This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The association between tobacco use and HIV/AIDS epidemics represents an area of growing clinical and public health importance. The present application focuses on a novel interaction between the HIV-1 envelope neurotoxin gp120, the a7 nicotinic acetylcholine receptor (a7 nAChR), and nicotine. HIV seropositive smokers display higher viral loads and lower CD4+ cell counts than HIV seropositive nonsmokers (Wojna et al., 2007) which may be the result of chronic activation of the upregulated a7 nAChR (due to gp120 chronic exposure) in immune cells by nicotine which could lead to calcium overloading of immune cells and ultimately apoptosis. We hypothesize that drugs which interefere with the a7 nAChR functionality could potentially alleviate the pathological consequences that may result from the chronic nicotine stimulation of the upregulated a7 nAChR. The long-term goal of these studies is to define whether a smoking cessation therapy based on the use of a nicotinic receptor antagonist will improve the immunological profile of HIV-seropositive smokers and to investigate whether smoking cessation medication can be used as adjunctive therapy during HIV infection. The rationale for using antagonists is that by interfering with the upregulated a7 nAChR activity, antagonists are expected to reduce calcium overloading and the potentially related apoptosis. Bupropion will be studied as a model a7 nAChR antagonist. Our extensive experience in the study of nAChRs and MDMs, our established expertise in confocal imaging and electrophysiological techniques, and our strong collaborations with clinicians from the NeuroAIDS Program at UPR-MSC place us in a priviledged position to carry out the proposed studies successfully and complete the work in a timely manner. We propose the following aims: (1) To elucidate whether a7 nAChR antagonist bupropion protects MDMs against calcium overloading due to gp120 exposure, (2) To determine the effects of bupropion on agonist-induced single-channel ?7 nAChR currents in MDMs, and (3) To correlate the gp120-induced ?7 nAChR upregulation in MDMs with apoptosis using flow cytometry and determine whether bupropion at therapeutic concentrations protects against apoptosis.
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