Human immunodeficiency virus infection results in significant organ injury due to inflammation. The lung and the heart are particularly prone to develop inflammation-mediated damage, thus resulting in cardiopulmonary morbidity and mortality. In recent years, it has become apparent that reactive oxygen and nitrogen species play a fundamental role in the initiation, amplification and cell destruction of innate and acquired inflammatory processes. The Tat protein of HIV, a viral regulator required for efficient transcription of the HIV genome during host infection, also activates the transcription of NF-K-B-dependent key inflammatory molecules. We demonstrated that Tat induces oxidative stress and partial depletion of glutathione. This effect is partly mediated by Tat-dependent inhibition of Mn-superoxide dismutase (MnSOD) expression, resulting in increased levels of oxidants. We have also demonstrated that one of the downstream effects of Tat-mediated oxidative stress is the activation of endothelial cell NF-KB, which is a potent inducer of proinflammatory molecules such as the leukocyte adhesion molecule ELAM and the cytokines TNF-a, IL-1 and IL-6. The enhanced oxidative stress in patients with HIV infection may result in direct tissue damage. We hypothesize that HIV-1 Tat protein represses antioxidant systems, resulting in increased free radical species generation and enhanced activation of NF-kB-dependent pro-inflammatory mediators. Lung Tat expression leads to chronic inflammatory injury per se and amplifies lung tissue destruction in the setting of increased oxidative stress due to environmental stimuli or in pro-inflammatory states induced by bacterial products. Abrogation of Tat-induced oxidative stress may lead to significant lung protection against HIV-induced lung inflammation. To address this hypothesis, we have engineered several transgenic (Tg) mouse lines with either low, intermediate or high lung-specific expression of the Tat protein. Preliminary evidence suggests these mice are oxidatively stressed and are sensitized to pro-inflammatory agents. Using this animal model of Tat-mediated pulmonary oxidative stress, we propose to address the following questions: 1) Does expression of the HIV-1 Tat increase basal oxidant stress in lungs? 2) Does Tat-mediated oxidative stress increase basal NF-&-dependent pro- inflammatory mediators and amplify inflammatory damage? 3) Does antioxidant treatment reduce inflammation induced by Tat alone or that induced by the combination of oxidative stress and Tat? This animal model will provide important insight on how retroviral products reset the OxidanVantioxidant balance and thus predispose to or cause inflammatory cell-mediated organ injury and disease. Furthermore, these studies should provide important information regarding the rationale for an antioxidant regime to treat HIV-induced organ dysfunction.