TLR7/8 agonist induces a post-entry SAMHD1-independent block to HIV-1 infection of monocytes.
TLR7/8 agonist induces a post-entry SAMHD1-independent block to HIV-1 infection of monocytes.
复制标题
DOI：
10.1186/s12977-016-0316-3
复制
发表时间：
2016-12-01
期刊：
影响因子：
3.3
通讯作者：
Landau NR
中科院分区：
文献类型：
--
作者：
Hofmann H;Vanwalscappel B;Bloch N;Landau NR
单核细胞是外周血中主要的髓系细胞类型，由于慢病毒限制因子SAMHD1的作用，它对HIV-1感染具有抵抗力。Toll样受体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。模拟微生物配体的TLR激动剂已被发现在巨噬细胞中具有抗HIV-1的活性。TLR激动剂激活对单核细胞内限制性因子的诱导作用尚未得到很好的研究。为了分析TLR激活在单核细胞中诱导的限制因子，我们使用了咪唑喹啉TLR7/8激动剂R848，并感染了HIV-1报告病毒，该病毒含有包装的病毒辅助蛋白VPX，使病毒能够逃避SAMHD1介导的限制，阻止了含有VPX的HIV-1和HIV-2在外周血单核细胞和单核细胞中的复制。阻断是在病毒基因组RNA反转录之前进入之后的。这种限制与即将到来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细胞不能保护它们免受感染，但处理过的单核细胞产生高水平的促炎细胞因子，包括保护旁观者激活的T细胞免受感染的I型干扰素。TLR7/8的激活对单核细胞中的HIV-1复制有两个独立的限制：一个是细胞内的阻断，它在进入后作用于阻止逆转录；另一个是细胞外阻断，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)，保护旁观者单核细胞和T淋巴细胞。细胞固有的阻断可能是由一种新的限制因子的诱导引起的，这种限制因子可以被称为Lv5，它通过诱导宿主核糖核酸酶或通过破坏病毒衣壳来破坏进入的病毒基因组RNA的稳定。TLR激动剂正在开发用于治疗，以减少HIV-1感染者的潜伏前病毒储存库的大小。这类药物可能会在治疗过程中诱导潜伏的前病毒表达，并限制病毒复制。本文的在线版本(doi：10.1186/s12977-0160316-3)包含补充材料，授权用户可以使用。
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. 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. The online version of this article (doi:10.1186/s12977-016-0316-3) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
5.4
作者：
Hofmann, Henning;Norton, Thomas D.;Landau, Nathaniel R.
通讯作者：
Landau, Nathaniel R.
影响因子：
5.4
作者：
Dull, T;Zufferey, R;Naldini, L
通讯作者：
Naldini, L
影响因子：
5.4
作者：
Fujita, Mikako;Otsuka, Masami;Adachi, Akio
通讯作者：
Adachi, Akio
影响因子：
3.3
作者：
Brandariz-Nuñez A;Valle-Casuso JC;White TE;Laguette N;Benkirane M;Brojatsch J;Diaz-Griffero F
通讯作者：
Diaz-Griffero F