ACTIVATION OF HIV-1 BY SMOKING AND TUBERCULOSIS

在感染人类免疫缺陷病毒-1（HIV）的人中，肺 机会性感染和非感染性并发症的主要目标。 此外，最近的流行病学研究表明，某些肺 感染和刺激物，特别是肺结核和香烟 吸烟会增加艾滋病的进展速度。 的手段 然而，结核病和吸烟哪一种会加速艾滋病的发展尚不清楚。 我们实验室的研究表明， 吸烟者在体外感染艾滋病毒的可能性要高出几倍， 他们来自不吸烟者。 抗氧化剂N-乙酰半胱氨酸与肿瘤 坏死因子α（TNF）抑制剂戊茶碱抑制HIV产生 在吸烟者中。 NF κ B的细胞质抑制剂IkappaB是 减少和艾滋病毒转录激活因子，芳香烃 受体（AhR）在吸烟者的AM中被激活。 分枝杆菌 刺激来自HIV感染者的AM增加了 艾滋病毒， 这些和其他初步数据和考虑表明， 吸烟者和结核病患者AM中HIV转录激活假说 患者涉及增加的活性氧中间体（R 01）和TNF 其激活BfkappaB和/或AhR。 具体目标是：1。 到 阐明nFkappaB和AhR激活细胞核的机制， 与吸烟者和结核病患者AM中的HIV LTR结合， R 01、TNF、IkappaB和SAPK的作用。 2. 现在有把握地确定 使用病毒学和分子方法， 转录激活吸烟者和结核病患者AM中的HIV 和潜在的机制。 3. 评估吸烟的影响 在激活艾滋病毒的各自途径上停止和治疗结核病 在上午转录。

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.