HIV/TB INTERACTION IN THE LUNG

我们已经证明，HIV-1复制在未发炎的肺中受到抑制 并在肺结核期间增加。在体外，我们最近展示了 单核细胞在感染结核分枝杆菌后增加HIV-1的复制。但, 令人惊讶的是，我们现在发现结核分枝杆菌感染抑制了HIV-1在 巨噬细胞。抑制HIV-1复制与 抑制HIV-1 LTR和诱导干扰素ISGF-3的产生 α/β(干扰素)特异性转录因子复合体。单核细胞可以 干扰素治疗或感染结核分枝杆菌后不诱导ISGF-3。完好无损 HIV-1 LTR负性调控元件(NRE)中的C/EBP位点为 启动子抑制所必需的。巨噬细胞但不能诱导单核细胞 一种与HIV-1 LTR一致的抑制性16 kDa C/EBP-β亚型 压抑。小剂量干扰素-β抑制HIV-1 LTR并诱导 16 kDa抑制性C/EBP-β。在LTR抑制过程中，C/EBP-Beta是 存在于95%以上的NRE/蛋白质复合体中。老鼠的骨头- 缺乏干扰素受体的骨髓巨噬细胞不会产生 炎症刺激后的C/EBP-β抑制因子。加在一起， 这些数据表明，在体外，促炎症刺激 巨噬细胞产生抗病毒的干扰素反应，诱导C/EBP-β 转录抑制因子，并抑制LTR介导的转录。 在体内，未发炎肺的肺泡巨噬细胞类似巨噬细胞。 干扰素-β体外作用下，两者均强烈表达抑制性16-kDa C/EBP-Beta，抑制HIV-1复制。肺结核 取消C/EBP-Beta表达并诱导新的C/EBP DNA结合 HIV-1感染和感染的受累肺段的蛋白质 免疫能力强的病人。STAT-1同源二聚体(一种干扰素-γ特异性的 转录因子)也被诱导，但仅在免疫活性中 结核病患者。对于这些观察结果，一个可信的假设是 在没有炎症的情况下，肺泡巨噬细胞 用低剂量的干扰素-β启动。人的细胞免疫反应 肺结核扰乱这种先天免疫，转换C/EBP 在HIV-1感染患者和免疫功能正常患者中均有表达。这个 艾滋病患者不能产生干扰素-γ使高水平的病毒 复制。 这项建议将研究干扰素介导的免疫调节。 在未发炎的肺部和肺结核中。它还将模拟刺激 并评估HIV-1感染是如何 改变干扰素反应。它将研究这种病毒的作用机制和效果。 抑制C/EBP-β诱导。

We have shown that HIV-1 replication is suppressed in uninflamed lung and increased during tuberculosis. In vitro, we recently showed that monocytes increase HIV-1 replication after infection with M. tb. but, surprisingly, we now show M. tb infection inhibits HIV-1 replication in macrophages. Suppression of HIV-1 replication is associated with repression of the HIV-1 LTR and induction of ISGF-3, an interferon- alpha/beta (IFN)-specific transcription-factor complex. Monocytes do not induce ISGF-3 after IFN treatment or infection with M. tb. Intact C/EBP sites in the HIV-1 LTR negative regulatory element (NRE) are required for promoter repression. Macrophages but not monocytes induce an inhibitory 16-kDa C/EBP-Beta isoform coincident with the HIV-1 LTR repression. Low-dose IFN-Beta represses the HIV-1 LTR and induces the 16-kDa inhibitory C/EBP-Beta. During LTR repression, C/EBP-Beta is present in over 95 percent of the NRE/protein complexes. Mouse bone- marrow macrophages deficient in an IFN receptor do not produce the C/EBP-Beta repressor after an inflammatory stimulus. Taken together, these data suggest that, in vitro, proinflammatory stimulation of macrophages produces an antiviral IFN response that induces a C/EBP-Beta transcriptional repressor and inhibits LTR-mediated transcription. In vivo, alveolar macrophages from uninflamed lung are like macrophages treated with IFN-Beta in vitro; both strongly express inhibitory 16-kDa C/EBP-Beta and inhibit HIV-1 replication. Pulmonary tuberculosis abolishes C/EBP-Beta expression and induces a novel C/EBP DNA binding protein in involved lung segments of both HIV-1- infected and immunocompetent patients. Stat-1 homodimer (an IFN-gamma-specific transcription factor) is also induced, but only in immunocompetent tuberculosis patients. A plausible hypothesis for these observations is as follows: In the absence of inflammation, alveolar macrophages are primed by low doses of IFN-Beta. The cellular immune response in pulmonary tuberculosis disrupts this innate immunity, switching C/EBP expression in both HIV-1-infected and immunocompetent patients. The failure to produce IFN-gamma in AIDS patients allows high-level viral replication. This proposal will investigate the regulation of IFN-mediated immunity in uninflamed lung and in tuberculosis. It will also model stimulation of viral replication in tuberculosis and assess how HIV-1 infection alters IFN response. It will investigate the mechanism and effects of inhibitory C/EBP-Beta induction.