A chimeric adenovirus vector encoding reovirus attachment protein sigma1 targets cells expressing junctional adhesion molecule 1.
The utility of adenovirus (Ad) vectors for gene transduction can be limited by receptor specificity. We developed a gene-delivery vehicle in which the potent Ad5 vector was genetically reengineered to display the mucosal-targeting sigma1 protein of reovirus type 3 Dearing (T3D). A sigma1 construct containing all but a small virion-anchoring domain was fused to the N-terminal 44 aa of Ad5 fiber. This chimeric attachment protein Fibtail-T3Dsigma1 forms trimers and assembles onto Ad virions. Fibtail-T3Dsigma1 was recombined into the Ad5 genome, replacing sequences encoding wild-type fiber. The resulting vector, Ad5-T3Dsigma1, expresses Fibtail-T3Dsigma1 and infects Chinese hamster ovary cells transfected with human or mouse homologs of the reovirus receptor, junctional adhesion molecule 1 (JAM1), but not the coxsackievirus and Ad receptor. Treatment of Caco-2 intestinal epithelial cells with either JAM1-specific antibody or neuraminidase reduced transduction by Ad5-T3Dsigma1, and their combined effect decreased transduction by 95%. Ad5-T3Dsigma1 transduces primary cultures of human dendritic cells substantially more efficiently than does Ad5, and this transduction depends on expression of JAM1. These data provide strong evidence that Ad5-T3Dsigma1 can be redirected to cells expressing JAM1 and sialic acid for application as a vaccine vector.
Mercier
George T
GT
Department of Bioengineering, Rice University, Houston, TX 77005, USA.
Campbell
Jacquelyn A
JA
Chappell
James D
JD
Stehle
Thilo
T
Dermody
Terence S
TS
Barry
Michael A
MA
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D016466:CHO Cells; D018938:Caco-2 Cells; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D005822:Genetic Vectors; D006801:Humans; D062726:Junctional Adhesion Molecules; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics* / Q000378:metabolism; D012087:Reoviridae / Q000502:physiology*; D014162:Transfection
D015815:Cell Adhesion Molecules; D062726:Junctional Adhesion Molecules; D011991:Receptors, Virus; D019158:N-Acetylneuraminic Acid