Acquired immune deficiency syndrome (AIDS) is now recognized to be one of the most serious threats to human health in this century. Since a large, and growing, proportion of AIDS victims are heroin abusers who have become infected with the AIDS virus (HIV) through sharing of syringes, the possible effects of heroin and related opioids on the development of this disease is a major concern. A large number of studies indicate that opioids on the development of this disease is a major concern. A large number of studies indicate that opioids alter a wide range of immune functions in vivo and in vitro, including T-cell proliferation, natural killer cell activity, monocyte chemotaxis, and response to implanted tumors. However, few studies have examined the possible effects of opioids on those processes that generate immuno-competent cells, and which thus may most directly affect the development of AIDS. These processes include (1) the formation of lymphoid cells by differentiation of pluripotent stem cells from the bone marrow; and (2) the production of interleukin-2 (IL-2) by T-cells in response to an antigen or mitogen, which leads to indefinite proliferation of these cells. We propose to make a detailed examination of the role of endogenous and exogenous opioids in these processes. We will thoroughly characterize opioid effects on (1) differentiation of pluripotent stem cell population from mice into lymphoid, myeloid, and erythroid colonies in vivo and in vitro, and the ability of growth factors M-CSF, erythropoietin (EPO), and IL-3 to reverse these effects; and (2) the ability of mature murine T-cells to produce IL-2 and to respond to exogenous IL-2. We will also identify and quantitate endogenous opioids in both stem cells and mature T-cells, and determine the effects of differentiation and proliferation, respectively, on the levels of these and of opioid receptors in these cells. Finally, we will begin attempts to purify opioid receptors present on T-cells, and explore their role in mediating opioid effects on T-cell proliferation. These studies should increase our understanding of how drug abuse increases the risk of HIV- infected individuals for developing AIDS. They may also lead to clinical manipulations that could enhance the regeneration of immune effector cells that are destroyed by AIDS.
