Lentiviral vectors have remarkable cell entry and gene delivery properties that make them highly attractive for gene therapy. However, all integration-competent gene delivery systems have come under scrutiny for possible adverse insertional events. Circumventing the risk of insertional mutagenesis, integration-deficient human immunodeficiency virus (HIV)-1–derived vectors have been shown to support durable transcription of transgenes in certain nonmitotic cell lineages. In mitotic cell populations, such nonintegrated viral forms are lost during cell division and so have time-limited effects. Hybrid lentiviral vectors that harness the cell entry properties of HIV to facilitate carriage of alternative DNA modification systems into cells may allow durable genetic modification with more favorable integration profiles. Thus, systems, which have previously been plasmid-based such as those based on nuclease-enhanced homologous recombination (HR) and artificial transposons, have been incorporated into the viral genome to allow them to “hitch-hike” into cells that are difficult to transfect. Here, we review recent progress in the development of such hybrid lentiviral systems and consider potential applications of such vectors.
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