This project is directed at delineating the pathogenesis of human immunodeficiency virus (HIV) infection in thymus and bone marrow. We have identified in vivo and in vitro infection of CD34+ bone marrow progenitor cells. Viral burden in the bone marrow is not consistently higher than that in the peripheral blood; stromal degeneration may occur in HIV infected bone marrows. 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 may be associated with increased apoptosis in the HIV infected thymus. Thymic epithelial cells are also productively infected with HIV and may serve as a viral reservoir in the thymus. Degeneration of thymic epithelial cells occurs independently of infection and function of these cells may be disrupted. After implantation in the scid mouse human fetal lymph node and intestine can be infected by intravenous injection of virus. HIV expression can be regulated by CD8+ T cells from asymptomatic patients, which can suppress viral replication in autologous and allogeneic CD4+ T cells by production of a soluble factor. Suppression of virus expression is not associated with decreased proliferation of CD4+ T cells. Virus expression is also regulated by cytokines, and, after ultraviolet irradiation, epidermal keratinocytes produce a factor or factors which induce the production of HIV from chronically infected U1 and ACH-2 cells. Tumor necrosis factor-alpha is one of the cytokines produced by irradiated epidermal keratinocyte cells which mediates this effect.