Human immunodeficiency virus (HIV) is etiologically associated with AIDS. New approaches are needed to control HIV infection and AIDS. Gene therapy using retroviral vectors holds great promise. One objective of this project is to develop HIV-based retroviral vectors, particularly HIV-2. HIV has the obvious advantage of cell tropism and HIV-2 has the added advantage of being able to infect stem cells. A series of HIV-2-based expression and delivery vectors have been constructed. These contain long terminal repeats for regulated expression, gag sequences for packaging efficiency, neo gene for cell selection, and other segments for regulating expression. These vectors are being used to precisely define the genetic information necessary for efficient packaging and expression of heterologous protective ribonucleic acid encased within the subgenomic HIV-2 ribonucleic acid. Similarly, HIV-2 vector transduced cell lines are being developed to provide the packaging machinery. During previous studies of the mapping of HIV-2 Tat functional domains, it was discovered that HIV-2 provirus downmodulated HIV-1 expression. Further studies have confirmed apparent receptor-independent HIV-2-mediated intracellular inhibition of HIV involving transcriptional downmodulation of HIV-1 expression. This inhibition is non-reciprocal, thus identifying a remarkable difference between HIV-1 and HIV-2. The recent report of possible protection of HIV-2-infected individuals from HIV-1 infection highlights the importance of these observations. It is increasingly clear that HIV-2 is not HIV-1. Apart from their natural history, a body of evidence is being accumulated for the divergent molecular behavior of HIV-1 and HIV-2. These studies, combined with the development of the HIV-2 vectors, could provide powerful tools for gene therapy of HIV infection and AIDS. In addition, the vectors will have a general utility for gene transfer in cancer and other human diseases.