Maximal HIV-1 replication in alveolar macrophages during tuberculosis requires both lymphocyte contact and cytokines.
Maximal HIV-1 replication in alveolar macrophages during tuberculosis requires both lymphocyte contact and cytokines.
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DOI：
10.1084/jem.20011614
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发表时间：
2002-02-18
期刊：
影响因子：
--
通讯作者：
Weiden M
中科院分区：
文献类型：
--
作者：
Hoshino Y;Nakata K;Hoshino S;Honda Y;Tse DB;Shioda T;Rom WN;Weiden M
在肺结核（TB）期间，HIV-1复制在肺泡巨噬细胞（AM）中显著上调。这与抑制性CCAAT增强子结合蛋白β（C/EBPβ）转录因子的丢失和核因子（NF）-κB的活化有关。由于肺TB中的细胞免疫应答需要淋巴细胞-巨噬细胞相互作用，因此开发了将淋巴细胞添加到AM中的模型系统。淋巴细胞与AM的接触降低了抑制性C/EBPβ，激活了NF-κB，增强了HIV-1的复制。如果阻止淋巴细胞和巨噬细胞之间的接触，则抑制性C/EBPβ表达得以维持，并且尽管NF-κB被激活，但HIV-1长末端重复序列（LTR）并未受到最大刺激。交联巨噬细胞表达B-7的抗体，以及血管细胞粘附分子和CD 40用于模拟淋巴细胞接触。需要所有三种交联抗体来消除抑制性C/EBPβ表达。然而，HIV-1 LTR没有被最大程度地刺激，NF-κB没有被激活。最大的HIV-1-LTR刺激需要淋巴细胞衍生的可溶性因子和巨噬细胞表达的共刺激分子的交联。当将IL-1β、IL-6和TNF-β加入具有交联共刺激分子的巨噬细胞中时，也实现了高水平的HIV-1-LTR刺激。活化的淋巴细胞和巨噬细胞之间的接触对于下调抑制性C/EBPβ是必要的，从而解除HIV-1 LTR的抑制。淋巴细胞衍生的细胞因子激活NF-κB，进一步增强HIV-1 LTR。
HIV-1 replication is markedly upregulated in alveolar macrophages (AM) during pulmonary tuberculosis (TB). This is associated with loss of an inhibitory CCAAT enhancer binding protein β (C/EBPβ) transcription factor and activation of nuclear factor (NF)-κB. Since the cellular immune response in pulmonary TB requires lymphocyte–macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBPβ, activated NF-κB, and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBPβ expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-κB was activated. Antibodies that cross-linked macrophage expressed B-7, and vascular cell adhesion molecule and CD40 were used to mimic lymphocyte contact. All three cross-linking antibodies were required to abolish inhibitory C/EBPβ expression. However, the HIV-1 LTR was not maximally stimulated and NF-κB was not activated. Maximal HIV-1–LTR stimulation required both lymphocyte-derived soluble factors, and cross-linking of macrophage expressed costimulatory molecules. High level HIV-1–LTR stimulation was also achieved when IL-1β, IL-6, and TNF-β were added to macrophages with cross-linked costimulatory molecules. Contact between activated lymphocytes and macrophages is necessary to down-regulate inhibitory C/EBPβ, thereby derepressing the HIV-1 LTR. Lymphocyte-derived cytokines activate NF-κB, further enhancing the HIV-1 LTR.
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