A chimeric adenovirus vector encoding reovirus attachment protein σ1 targets cells expressing junctional adhesion molecule 1

doi:10.1073/pnas.0400542101

A chimeric adenovirus vector encoding reovirus attachment protein σ1 targets cells expressing junctional adhesion molecule 1

^*Department of Bioengineering, Rice University, Houston, TX 77005; Departments of ^†Microbiology and Immunology, ^§Pathology, and ^∥Pediatrics and ^‡Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN 37232; ^¶Laboratory of Developmental Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; and Departments of ^††Molecular and Human Genetics and ^‡‡Immunology and ^§§Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030

Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY (received for review January 23, 2004)

Abstract

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 σ1 protein of reovirus type 3 Dearing (T3D). A σ1 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-T3Dσ1 forms trimers and assembles onto Ad virions. Fibtail-T3Dσ1 was recombined into the Ad5 genome, replacing sequences encoding wild-type fiber. The resulting vector, Ad5-T3Dσ1, expresses Fibtail-T3Dσ1 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-T3Dσ1, and their combined effect decreased transduction by 95%. Ad5-T3Dσ1 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-T3Dσ1 can be redirected to cells expressing JAM1 and sialic acid for application as a vaccine vector.

Footnotes

↵ ** To whom correspondence may be addressed. E-mail: terry.dermody{at}vanderbilt.edu or mab{at}bcm.tmc.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: Ad, adenovirus; CAR, coxsackievirus and Ad receptor; DC, dendritic cell; T3D, type 3 Dearing; JAM1, junctional adhesion molecule 1; CHO, Chinese hamster ovary; h, human; CMV, cytomegalovirus; m, murine.