Over the past 8 years we have identified several novel and potentially serious health consequences associated with crack cocaine. Our research has examined two general areas: 1) the effects of crack cocaine on lung inflammation, injury and physiology and 2) the impact of cocaine on immunity and host defense. This second line of investigation, the impact of cocaine on immunity and host defense, has become the primary focus for this competitive renewal. In this respect, we have demonstrated that alveolar macrophages recovered from the lungs of crack users exhibit a marked deficiency in their ability to upregulate inducible nitric oxide synthase, produce nitric oxide, and limit the growth of Staphylococcus aureus. When tested in a mouse model, cocaine adversely regulated T-helper cytokine (Thl/Th2) balance leading to over-expression of TGF-beta and IL-10, suppressed T cell function, and allowed the uncontrolled growth of implanted lung tumor cells. Novel experiments have identified sigma receptors as likely to be involved in these effects both in vitro and in vivo. We have also developed an important new model for studying the interaction between cocaine and HIV. Administration of cocaine to severe-combined immunodeficiency (SCID) mice reconstituted with human peripheral blood leukocytes (huPBL/SCID), and infected with HIV, results in dramatic increases in viral replication, down-regulation of CD4 counts and CD4/CD8 ratios, and changes in expression of HIV co-receptors. More recently, we have identified altered immune function in blood collected from crack-abusing subjects. Building on these findings, we propose 3 specific aims' 1) To define the mechanisms by which cocaine enhances HIV replication and infection in vivo in the huPBL/SCID and SCID-hu models. 2) To determine the pathway(s) by which cocaine suppresses immune responses in a murine model of anti-tumor immunity (effects on T cells, dendritic cells, cytokines) and delineate the role of the sigma-receptor signaling in this process. 3) To demonstrate the type and magnitude of cocaine-related alterations in HIV co-factors and immune function as they occur in a well-described cohort of crack cocaine users. Correlations will also be sought between a history of crack use and the development and progression of HIV-related diseases in an established database from the Multicenter AIDS Cohort Study (MACS). By the completion of these studies we will have relevant animal data and human clinical correlates linking inhaled cocaine abuse to the regulation of immune function and host defense, and the modulation of risk factors important to the pathogenesis and progression of HIV.