HIV growth in infected people is now partially controlled by anti-retroviral therapies. If we are to eliminate HIV, more effective means of countering the virus are needed. One conceivable mode of therapy is to program CD4-positive T cells, the main cells that grow HIV in the body, to make a molecule that would prevent HIV from growing in the cells. We have called this """"""""intracellular immunization."""""""" We have successfully demonstrated such an approach using a lentivirus vector to carry into the cell genome a cassette that can specify synthesis of a small RNA able to interfere with the production of the cellular receptor for HIV, CCR5. We now propose to develop this idea further. We will optimize the interfering RNA so that it is as efficient as Possible at inhibiting CCR5 synthesis. This will be done by an efficient but comprehensive tiling process. Because HIV can mutate so that it no longer requires CCR5, we need to hit multiple targets. Thus we will develop vectors with multiple cassettes, some against the viral genome. These too will have to be optimized. Then the vectors must be tested in human T cells in culture. Ultimately, their safety and efficacy in humans will have to be investigated. ? ?