Cellular and Viral Determinants of Innate HIV Recognition in Macrophages

巨噬细胞先天性 HIV 识别的细胞和病毒决定因素

• 批准号: 318287247
• 负责人: Professor Dr. Veit Hornung
• 金额: --
• 依托单位: Genzentrum - Laboratorium für molekulare Biologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/318287247?language=en
• 关键词: Cellular; Viral; Determinants; Innate; HIV

Besides CD4 T-cells, macrophages constitute the major target cells for HIV infection. Macrophages comprise a critical in vivo-reservoir and play an important role in shaping the immune response. Little is known about their innate sensing mechanisms to detect HIV and the downstream consequences. During the first funding period within SPP1923 we demonstrate that (a) lentiviral Vpx proteins can overcome a SAMHD1- and dNTP-independent restriction at the level of HIV reverse transcription in resting CD4 T-cells, but not in primary macrophages, (b) trans-differentiated BLaER1 cells express myeloid surface markers, the known restriction factors SAMHD1 and Mx2, and are highly phagocytic, and (c) IFNα-induced Mx2 restricts HIV-1 infection in the trans-differentiated BLaER1 cell model as well as in primary macrophages at the level of nuclear import. (d) An educated screening for putative sensors and restriction factors of lentiviruses in the trans-differentiated BLaER1 cell model indicates a thus far unappreciated suppressive role of NLRP3 and DDX1 on HIV-1 infection in myeloid cells. Building on these findings we will during the second funding period further dissect the cellular and viral determinants, PRR sensing pathways and outcomes of innate HIV recognition and restriction in human macrophages and related myeloid models. To this end, the following specific aims will be pursued: (i) Gain insight into the regulation of the Mx2-imposed restriction to HIV-1 infection, (ii) study the impact and mode of action of NLRP3 and DDX1 on infection and sensing of HIV pre-integration, (iii) define the HIV PAMPs involved in pre- and post-integration sensing, and (iv) identify the putative post-integration sensor for HIV in myeloid cells. Collectively, these studies will contribute to our understanding of the mechanisms and functional consequences of HIV recognition by the innate immune system in macrophages.

除了CD 4 T细胞外，巨噬细胞也是艾滋病毒感染的主要靶细胞。巨噬细胞是重要的体内储库，在形成免疫应答中起重要作用。关于它们检测HIV的先天传感机制及其下游后果知之甚少。在SPP 1923的第一个资助期内，我们证明了（a）慢病毒Vpx蛋白可以在静息CD 4 T细胞中克服HIV逆转录水平上的SAMHD 1和dNTP非依赖性限制，但在原代巨噬细胞中不能，（B）转分化的BLaER 1细胞表达髓样表面标志物，已知的限制因子SAMHD 1和Mx 2，并且是高度吞噬的，和（c）IFNα诱导的Mx2在转分化的BLaER 1细胞模型中以及在原代巨噬细胞中在核输入水平上限制HIV-1感染。(d)在转分化的BLaER 1细胞模型中对慢病毒的推定传感器和限制因子的有根据的筛选表明，NLRP 3和DDX 1对骨髓细胞中的HIV-1感染具有迄今为止未被认识到的抑制作用。在这些发现的基础上，我们将在第二个资助期内进一步剖析细胞和病毒决定因素，PRR传感途径以及人类巨噬细胞和相关骨髓模型中先天HIV识别和限制的结果。为此，将努力实现以下具体目标：（i）深入了解Mx 2对HIV-1感染施加的限制的调节，（ii）研究NLRP 3和DDX 1对HIV整合前感染和感测的影响和作用模式，（iii）定义参与整合前和整合后感测的HIV PAMP，和（iv）鉴定骨髓细胞中HIV的推定整合后感受器。总的来说，这些研究将有助于我们理解巨噬细胞中先天免疫系统识别HIV的机制和功能后果。