The perforin-dependent immunological synapse allows T-cell activation-dependent tumor targeting by MLV vector...

We have reported that retroviral particles adhered to the surface of antigen-specific T cells can be carried to metastases following adoptive transfer in vivo, a process we have called viral hitch hiking. Following antigen-driven T-cell accumulation at tumors, viral particles productively infect tumor cells via envelope/receptor dependent interactions ('hand on' of virus from the T cell to the tumor cell). We describe here a second envelope/receptor independent pathway of viral hand on from T cells, dependent on T-cell activation. We show that the endosomolytic property of perforin promotes release of viral particles from endosomes into which they are co-delivered along with cytotoxic granules from the activated T cell. Therefore, hand on of MLV particles lacking any envelope can be used for in vivo delivery of vectors, where targeting is at the extremely specific level of recognition of antigen by the T-cell receptor, thereby dispensing with the need to engineer viral envelopes. These data reveal a novel pathway by which MLV viral particles exploit a functional immunological synapse and present new opportunities both to improve the efficacy of adoptive T-cell transfer and to target vectors for systemic gene delivery.