Fig. (2) Mechanism of HSV-1 entry into the host cell. The initial contact of the virus with the cell is the binding to the heparan sulfate (HS) proteoglycans on the cell surface, mediated by gC and gB, with consequent binding of gB to the PILRalpha receptor. Subsequently, gD binds to one of its cellular receptors, including HVEM, a member of the TNF-receptor family; nectin-1 or 2, two related members of the immunoglobulin superfamily; or sites generated in HS by the action of specific 3-O sulfotransferases. This last binding triggers the fusion between the cell membrane and the viral envelope, which requires the action of gB, gD and gH-gL, with subsequent release of the viral nucleocapsid and tegument into the cytoplasm. Gene therapy strategies aimed to target viral infection to particular cells can be obtained by modifying the first steps of the virus life cycle, that is, adsorption and penetration. The three main glycoproteins involved in these two phases are gB, gC and gD and their ORF backbone has been engineered to redirect infection to the target cell by deleting regions that affect binding to the main HSV receptors and/or inserting ligands that favour interaction with the new receptors. Envelope-HSV glycoproteins may also interact with TLRs on the cell surface, triggering signals that stimulate innate immunity.