Advances in gene delivery, including development of synthetic and viral vectors, has provided a means of manipulation of the cell for study both in vitro and in vivo. Recent focus on specific cell targeting to reduce viral particle manipulation of the cell for study both in vitro and in vivo. Recent focus on specific cell type targeting to reduce viral particle load and immune induction has led to the development of tools aimed at gene delivery to defined sites in the whole animal. In particular, the adenoviral vector system has received attention as a prominent candidate for use in treating disease and inborn errors of metabolism. Previous efforts to target adenoviral vectors to specific cell types have had limited success. Most of the human adenoviruses use the Coxsackie- Adenovirus receptor (CAR) for cell attachment. CAR is found on a wide variety of cells in low number. Contact between the adenovirus and CAR is mediated by a single type of viral fiber protein. The exceptions, subgroups B and F, are thought to make cell contact through unidentified receptors, Subgroup F adenoviruses display a strong tropism for intestinal epithelial cells which are not efficiently infected by the commonly used Ad2 and Ad5 serotypes. This project will generate Ad5 vectors displaying the subgroup F virus, Ad41, surface fiber proteins. The subgroup F viruses possess two different fiber proteins unlike other subtypes that possess only one. The goal of this proposal is to understand the relative contributions of each of the two Ad41 fiber proteins to intestinal cell specificity by placing the fiber proteins in separate virions. In addition to CAR, the unknown receptor for Ad41 will be identified using the pseudotyped virus. Together these studies will lead to advances in virology and will provide a first step toward developing gene therapy for diseases of the bowel.
