Since opiates and other drugs of abuse have been shown to have immunomodulatory properties, the association of drug abuse with AIDS has engendered the question of whether drugs of abuse serve as direct co- factors in the development of AIDS. Recent evidence suggests that for such co-factor involvement to transpire, it must happen as the result of the interaction of drugs of abuse with the entire neuroimmune network. That is, by influencing the function of cells of the immune system directly as well as through the indirect induction of immunomodulatory products within the neural, endocrine and immune systems. Since the complexities of such direct and indirect effects cannot be dissected experimentally through in vivo studies alone, we have taken an in vitro, reductionistic approach to model these effects and penetrate their complexities. This approach centers around the hypothesis that the immunomodifying effects of drugs of abuse are mediated, primarily, through interaction of these drugs and their inducted-products with surface receptors on cells of the immune system. Accordingly, we have targeted receptor modulation as the focus of our studies, limiting these efforts to the study of T-cells since they are known to be modulated by drugs of abuse as well as being the primary effectors of specific cell- mediated immunity and principle components in the infectivity of HIV-1 and the pathogenesis of AIDS. Using bioassay sensitive to modulation of T-cell receptor expression by drugs of abuse and their inducted-products, along with electrophysiological and biochemical assessments of the consequences of this modulation, we intend to investigate the nature, extent, and pharmacological specificity of this modulation. Information from such studies will then be used to characterize drug effects on T- cell proliferation and on the trafficking, homing and adhesion properties of T-cells since these immunological attributes are known to be affected in vivo by drugs of abuse. Also, we will characterize the effects of receptor modulation by drugs of abuse on the ability of HIV-1 to bind to, and replicate in T-cells. Together these approaches should provide needed information about the involvement of drugs of abuse as cofactors in AIDS.
