This project proposes to test the survival and antiviral efficacy of human or murine CD4 or CD8 T cells in SCID mice transplanted with human peripheral blood cells (hu-PBLSCID mice). Human CD8 T cells will be modified by gene transfection to increase their survival and helper cell independence. Human CD4 T cells will be modified to increase or maintain the Th1 (IL-2, IFN-g secretion) phenotype. Murine T cells will be derived from mice transgenic for human HLA-A2.1 and/or CD8 and bcl-2.
The specific aims of this project are: (1) to compare transfected and untransfected human CTL for their ability to survive in hu-PBL-SCID mice, and for their relative efficacy in preventing HIV-1 infection. Cell survival, distribution, dosing schedule for maximum efficacy, HLA- restriction of antiviral effects, and interaction with other human or murine cells will be determined; (2) to compare CTL derived from HLA A2.1 transgenic mice with human A2.1 restricted CTL for survival and anit-HIV efficacy in the hu-PBL-SCID model, using parallel studies of transfected and untransfected human and murine CTL; (3) to adoptively transfer modified human CD4 T cells with different cytokine profiles to SCID mice, and measure their in vivo sensitivity to HIV, and their impact on the survival of separately introduced HIV-infected cells, as well as adding CD4 clones with high IL-2 expression to CD8 CTL clones to determine if in vivo helper activity augments CTL efficacy. These basic studies are intended to provide a strong preclinical data base that will guide the use of immune reconstitution in HIV-infected individuals.
| Mosier, D E (2000) Human xenograft models for virus infection. Virology 271:215-9 |
| Mosier, D E (1996) Small animal models for acquired immune deficiency syndrome (AIDS) research. Lab Anim Sci 46:257-65 |
