This project is directed at delineating the pathogenesis of human immunodeficiency virus (HIV) infection in thymus and bone marrow and developing mechanisms to reconstitute the damaged immune system. We have identified in vivo and in vitro infection of CD34+ bone marrow progenitor cells. Human thymus is reproducibly infected with HIV in the SCID-hu mouse using primary isolates and is associated with infection of CD4/CD8 double positive, CD4 single positive and CD8 single positive thymocytes. Thymocyte depletion is marked and is associated with increased apoptosis within the thymus. Thymic epithelial cells are also productively infected with HIV and may serve as a viral reservoir in the thymus since they do not appear to undergo cytolysis in response to infection. Other cytopathic effects are observed in the thymus unrelated to direct HIV infection and may represent alterations in growth factor and cytokine production. The SCID-hu mouse provides a model for study of HIV-related superantigen effects which may play a role in the depletion of T cells in infected individuals. We have also shown that cyclosporin A can block HIV infection in the SCID-hu thymus and this may be related to a decrease in cellular activation. Human fetal lymph node and intestine can be infected with intravenously inoculated HIV after implantation in the SCID mouse but further improvements in transplant survival are needed. Reconstitution of the SCID mouse with multiple human tissues (thymus, liver, lymph node, intestine and bone) results in a transient circulating human immune system. These tissues can be infected by intravenous inoculation of HIV and this may provide a model for studying the human immune system in a small animal. CD8+ T cells from certain HIV-infected individuals produce a soluble factor which can suppress HIV expression in CD4+ T cells. CD8+ T cells from various HIV-infected individuals have been immortalized in order to facilitate isolation and characterization of the soluble factor.
