The purpose of this application is the development of the human peripheral blood leukocyte (PBL)-reconstituted SCID (hu-SCID) mouse model for the testing of therapeutic agents in AIDs. We have shown that hu-SCID mice can be reconstituted with a functional human immune system and can be infected with both cell-associated and free HIV-1. The goals of the proposed research are to define the optimal model of models in terms of virus infection by varying sources of HIV-1 or HIV-2 with respect to: 1) fresh isolates vs. tissue culture strains; II) T cell- tropic vs. macrophage-tropic; and III) molecularly cloned isolates that are both pathogenic and non-pathogenic. Standard parameters of infection will be determined including; 1) minimum infectious dose; II) cell- associated vs. free virus; and (III) optimum route of infection. Additional work will focus on standardizing quantitative assays of virus recovery from infected hu-SCID mice. At the same time, we will optimize the immunologic function of hu-scid mice by using strategies to improve human monocyte generation and survival, to stimulate growth of T cells, and to allow mouse cells to present antigens to engrafted human cells. Among these strategies is the generation of altered SCID mice expressing human class II MHC molecules. The final goal of this research is to begin evaluation of therapeutic agents in an optimized model of HIV infection in hu-SCID mice. Therapeutic trials will begin with azidothymidine a(AZT) in combination with dideoxycytidine (ddc),and progress to trials of soluble CD4 molecules in both their native form and as hybrid CD4 immunoglobulin constructs. The project is designed to develop a reproducible and reliable small animal model for AIDS and AIDS therapy in as expeditious a manner as possible.