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Journal of Virology, June 1999, p. 5156-5161, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

RGD Inclusion in the Hexon Monomer Provides Adenovirus Type 5-Based Vectors with a Fiber Knob-Independent Pathway for Infection

Emmanuelle Vigne, Irene Mahfouz,dagger Jean-Francois Dedieu,dagger Anne Brie, Michel Perricaudet, and Patrice Yeh*

CNRS-IGR-Rhône Poulenc Rorer UMR1582, Institut Gustave Roussy, 94805 Villejuif Cedex, France

Received 19 November 1998/Accepted 1 February 1999

Hypervariable region 5 (HVR5) is a hydrophilic, serotypically nonconserved loop of the hexon monomer which extrudes from the adenovirus (Ad) capsid. We have replaced the HVR5 sequence of Ad5 with that of heterologous peptides and studied their effects on virus viability and peptide accessibility. A poliovirus model epitope was first inserted in a series of nine "isogenic" viruses that differed in their flanking spacers. Whereas virus productivity was not profoundly altered by any of these modifications, immunoprecipitation experiments under nondenaturing conditions demonstrated that epitope recognition by its cognate monoclonal antibody (C3 MAb) was strongly linker dependent and correlated perfectly with the ability of C3 MAb to inhibit transgene delivery and expression. An alpha v-specific ligand (DCRGDCF) was then inserted in a suitable linker context to investigate whether hexon-modified capsids would enhance the transduction of cells displaying limiting amounts of the virus attachment receptors. Interestingly, although hexon has never been implicated in Ad entry, the modified virus significantly increased the transduction of human vascular smooth muscle cells in vitro. Competition experiments with 293 cells saturated with recombinant knob further indicated that the hexon-modified virus could use an additional, knob-independent pathway for entry. We concluded that genetic engineering of the Ad5 hexon monomer constitutes a novel and feasible approach to equip the virus with additional targeting ligands.

* Corresponding author. Mailing address: CNRS-IGR-Rhône Poulenc Rorer UMR1582, Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France. Phone: (33-1) 42 11 50 89. Fax: (33-1) 42 11 52 46. E-mail: pyeh{at}igr.fr.

dagger Present address: Vector Development, Rhône-Poulenc Rorer Gencell, CRVA, 94403 Vitry-Sur-Seine, France.

Journal of Virology, June 1999, p. 5156-5161, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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