HIV/TB INTERACTION IN THE LUNG

我们已经证明，HIV-1的复制在未发炎的肺中受到抑制， 在肺结核期间增加。 在体外，我们最近发现， 单核细胞感染M. TB.但是， 令人惊讶的是，我们现在显示M。结核病感染抑制HIV-1复制 巨噬细胞 HIV-1复制的抑制与 抑制HIV-1 LTR和诱导ISGF-3，一种干扰素- α/β（IFN）特异性转录因子复合物。 单核细胞 IFN处理或M感染后不诱导ISGF-3。TB. 完整 HIV-1 LTR负调控元件（NRE）中的C/EBP位点是 启动子抑制所必需的。 巨噬细胞而不是单核细胞诱导 一种与HIV-1 LTR一致的抑制性16 kDa C/EBP-β亚型 镇压 低剂量IFN-β抑制HIV-1 LTR并诱导HIV-1 LTR的表达。 16-kDa抑制性C/EBP-β。 在LTR抑制过程中，C/EBP-β是 存在于超过95%的NRE/蛋白质复合物中。 老鼠骨头- 缺乏IFN受体的骨髓巨噬细胞不产生 炎症刺激后的C/EBP-β阻遏物。 综合起来看， 这些数据表明，在体外， 巨噬细胞产生抗病毒IFN应答，诱导C/EBP-β 转录抑制因子并抑制LTR介导的转录。 在体内，来自未发炎肺的肺泡巨噬细胞类似于巨噬细胞 在体外用IFN-β处理;两者均强烈表达抑制性16-kDa C/EBP-β和抑制HIV-1复制。肺结核 消除C/EBP-β表达并诱导新的C/EBP DNA结合 在HIV-1感染者和 免疫功能正常的患者。Stat-1同源二聚体（IFN-γ特异性 转录因子）也被诱导，但仅在免疫活性 肺结核患者。这些观察的一个合理假设是 如下：在没有炎症的情况下，肺泡巨噬细胞是 被低剂量的干扰素β刺激 中的细胞免疫应答 肺结核破坏了这种先天免疫， 在HIV-1感染和免疫活性患者中的表达。的 艾滋病患者体内不能产生IFN-γ， 复制的 本研究将探讨干扰素介导的免疫调节 在未发炎的肺和肺结核中。 它还将模拟刺激 结核病中病毒复制的研究，并评估HIV-1感染 改变IFN应答。 它将探讨的机制和影响， 抑制性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.