ACTIVATION OF HIV-1 BY SMOKING AND TUBERCULOSIS

吸烟和结核病激活 HIV-1

• 批准号: 2460236
• 负责人: ELIZABETH A RICH
• 金额: $ 30.6万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-29 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2460236
• 关键词: acetylcysteine; alveolar macrophages; antioxidants; aromatic hydrocarbon receptor; clinical research; free radical oxygen; human immunodeficiency virus 1; human subject; irritation /irritant; latent virus infection; molecular pathology; nuclear factor kappa beta; nucleic acid repetitive sequence; opportunistic infections; pentoxifylline; receptor expression; respiratory infections; smoking; tobacco abuse; transcription factor; tuberculosis; tumor necrosis factor alpha; virus genetics; virus replication; virus virus interaction

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.

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 感染和刺激性，特别是肺结核（TB）和香烟 吸烟，增加艾滋病毒疾病进展的速度。 手段 但是，TB和吸烟增加了HIV的进展是未知的。 我们实验室的研究表明，肺泡巨噬细胞（AM） 吸烟者在体外更容易受到艾滋病毒感染的影响 是来自非吸烟者。 抗氧化剂N-乙酰赛糖苷和肿瘤 坏死因子α（TNF）抑制剂戊昔丁素抑制HIV产生 在吸烟者中。 ikappab的Nfkappab的细胞质抑制剂是 减少和HIV转录激活剂芳香烃 受吸烟者的AM激活受体（AHR）。 分枝杆菌 来自HIV感染受试者的AM的刺激增加了 艾滋病毒，这些和其他初步数据和注意事项表明 假设吸烟者和结核病中AM中HIV的转录激活 患者涉及活性氧中间体（R01）和TNF的增加 激活bfkappab和/或ahr。 具体目标是； 1 阐明NFKappab和AHR激活的机制 吸烟者和结核病患者的AM中与HIV LTR结合。 R01，TNF，IKAPPAB和SAPK的角色。 2。明确建立 使用病毒和分子方法NFKappab和AHR的能力 从吸烟者和结核病患者的AM中转录激活HIV 以及基本机制。 3。评估吸烟的影响 在激活HIV的各个途径上停止和处理结核病 AM的转录。