Toll-Like Receptor (TLR) Signaling Enables Cyclic GMP-AMP Synthase (cGAS) Sensing of HIV-1 Infection in Macrophages.
Toll-Like Receptor (TLR) Signaling Enables Cyclic GMP-AMP Synthase (cGAS) Sensing of HIV-1 Infection in Macrophages.
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DOI：
10.1128/mbio.02817-21
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发表时间：
2021-12-21
期刊：
影响因子：
6.4
通讯作者：
Yamashita M
中科院分区：
文献类型：
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作者：
Siddiqui MA;Yamashita M
HIV-1 在表达多种先天免疫传感器的细胞中复制，并且可能与其他病原体同时复制。然而，共存的先天免疫刺激如何影响 HIV-1 传感的结果仍然知之甚少。在这里，我们证明第二个信号通路的激活能够使环 GMP-AMP 合酶 (cGAS) 依赖性 I 型干扰素 (IFN-I) 对 HIV-1 感染做出反应。我们使用 RNA 测序来确定 HIV-1 单独在 THP-1 细胞中很少或没有诱导 IFN-I 反应的迹象。相反，当补充次优水平的细菌脂多糖（LPS）时，HIV-1感染会引发IFN-I水平升高和干扰素刺激基因的显着上调。 HIV-1感染时LPS介导的IFN-I产生增强（在原代巨噬细胞中观察到）通过阻断逆转录和超稳定衣壳而消失，这表明病毒DNA是一种重要的免疫刺激分子。 LPS 还可以协同增强环 GMP-AMP (cGAMP)（cGAS 的第二信使）产生 IFN-I。这些观察结果表明，DNA 传感器 cGAS 与 LPS 受体 Toll 样受体 4 (TLR4) 协同作用，负责对 HIV-1 的 I 型 IFN 反应。少量的 TLR2 激动剂也可与 HIV-1 协同诱导 I 型干扰素的产生。这些结果表明，微妙的免疫调节活性如何使 HIV-1 能够通过 cGAS 和 TLR 传感途径之间的正向串扰引发 IFN-I 反应。
HIV-1 replicates in cells that express a wide array of innate immune sensors and may do so simultaneously with other pathogens. How a coexisting innate immune stimulus influences the outcome of HIV-1 sensing, however, remains poorly understood. Here, we demonstrate that the activation of a second signaling pathway enables a cyclic GMP-AMP synthase (cGAS)-dependent type I interferon (IFN-I) response to HIV-1 infection. We used RNA sequencing to determine that HIV-1 alone induced few or no signs of an IFN-I response in THP-1 cells. In contrast, when supplemented with suboptimal levels of bacterial lipopolysaccharide (LPS), HIV-1 infection triggered the production of elevated levels of IFN-I and significant upregulation of interferon-stimulated genes. LPS-mediated enhancement of IFN-I production upon HIV-1 infection, which was observed in primary macrophages, was lost by blocking reverse transcription and with a hyperstable capsid, pointing to viral DNA being an essential immunostimulatory molecule. LPS also synergistically enhanced IFN-I production by cyclic GMP-AMP (cGAMP), a second messenger of cGAS. These observations suggest that the DNA sensor cGAS is responsible for a type I IFN response to HIV-1 in concert with LPS receptor Toll-like receptor 4 (TLR4). Small amounts of a TLR2 agonist also cooperate with HIV-1 to induce type I IFN production. These results demonstrate how subtle immunomodulatory activity renders HIV-1 capable of eliciting an IFN-I response through positive cross talk between cGAS and TLR sensing pathways.