Genetically targeted adenovirus vector directed to CD40-expressing cells.
The success of gene therapy depends on the specificity of transgene delivery by therapeutic vectors. The present study describes the use of an adenovirus (Ad) fiber replacement strategy for genetic targeting of the virus to human CD40, which is expressed by a variety of diseased tissues. The tropism of the virus was modified by the incorporation into its capsid of a protein chimera comprising structural domains of three different proteins: the Ad serotype 5 fiber, phage T4 fibritin, and the human CD40 ligand (CD40L). The tumor necrosis factor-like domain of CD40L retains its functional tertiary structure upon incorporation into this chimera and allows the virus to use CD40 as a surrogate receptor for cell entry. The ability of the modified Ad vector to infect CD40-positive dendritic cells and tumor cells with a high efficiency makes this virus a prototype of choice for the derivation of therapeutic vectors for the genetic immunization and targeted destruction of tumors.
Belousova
Natalya
N
Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, USA.
Korokhov
Nikolay
N
Krendelshchikova
Valentina
V
Simonenko
Vera
V
Mikheeva
Galina
G
Triozzi
Pierre L
PL
Aldrich
Wayne A
WA
Banerjee
Papia T
PT
Gillies
Stephen D
SD
Curiel
David T
DT
Krasnykh
Victor
V
D000257:Adenoviridae Infections / Q000821:virology; D000260:Adenoviruses, Human / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity*; D017122:Bacteriophage T4 / Q000235:genetics / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D002213:Capsid / Q000378:metabolism; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003713:Dendritic Cells / Q000821:virology; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D019013:CD40 Antigens; D036022:Capsid Proteins; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; C057839:fibritin protein, Enterobacteria phage T4; C018315:hexon capsid protein, Adenovirus; D023201:CD40 Ligand