Gene therapy is expected to become a common medical practice in years to come. Several vector systems are being developed to affect gene transfer to correct inherited or acquired diseases, such as cancer and AIDS. Lentiviral vectors are specially well suited for gene transfer into non-dividing as well as dividing cells, including stem cells. Exploiting our considerable expertise in human lentivirus (HIV-1 and HIV-2) gene regulation, we have designed novel HIV-2 vectors which have certain advantages over previously designed HIV-1 vectors. To make informed choice, we have undertaken a comparative study of the packaging efficiency, gene transfer ability, and biological safety of HIV-1 and HIV-2 vectors. Partly influenced by the availability of animal models, we have chosen a number of genes to affect gene transfer with lentiviral vectors. These represent different disease entitities and target cell specificities. They include the Bax and caspase genes in neuroblastoma representing apoptosis in neoplasia, the AADC gene in Parkinson disease representing a biochemical pathway defect, the alpha-glactosidase gene in Fabry disease representing an in-born error of metabolism, and the chemokine gene in infectious disease representing HIV in AIDS. We are also using these vectors for antigen delivery as DNA vaccines, including ex vivo genetic modification of dendritic cells, and for prime/boost strategy for vaccination. The vectors containing these genes as transgenes were fully functional in appropriate target cells in vitro. For example, tranduction of human neuronal and glial cells with the AADC vector imparted on them the ability to convert L-Dopa into dopamine. Similarly, transduction of human peripeheral blood mononuclear cells with the chemokine RANTES vector made them resistant to virus infection when challenged with the R5 but not X4 HIV-1. These in vitro studies have set the stage for the pre-clinical in vivo studies in the respective animal models. These studies are now in progress.
