ACTIVATION OF HIV-1 BY SMOKING AND TUBERCULOSIS

在感染人类免疫缺陷病毒-1(HIV)的人中，肺是 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，某些肺部疾病 感染和刺激物，特别是肺结核和香烟 吸烟，会增加艾滋病毒疾病的进展速度。手段是通过 然而，哪些结核病和吸烟会增加艾滋病毒的进展还不得而知。 我们实验室的研究表明，肺泡巨噬细胞(AM)来自于 吸烟者在体外对艾滋病毒感染的易感性是 AM来自非吸烟者。抗氧化剂N-乙酰半胱氨酸与肿瘤 肿瘤坏死因子抑制剂己酮可可碱抑制HIV的产生 在AM中来自吸烟者。NFkappaB的细胞质抑制物IkappaB是 减少和HIV转录激活剂，芳香烃 吸烟者AM中的受体(AhR)被激活。分枝杆菌 HIV感染者AM的刺激增加转录 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转录激活的假说 患者涉及活性氧中间体(R01)和肿瘤坏死因子(TNF)升高 激活BfkappaB和/或AhR。具体目标是：1. 阐明nFkappaB和AhR对核的激活机制 吸烟者和结核病患者AM中与HIV LTR的结合 R01、肿瘤坏死因子、IkappaB和SAPK的作用。2.明确确立 用病毒学和分子生物学方法研究nFkappaB和AhR的功能 通过转录激活吸烟者和结核病患者AM中的HIV 以及潜在的机制。3.评估吸烟的影响 结核病在激活HIV的各自途径上的停止和治疗 AM中的转录

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.