7.

Influence of chimeric human-bovine fibers on adenoviral uptake by liver cells and the antiviral immune response.

Human adenoviruses (HAdV) are widely used for in vitro and in vivo gene transfer. Viral hepatotropism, inflammatory responses and neutralization by pre-existing antibodies (NAbs) are obstacles for clinical applications of HAdV vectors. Although the multifactorial events leading to innate HAdV toxicity are far from being elucidated, there is a consensus that the majority of intravenously injected-HAdV vectors is sequestered by Kuppfer cells, probably independently of coagulation factors.

Non-heparan sulfate GAG-dependent infection of cells using an adenoviral vector with a chimeric fiber conserving its KKTK motif.

Recently, the potential involvement of the putative heparan sulfate proteoglycans (HSPG) binding motif, KKTK, in mediating HAdV-5 liver cell infection following intravascular virus delivery has been debated. In the present study, we demonstrated that HSPGs were not involved in the in vitro infection process of an adenoviral vector harboring chimeric fibers without mutation in the KKTK motif, HAdV-5-F2/BAdV-4. The entry of HAdV-5-F2/BAdV-4 into cells occurs by two mechanisms 1) the attachment of HAdV-5-F2/BAdV-4 to the surface of cells requires N-glycosylation, 2) the uptake of the virus is effective after interaction with a co-receptor, putatively the chondroitin sulfate C.

Intracellular trafficking of a fiber-modified adenovirus using lipid raft/caveolae endocytosis.

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.