Currently, HIV infection is studied in mouse models where human stem cells are transplanted into mice, serving as targets for HIV-1 infection. These models are used extensively for investigation of the impact of gene modification of stem cells with anti-HIV gene therapeutics. One limitation of these models is that the transplant with anti-HIV gene-modified human stem cells is established first then followed by HIV-1 infection. This model is the reverse order of a therapeutic transplant in humans where individuals are transplanted with anti-HIV gene-modified stem cells after HIV-1 infection. We propose to develop a more representative model where we first transplant stem cells to establish a human immune system in mice, then infect with HIV-1, and then conduct a second transplant with gene-modified human stem cells. This model would more closely mimic the human clinical situation. We have successfully identified conditions for two transplants in mice and are now evaluating whether this new humanized mouse model can be used to study protection from HIV-1 by anti-HIV gene modification of stem cells.