Infection with human immunodeficiency virus-1 (HIV-1) leads to complications such as myocarditis, alveolitis and pulmonary hypertension that cannot be attributed to viral or bacterial pathogens, resulting in cardiopulmonary dysfunction, morbidity and mortality. The HIV- 1 Tat protein, a viral transcriptional regulator essential for viral replication, is secreted from infected cells, taken up by uninfected cells and acts as a cellular transcription activator. Dr. Flores found that soluble Tat induces oxidative stress via inhibition of antioxidant enzymes and activates proinflammatory molecules. Upon joining Dr. Flores' group 1 discovered that Tat up-regulates expression of the NF-kB family member, RelB. RelB regulates immune responses including antigen presentation and inflammation. This proposal is based on the premise that higher levels of RelB in essence reset the threshold for inflammation resulting in a """"""""primed"""""""" immune system that is increasingly sensitive to further inflammatory stimuli. The research plan addresses the mechanisms of Tat-mediated RelB activation and whether Tat affects RelB expression in vivo. Using an in vitro tissue culture system, the following specific questions will be addressed: 1) What are the mechanisms of Tat-mediated RelB up-regulation? 2) What are the downstream effects of Tat-activated RelB? A transgenic mouse model with targeted expression of Tat in the lungs, engineered by Dr. Flores, will be used to address the following specific question: 1) Is there evidence of inflammation in the lungs of Tat-transgenic mice? 2) Is RelB up-regulated in transgenic mouse lung tissues or in alveolar macrophages? 3) Does Tat enhance endotoxin-mediated Relb overexpression in lungs? The proposed research plan should provide new insights into the mechanisms of dysregulated inflammation in AIDS. As part of the career development of the candidate, there will be an advisory committee composed of the co-members as well as three additional members with expertise in various areas relevant to the project. The candidate will be in frequent communication with the committee and will meet at least once a year to assess progress. The candidate will enroll in formal course work on material relevant to the research and will obtain further experience on the technique of in vivo radiolabeling in Dr. Granger's laboratory at LSU Medical Center. The plan is designed to shape the candidate into an independent and investigator.
