IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication
IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication
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DOI：
10.1073/pnas.1311669110
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发表时间：
2013-11-26
影响因子：
11.1
通讯作者：
Paludan, Soren R.
中科院分区：
文献类型：
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作者：
Jakobsen, Martin R.;Bak, Rasmus O.;Paludan, Soren R.
慢病毒的复制产生不同的DNA形式，包括RNA：DNA杂交体、ssDNA和dsDNA。核酸刺激先天免疫反应，检测dsDNA的模式识别受体已经被识别出来。然而，单链DNA传感器还没有报道，RNA：DNA杂交体刺激先天免疫反应的能力也存在争议。利用来自HIV-1前病毒DNA的单链DNA，我们报告了这种DNA形式在原代人巨噬细胞中有效地诱导了IFN的表达。这种反应是由DNA结构中的干区刺激的，依赖于干扰素诱导蛋白16(IFI16)，IFI16直接与免疫刺激DNA结合，并激活干扰素基因-坦克结合蛋白1-干扰素调节因子3/7(STING-TBK1-IRF3/7)途径的刺激因子。重要的是，IFI16与巨噬细胞胞浆中的慢病毒DNA共定位并与之相关，并且IFI16在这种细胞类型中的敲除增强了慢病毒的转导和HIV-1的复制。因此，IFI16是慢病毒复制周期中产生的DNA形式的传感器，并调节巨噬细胞中的HIV-1复制。
Replication of lentiviruses generates different DNA forms, including RNA: DNA hybrids, ssDNA, and dsDNA. Nucleic acids stimulate innate immune responses, and pattern recognition receptors detecting dsDNA have been identified. However, sensors for ssDNA have not been reported, and the ability of RNA: DNA hybrids to stimulate innate immune responses is controversial. Using ssDNAs derived from HIV-1 proviral DNA, we report that this DNA form potently induces the expression of IFNs in primary human macrophages. This response was stimulated by stem regions in the DNA structure and was dependent on IFN-inducible protein 16 (IFI16), which bound immunostimulatory DNA directly and activated the stimulator of IFN genes -TANK-binding kinase 1 - IFN regulatory factors 3/7 (STING-TBK1-IRF3/7) pathway. Importantly, IFI16 colocalized and associated with lentiviral DNA in the cytoplasm in macrophages, and IFI16 knockdown in this cell type augmented lentiviral transduction and also HIV-1 replication. Thus, IFI16 is a sensor for DNA forms produced during the lentiviral replication cycle and regulates HIV-1 replication in macrophages.