In persons infected with human immunodeficiency virus-1 (HIV), the lung is a major target of opportunistic infections and noninfectious complications. Further, recent epidemiologic studies suggest that certain pulmonary infections and irritants, notably pulmonary tuberculosis (TB) and cigarette smoking, increase the rate of progression of HIV disease. The means by which TB and smoking increase HIV progression are, however, unknown. Studies in our laboratory demonstrate that alveolar macrophages (AM) from smokers are several fold more susceptible to HIV infection in vitro that are AM from nonsmokers. The antioxidant N-acetylacysteine and the tumor necrosis factor alpha(TNF) inhibitor pentoxifylline inhibit HIV production in AM from smokers. The cytoplasmic inhibitor of NFkappaB, IkappaB, is decreased and the HIV transcriptional activator, aromatic hydrocarbon receptors (AhR), are activated in AM from smokers. Mycobacterial stimulation of AM from HIV-infected subjects increases transcription of HIV., These and other preliminary data and considerations suggest the hypothesis that transcriptional activation of HIV in AM from smokers and TB patients involves increased reactive oxygen intermediates (R01) and TNF which activate BfkappaB and/or AhR.
The Specific Aims are; 1. To elucidate the mechanisms of activation of nFkappaB and AhR for nuclear binding to the HIV LTR in AM from smokers and patients with TB focusing on the roles of R01, TNF, IkappaB, and SAPK. 2. To definitively establish using virologic and molecular approaches the capacity of nFkappaB and AhR to transcriptionally activate HIV in AM from smokers and patients with TB and the underlying mechanisms. 3. To assess the impact of smoking cessation and treatment of TB on the respective pathways activating HIV transcription in AM.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057940-02
Application #
2460236
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (S1))
Project Start
1996-09-29
Project End
2001-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106