Sensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages
Sensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages
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DOI：
10.1128/jvi.00147-17
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发表时间：
2017-08-01
影响因子：
5.4
通讯作者：
Benaroch, Philippe
中科院分区：
文献类型：
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作者：
Decalf, Jeremie;Desdouits, Marion;Benaroch, Philippe
巨噬细胞沿着CD 4（+）T淋巴细胞，是HIV-1复制的主要细胞来源和潜在的病毒储存库。在巨噬细胞中进入和逆转录后，HIV-1衣壳对病毒cDNA的掩蔽限制了其胞质检测，使其能够有效复制。然而，进入的HIV-1颗粒是否在逆转录之前被巨噬细胞感知仍然不清楚。在这里，我们表明，HIV-1触发了广泛的表达干扰素（IFN）刺激基因（ISG）在单核细胞衍生的巨噬细胞感染后几个小时内。这种反应不需要病毒逆转录或颗粒内HIV-1 RNA的存在，但病毒融合是必不可少的。这种反应是由携带不同包膜蛋白的病毒引起的，因此携带不同的受体以进行病毒进入。响应病毒进入的ISG表达需要TBK 1活性和I型IFN信号传导。值得注意的是，ISG反应是短暂的，但会影响随后的病毒传播。总之，我们的研究结果揭示了早期步骤的HIV-1的感应巨噬细胞在进入的水平，这赋予了早期的保护，通过I型干扰素信号，并在控制infection.IMPORTANCE HIV感染仅限于T淋巴细胞和巨噬细胞。HIV-1感染的巨噬细胞存在于感染患者的许多组织中，即使在抗逆转录病毒治疗下，也被认为是病毒储存库。HIV-1是如何被检测到的，以及在检测时会引起什么样的反应，在很大程度上仍然是难以捉摸的。响应HIV的细胞因子（如干扰素）的产生的动力学和定位对于理解感染和免疫应答是如何建立的至关重要。我们的研究提供了证据表明，巨噬细胞可以检测HIV-1，只要它进入细胞。有趣的是，这种传感不依赖于颗粒内病毒核酸的存在，但需要它们与巨噬细胞融合。这会触发低干扰素反应，激活抗病毒程序，保护细胞免受进一步的病毒攻击，从而可能限制感染的传播。
Along with CD4(+) T lymphocytes, macrophages are a major cellular source of HIV-1 replication and a potential viral reservoir. Following entry and reverse transcription in macrophages, cloaking of the viral cDNA by the HIV-1 capsid limits its cytosolic detection, enabling efficient replication. However, whether incoming HIV-1 particles are sensed by macrophages prior to reverse transcription remains unclear. Here, we show that HIV-1 triggers a broad expression of interferon (IFN)-stimulated genes (ISG) in monocyte-derived macrophages within a few hours after infection. This response does not require viral reverse transcription or the presence of HIV-1 RNA within particles, but viral fusion is essential. This response is elicited by viruses carrying different envelope proteins and thus different receptors to proceed for viral entry. Expression of ISG in response to viral entry requires TBK1 activity and type I IFNs signaling. Remarkably, the ISG response is transient but affects subsequent viral spread. Together, our results shed light on an early step of HIV-1 sensing by macrophages at the level of entry, which confers an early protection through type I IFN signaling and has potential implications in controlling the infection.IMPORTANCE HIV infection is restricted to T lymphocytes and macrophages. HIV-1-infected macrophages are found in many tissues of infected patients, even under antiretroviral therapy, and are considered a viral reservoir. How HIV-1 is detected and what type of responses are elicited upon sensing remain in great part elusive. The kinetics and localization of the production of cytokines such as interferons in response to HIV is of critical importance to understanding how the infection and the immune response are established. Our study provides evidence that macrophages can detect HIV-1 as soon as it enters the cell. Interestingly, this sensing is independent of the presence of viral nucleic acids within the particles but requires their fusion with the macrophages. This triggers a low interferon response, which activates an antiviral program protecting cells against further viral challenge and thus potentially limiting the spread of the infection.