Intravenous drug abuse continues to be a major contributor in the perpetuation of the AIDS epidemic. Primarily, this situation relates to the needle-sharing and sexual practices of addicts. However, there is also ample evidence to suggest that the drugs themselves are an integral part of the problem through their immunomodulatory properties. Since intravenous drug addiction is accompanied by many factors, including drugs, that are capable of modulating immune responses, determination of the potential of drugs to alter immunity and influence contraction and outcome of HIV1 infection cannot be effectively addressed solely by studying drug addicts themselves. Because of this situation, efforts in this renewal proposal are directed toward investigation of in vitro effects of drugs of abuse on specific immunological properties of T-cell lymphocytes and their ability to cope with HIV infection. These studies maintain relevance to the human circumstance by focusing on immune properties of T-cells which have already been shown to be modulated in drug addicts as well as being of known relevance to HIV1 infection and AIDS. Using a kinetic marker modulation assay developed in this laboratory, and a newly defined, tandem, direct-staining assay, investigations of the ability of morphine, cocaine and other abused drugs to modulate expression of CD2, CD4 and CD8 surface antigenic markers of T-cells are to continue. By exploring the biological, physiological and pharmacological bases for modulation of markers in these assays, a better understanding of the means by which opiates modulate immune function and T-cell susceptibility to HIV1 infection ought to be achieved. Signal transduction mechanisms related to the function of guanine nucleotide binding (G) proteins and to ion channel activities are proving to be a particularly important target of these efforts which are now supported by new electrophysiology and cytofluorometry laboratories. Ultimately, the plan aims to link basic, mechanistic studies with analyses of the ability of the drugs of concern to modulate the functional capacity of T-cells associated with activation of cell division through the 'alternate', CD2, replicative pathway and with susceptibility of T-cells to HIV1 infection via CD4. Taken together, these efforts should yield important clues to the role of abused drugs in AIDS.
