Xenogeneic thymic replacement to achieve immune restoration in HIV infection

The thymus is a target of human immunodeficiency virus (HIV)-1 infection in humans, and destruction of thymic progenitors and of the thymic microenvironment by HIV may preclude the generation of functional naive T cells to repopulate the peripheral CD4 T cell pool in HIV-infected people. Xenogeneic thymic grafting might provide a useful strategy for overcoming this obstacle, as xenogeneic thymi might resist HIV infection, and xenogeneic donors could provide essentially unlimited amounts of thymic tissue. We have recently demonstrated that a highly disparate (porcine) xenogeneic thymus graft can be used to replace the host thymus to reconstitute CD4⁺ T cells in thymectomized, T cell-depleted mice, and that these CD4⁺ T cells that repopulate the periphery after developing in porcine thymic xenografts are fully functional, confer resistance to opportunistic infections, and show specific tolerance to the porcine donor and the recipient. Studies in immunodeficient mice show that porcine thymic tissue is likewise capable of generating mature, functional human T cells from hematopoietic progenitors, and that these human cells are specifically tolerant of the porcine donor. Preliminary studies suggest that porcine thymic tissue may confer resistance to the destructive effects of HIV-1 infection on human thymopoiesis. Attempts to apply this approach in nonhuman primates, including simian immunodeficiency virus (SIV)-infected rhesus monkeys, have demonstrated the importance of overcoming the powerful recipient anti-pig T cell response in order to avoid rejection of porcine thymic grafts. However, preliminary results provide encouragement that a tolerant primate T cell repertoire could be generated in a porcine thymic xenograft if this initial immune response were fully prevented.