In pig to primate transplants, xenografts are rejected by several means. Antibody-mediated destruction of the xenograft is an early event. The end stage mechanisms resulting in xenograft rejection involve cellular [T cell and natural killer (NK) cell] immune responses. The cellular responses to xenotransplants are much greater than allotransplants so that nonspecific immunosuppressive therapies used for allotransplants are not likely to be effective for xenotransplants. Overcoming cellular-mediated rejection of xenografts is therefore a major hurdle. Many viruses have evolved "stealth"; they have found ways to escape T cell observation and consequent destruction of the cells they have infected. The stealth of some viruses is due to their ability to shut off host major histocompatibility complex (MHC) expression. However, cells lacking MHC class I expression are highly susceptible to NK cell-mediated killing. The stealth technology of some viruses is sophisticated enough to deal with this. The principle hypothesis of this study is that the stealth technology viruses employ to evade host cellular immune responses can be exploited to make xenografts tolerated. Specific aims to explore this hypothesis encompass (1) eliminating pig MHC class I cell-surface expression by using viral genes known to affect MHC class I expression and characterizing human T cell responses to class I-deficient pig cells; (2) engineering pig cells to express human leukocyte-associated antigen (HLA)-E and cytomegalovirus (CMV) gpUL40 so as to suppress NK cell-mediated lysis; and (3) testing a set of genes that together will thwart rejection of xenografts by cellular and humoral immune responses. These studies are designed to make pig organs and tissues tolerated by the human immune system. While tolerance per se will not be induced, immune ignorance can be considered a form of tolerance induction. The proposed experiments provide the necessary backdrop to scale-up to transgenic pigs whose organs would be tested in primate models. Moreover, the proposed exploitation of viral stealth technology could be readily adopted for allotransplants especially those involving allogeneic stem cells.