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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004498-05
Application #
2117231
Study Section
Special Emphasis Panel (SRCD (52))
Project Start
1987-09-30
Project End
1993-09-29
Budget Start
1992-09-01
Budget End
1993-09-29
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Emory University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Wiederin, Jayme L; Donahoe, Robert M; Anderson, James R et al. (2010) Plasma proteomic analysis of simian immunodeficiency virus infection of rhesus macaques. J Proteome Res 9:4721-31
Haverland, Nicole; Pottiez, Gwenael; Wiederin, Jayme et al. (2010) Immunoreactivity of anti-gelsolin antibodies: implications for biomarker validation. J Transl Med 8:137
Donahoe, Robert M; O'neil, Shawn P; Marsteller, Frederick A et al. (2009) Probable deceleration of progression of Simian AIDS affected by opiate dependency: studies with a rhesus macaque/SIVsmm9 model. J Acquir Immune Defic Syndr 50:241-9
Madden, J J; Whaley, W L; Ketelsen, D et al. (2001) The morphine-binding site on human activated T-cells is not related to the mu opioid receptor. Drug Alcohol Depend 62:131-9
Donahoe, R M; Vlahov, D (1998) Opiates as potential cofactors in progression of HIV-1 infections to AIDS. J Neuroimmunol 83:77-87
Oleson, D R; DeFelice, L J; Quinn, M F et al. (1996) Cyclic adenosine 3',5'-monophosphate increases the open probability of potassium channels in activated human T cells. J Immunol 157:1080-6
Oleson, D R; DeFelice, L J; Donahoe, R M (1993) Ethanol increases K+ conductance in human T-cells. Alcohol Clin Exp Res 17:604-9
Oleson, D R; DeFelice, L J; Donahoe, R M (1993) A comparison of K+ channel characteristics in human T cells: perforated-patch versus whole-cell recording techniques. J Membr Biol 132:229-41
Donahoe, R M (1990) Immune effects of opiates in test tubes and monkeys. NIDA Res Monogr 105:89-95