One of the major obstacles to the development of any successful gene therapy lies in the delivery of a target protein to sufficient numbers of cells to elicit a therapeutic response. Although viral delivery strategies have proven to be more efficient than non-viral systems, high immunogenicity coupled with the inefficiency of in vivo transduction still limit the extent of gene transfer. The therapeutic benefit achieved by virally targeting a greater proportion of cells may, however, be outweighed by the potentially detrimental effects of the increased host immune response. A novel approach, presented in this month’s issue of ‘Gene Therapy’, which harnesses the unique ability of the herpes simplex type 1 (HSV-1) VP22 protein to spread from cell to cell, may provide a means to overcome this paradox. 1

The HSV-1 VP22 protein forms part of the viral tegument, a poorly understood region of the virion located between the capsid and the envelope. 2 The recent discovery that VP22 possesses novel trafficking properties in both transfected and virally infected cells3 has aroused significant interest in its potential as a protein delivery vehicle. In infected cells, cytoplasmically located VP22 is rapidly excreted via a Golgi-independent pathway and is subsequently imported into neighbouring uninfected cells by a process requiring an intact actin cytoskeleton. Imported VP22 accumulates in the nucleus, where it may affect the regulation of cellular factors, increasing susceptibility to HSV infection3. The inter-cellular spread of VP22 appears to be a highly efficient process, with VP22 synthesised in one microinjected cell capable of reaching up to 200 surrounding cells. 3 Although the precise role of VP22 trafficking in the virus life cycle has not been determined, exploiting its unique properties is clearly an attractive gene therapy strategy. The ability of VP22 to retain its trafficking function as a fusion protein genetically linked to a peptide tag or marker protein (GFP) initially demonstrated that VP22 could be used for inter-cellular delivery of heterologous proteins. 3 Furthermore, VP22-directed delivery could be achieved either by transfection or by exogenous application of a protein extract. 3 In spite of these promising results from the O’Hare group, a controversial report in the October issue of Gene Therapy declared that intercellular trafficking of a VP22-GFP fusion protein was not observed in cultured mammalian cells. 4 A brief communication5 in this issue, however, presents evidence that experimental conditions are critical to demonstrate the spread of VP22 fusion proteins.