Hofmann Henning, Vanwalscappel Bénédicte, Bloch Nicolin, Landau Nathaniel R
Department of Microbiology, NYU School of Medicine, New York, NY, USA.
Department of HIV and Other Retroviruses, Robert Koch Institute, Berlin, Germany.
Retrovirology. 2016 Dec 1;13(1):83. doi: 10.1186/s12977-016-0316-3.
Monocytes, the primary myeloid cell-type in peripheral blood, are resistant to HIV-1 infection as a result of the lentiviral restriction factor SAMHD1. Toll-like receptors recognize microbial pathogen components, inducing the expression of antiviral host proteins and proinflammatory cytokines. TLR agonists that mimic microbial ligands have been found to have activity against HIV-1 in macrophages. The induction of restriction factors in monocytes by TLR agonist activation has not been well studied. To analyze restriction factor induction by TLR activation in monocytes, we used the imidazoquinoline TLR7/8 agonist R848 and infected with HIV-1 reporter virus that contained packaged viral accessory protein Vpx, which allows the virus to escape SAMHD1-mediated restriction. RESULTS: R848 prevented the replication of Vpx-containing HIV-1 and HIV-2 in peripheral blood mononuclear cells and monocytes. The block was post-entry but prior to reverse transcription of the viral genomic RNA. The restriction was associated with destabilization of the genomic RNA molecules of the in-coming virus particle. R848 treatment of activated T cells did not protect them from infection but treated monocytes produced high levels of proinflammatory cytokines, including type-I IFN that protected bystander activated T cells from infection.
The activation of TLR7/8 induces two independent restrictions to HIV-1 replication in monocytes: a cell-intrinsic block that acts post-entry to prevent reverse transcription; and a cell-extrinsic block, in which monocytes produce high levels of proinflammatory cytokines (primarily type-I IFN) that protects bystander monocytes and T lymphocytes. The cell-intrinsic block may result from the induction of a novel restriction factor, which can be termed Lv5 and acts by destabilizing the in-coming viral genomic RNA, either by the induction of a host ribonuclease or by disrupting the viral capsid. TLR agonists are being developed for therapeutic use to diminish the size of the latent provirus reservoir in HIV-1 infected individuals. Such drugs may both induce latent provirus expression and restrict virus replication during treatment.
单核细胞是外周血中主要的髓样细胞类型，由于慢病毒限制因子SAMHD1的存在，其对HIV-1感染具有抗性。Toll样受体可识别微生物病原体成分，诱导抗病毒宿主蛋白和促炎细胞因子的表达。已发现模拟微生物配体的TLR激动剂在巨噬细胞中具有抗HIV-1活性。TLR激动剂激活单核细胞中限制因子的诱导作用尚未得到充分研究。为了分析TLR激活在单核细胞中对限制因子的诱导作用，我们使用咪唑喹啉TLR7/8激动剂R848，并感染含有包装病毒辅助蛋白Vpx的HIV-1报告病毒，Vpx可使病毒逃避SAMHD1介导的限制。
R848可阻止含Vpx的HIV-1和HIV-2在外周血单核细胞和单核细胞中的复制。该阻断作用发生在病毒进入后但在病毒基因组RNA逆转录之前。这种限制与进入的病毒颗粒的基因组RNA分子的不稳定有关。R848处理活化的T细胞并不能保护它们免受感染，但处理过的单核细胞会产生高水平的促炎细胞因子，包括I型干扰素，可保护旁观者活化的T细胞免受感染。
TLR7/8的激活在单核细胞中诱导了对HIV-1复制的两种独立限制：一种细胞内源性阻断，作用于病毒进入后以阻止逆转录；另一种细胞外源性阻断，其中单核细胞产生高水平的促炎细胞因子（主要是I型干扰素），可保护旁观者单核细胞和T淋巴细胞。细胞内源性阻断可能是由一种新的限制因子的诱导引起的，该因子可称为Lv5，其作用方式是通过诱导宿主核糖核酸酶或破坏病毒衣壳来使进入的病毒基因组RNA不稳定。正在开发TLR激动剂用于治疗，以减少HIV-1感染个体中潜伏前病毒库的大小。此类药物可能在治疗期间既诱导潜伏前病毒的表达又限制病毒复制。
