PROJECT SUMMARY The exceedingly high rate of smoking and its substantial contribution to morbidity and mortality in the HIV- infected population despite effective ART makes smoking a major health risk in the HIV-infected population. The mechanism by which smoking exerts synergistic effects on HIV-induced immune dysfunction remains unclear. Our central hypothesis is that the persistent HIV-induced immune dysfunction leaves the lung exceeding vulnerable to further insults by smoking. Smoking further drives immune-mediate pathways, such as increase in oxidative stress and inflammation, to cause further local tissue destruction. The lung pathology can result in activation of latently infected alveolar macrophages in the lung to produce low level HIV viremia, and perpetuates this pro-inflammatory environment. Additionally, the chronic oxidative imbalance can cause not only local tissue damage but cellular DNA damage, which results in epithelial gene expression alterations. Aim 1 seeks to identify in a cross-sectional study of ART-treated HIV smokers chronic immune effects of smoking by evaluating for differences in cytokine profile and immune cell phenotype and ROS production of cells isolated in the airways and blood from HIV-infected never smokers. The relationships of these local and systemic immune perturbations with airway epithelial gene transcriptome and evidence of residual viremia will be evaluated to identify biological pathways by which smoking interacts with HIV immune dysfunction. In Aim 2 to further test the hypothesis we propose a proof-of-concept smoking cessation clinical study to assess the degree and nature of reversibility of lung damage among HIV smokers who achieve smoking cessation compared to those who continue to smoke. In this single site study, we will employ an intensive smoking cessation program to help study participants who are recruited from a large urban HIV-infected outpatient clinic where a unique integrated clinical research infrastructure is in place, achieve smoking cessation. Longitudinally samples will be collected pre-cessation and post-cessation from those who are able to achieve 10-week cessation from the lung and blood. We will evaluate the change in level of inflammation, immune activation and oxidative stress, and determine if these immune-mediate pathways are related to changes in HIV residual viremia and epithelial gene expression in the lung. Lastly, leveraging existing resources, we will compare these finding to those in uninfected smokers from banked samples collected already by our collaborator. This smoking cessation study in HIV-infected patients will be the first of its kind, with longitudinal specimen collection from both the lung and blood compartments, and utilizing translational approaches through collaborations with experts in virology, immunology, gene transcription and health disparity research. Understanding the relative contribution and pathways by which smoking interacts with immune acti...