Biophysical targeting of adenovirus vectors for gene therapy

Advances in understanding the interaction of animal viruses with their cognate receptors has led to improvements in the development of cell-specific, targeted viral vectors. Research strategies to generate safe, non-inflammatory viral vectors that are capable of delivering a therapeutic gene to a specific population of cells are currently underway in many laboratories. One approach in the utilization of this cell targeting activity is to ablate the natural interaction of the virus with its native receptor, although this is not an absolute requirement. The initial development of 'viral targeting strategies' was based on the view that by modifying the viral protein/receptor interaction, it would be possible to redirect virus vectors to new host cells. As the understanding of virus/cell interactions increased it was observed, however, that many viruses can use different entry mechanisms for cell attachment and penetration. Adenovirus vectors have been used extensively for the delivery of genes to cells. The entry mechanism for adenoviruses into cells has recently been studied and is relatively well understood, however, there are many aspects of cell receptor/virus interactions, which have still to be elucidated. The single high-affinity receptor on mammalian cells for adenovirus type 5 is recognized as the coxsackie and adenovirus receptor. However, in the absence of coxsackie and adenovirus receptor other receptors are used. A thorough understanding of the biology of adenoviruses is essential in the further development of their use as vectors for cell targeting. One strategy is to modify the viral capsid, either through coating the surface using bispecific antibodies, or by chemically crosslinking the targeting ligand onto the virion surface. Another approach is to genetically modify the virus by incorporating the targeting ligand into the viral 'spike' (fiber) protein. This involves manipulating the adenovirus genome and generating a new targeting ligand on the surface of the fiber protein using recombinant DNA technology. The penton base protein has also received attention as a means of directing adenoviruses via insertion of novel targeting ligands.