title: Abolition of hCAR-dependent cell tropism using fiber knobs of Atadenovirus serotypes.
abstract: Most adenoviral vectors use in gene therapy protocols derive from species C. However, expression of the primary receptor (human Coxsackievirus and Adenovirus receptor, hCAR) for these AdV is variable on cancer cells. In vivo targeting of a therapeutic gene to specific cells has then become a major issue in gene therapy. The Ad fiber protein largely determines viral tropism through interaction with specific receptors. Hereto, we constructed a set of HAdV5 vectors carrying chimeric fibers with knob domains from nonhuman AdV, namely from the FAdV-1 (Aviadenovirus), DAdV-1, and BAdV-4 (Atadenovirus). Correspondents viruses were produced using an established new HEK293 cell line, which express the HAdV2 fiber. Recombinant HAdV harboring chimeric fibers constituted of the N-terminal domain of HAdV2, and knob domain of bovine adenovirus type 4 (BAdV-4) demonstrated the greatest reduction in fiber-mediated gene transfer into human cells expressing the hCAR. Moreover, this vector infects with a better efficiency than vector with wild-type fiber, the Chinese Hamster Ovarian (CHO) and SKOV3 cell lines, both from ovarian origin, hamster and human, respectively. These studies support the concept that changing the fiber knob domain to ablate hCAR interaction should result in a de- or retargeted adenoviral vector. The adenoviral vector with the chimeric HAdV2/BAdV-4 fiber lacking hCAR interaction and with an ovarian cell tropism could be a nice candidate to elaborate vectors for ovarian tumor therapy.
authors.affiliation: Inserm UR524, Institut de Recherche sur le Cancer de Lille, 59045 Lille cedex, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Renaut
authors.forename: Morvane
authors.initials: M
authors.lastname: Colin
authors.forename: José P G
authors.initials: JP
authors.lastname: Leite
authors.forename: Maria
authors.initials: M
authors.lastname: Benko
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: D'Halluin
mesh_terms: D000256:Adenoviridae / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification; D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics* / Q000378:metabolism; D036022:Capsid Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D018390:Gene Targeting; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D017434:Protein Structure, Tertiary / Q000235:genetics*; D011991:Receptors, Virus / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D016415:Sequence Alignment; D013045:Species Specificity; D018523:Tropism
chemical_list: D000956:Antigens, Viral; D036022:Capsid Proteins; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; C018315:hexon capsid protein, Adenovirus