Interferon-inducible mechanism of dendritic cell-mediated HIV-1 dissemination is dependent on Siglec-1/CD169.
Interferon-inducible mechanism of dendritic cell-mediated HIV-1 dissemination is dependent on Siglec-1/CD169.
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DOI：
10.1371/journal.ppat.1003291
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Gummuluru S
中科院分区：
文献类型：
--
作者：
Puryear WB;Akiyama H;Geer SD;Ramirez NP;Yu X;Reinhard BM;Gummuluru S
人类免疫缺陷病毒1型(HIV-1)与髓系树突状细胞(DC)的相互作用可导致病毒通过依赖于宿主细胞来源的糖鞘糖脂(GM3)的病毒粒子掺入的跨感染途径传播到CD4+T细胞。DC介导的反式感染机制是非常有效的，当这些细胞在DC表面进行探索性接触时，可以导致这些细胞感染这些细胞。虽然人们很早就意识到，具有诱导I型干扰素信号通路的配体激活的DC显著增强了DC介导的T细胞反式感染，但其发生的机制至今仍不清楚。在这里，我们证明了I型干扰素诱导的Siglec-1，CD169，是以GM3依赖的方式捕获HIV的DC受体。选择性地下调CD169的表达，中和CD169的功能，或从病毒粒子中去除GSLS，可以消除DC介导的HIV-1捕获和反式感染，而在受体幼稚细胞中外源表达CD169可以挽救GSL依赖的捕获和反式感染。HIV-1颗粒在捕获后立即与CD169共定位在DC表面，随后在非溶酶体隔间内，在启动T细胞接触时重新分布到DC-T细胞感染性突触。总之，这些发现描述了寄生宿主编码的细胞识别机制(GM3-CD169相互作用)的病原体寄生DC依赖的HIV传播的新机制。树突状细胞(DC)是HIV-1最初的细胞靶点之一，在体内决定病毒感染的过程中起着至关重要的作用。树突状细胞的前哨功能对于建立抗病毒状态是必不可少的，而HIV-1可以颠覆树突状细胞的功能来传播它。树突状细胞介导病毒传播的机制之一是通过跨感染途径，通过树突状细胞捕获HIV-1颗粒并将其保持在感染状态而不被感染，并在启动细胞接触时将这些感染颗粒传递给CD4+T细胞。在这篇报道中，我们证明了DC表面Siglec-1或CD169的表达通过结合存在于病毒粒子脂质双层中的神经节苷脂GM3来负责捕获HIV-1颗粒。CD169和GM3之间的这种相互作用靶标将病毒颗粒捕获到非降解的隔室，并导致病毒颗粒在DC中保留感染性。当T细胞开始与携带病毒的DC接触时，HIV-1颗粒被运送到DC-T突触连接，并转移到T细胞，以建立生产性感染。这些研究确定了一种新的宿主编码的受体-配体相互作用，这种相互作用推动了HIV-1的传播，并可用于开发新的抗病毒疗法。
Human immunodeficiency virus type 1 (HIV-1) interactions with myeloid dendritic cells (DCs) can result in virus dissemination to CD4+ T cells via a trans infection pathway dependent on virion incorporation of the host cell derived glycosphingolipid (GSL), GM3. The mechanism of DC-mediated trans infection is extremely efficacious and can result in infection of multiple CD4+ T cells as these cells make exploratory contacts on the DC surface. While it has long been appreciated that activation of DCs with ligands that induce type I IFN signaling pathway dramatically enhances DC-mediated T cell trans infection, the mechanism by which this occurs has remained unclear until now. Here, we demonstrate that the type I IFN-inducible Siglec-1, CD169, is the DC receptor that captures HIV in a GM3-dependent manner. Selective downregulation of CD169 expression, neutralizing CD169 function, or depletion of GSLs from virions, abrogated DC-mediated HIV-1 capture and trans infection, while exogenous expression of CD169 in receptor-naïve cells rescued GSL-dependent capture and trans infection. HIV-1 particles co-localized with CD169 on DC surface immediately following capture and subsequently within non-lysosomal compartments that redistributed to the DC – T cell infectious synapses upon initiation of T cell contact. Together, these findings describe a novel mechanism of pathogen parasitization of host encoded cellular recognition machinery (GM3 – CD169 interaction) for DC-dependent HIV dissemination. Dendritic cells (DCs) are one of the initial cellular targets of HIV-1 and can play a crucial role in determining the course of virus infection in vivo. While sentinel functions of DCs are essential for establishment of an antiviral state, HIV-1 can subvert DC function for its dissemination. One of the mechanisms by which DCs can mediate virus spread is via the trans infection pathway whereby DCs capture HIV-1 particles and retain them in an infectious state without getting infected, and pass these infectious particles to CD4+ T cells upon initiation of cellular contacts. In this report, we demonstrate that expression of Siglec-1or CD169, on DC surface is responsible for capture of HIV-1 particles by binding the ganglioside, GM3, present in the virion lipid bilayer. This interaction between CD169 and GM3 targets captured virus particles to non-degradative compartments and resulted in retention of virus particle infectivity within DCs. Upon initiation of T cell contacts with virus-laden DCs, HIV-1 particles were trafficked to the DC – T synaptic junctions and transferred to T cells for establishment of productive infection. These studies define a novel host-encoded receptor – ligand interaction that drives HIV-1 dissemination and can be used for development of novel anti-viral therapeutics.
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影响因子：
4.5
作者：
Garcia, E;Pion, M;Piguet, V
通讯作者：
Piguet, V
影响因子：
5.4
作者：
Hatch, Steven C.;Archer, Jacob;Gummuluru, Suryaram
通讯作者：
Gummuluru, Suryaram
影响因子：
5.4
作者：
Burleigh, L;Lozach, PY;Amara, A
通讯作者：
Amara, A
DOI：
10.1038/nri2587
发表时间：
2009-08
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.0511136103
发表时间：
2006-02-21
影响因子：
11.1
作者：
Brügger, B;Glass, B;Kräusslich, HG
通讯作者：
Kräusslich, HG