The overall goals of this investigation are to determine the effects of substance P on HIV infection of human monocyte/macrophages and the mechanism of these effects. The hypothesis to be investigated is that tachykinins, in particular substance P, may play a central role in stressed HIV-1 infected patients and further trigger progression to AIDS and immune deficiency by affecting monocyte/macrophage functions. The immunopathogenesis of HIV-1 infection and diseases with psychoneuroimmunologic manifestations are likely to be modulated by substance P. We will determine the effects of Substance P on HIV- 1 infection in vitro of monocytes/macrophages from healthy donors. Our preliminary data indicate that substance P enhances infectivity of certain strains of HIV-1 for human monocytes/macrophages as determined by reverse transcriptase activity and p24 antigen expression and that substance P reverses LPS induced inhibition of HIV-1 RT expression in primary monocyte- derived macrophages. We will study interaction between monocyte/macrophage activators and substance P in HIV-1 infected cells. We will determine the mechanism of the effects of substance P on HIV-1 infection of primary monocytes/macrophages in vitro. We will determine whether primary monocytes/macrophages produce endogenous substance P and whether production can be affected by HIV-1 infection in vitro. We will study the role of substance P in facilitating HIV-1 fusion. We will study the effects of substance P on HIV-1 LTR promoter in monocytes/macrophages and a promonocytic cell line. We will also determine whether treatment of primary monocyte/macrophage cultures with substance P has a direct effect on HIV-1 binding to the cells. We will study the effect of substance P on monokine production and CD4 receptor expression in monocytes/macrophages. These studies will provide new insights into substance P regulation of monocyte/macrophage function and the effects of HIV-1 infection on the mononuclear phagocyte system. These findings have direct relevance to the in vivo immunopathogenesis of the psychologic, psychiatric and neurologic complications of HIV-1 infection and AIDS. An understanding of the influence of substance P on HIV-1 infection of monocyte/macrophages should lead to new approaches toward therapeutic intervention.