SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells
SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells
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DOI：
10.1128/jvi.00069-15
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发表时间：
2015-07-01
影响因子：
5.4
通讯作者：
Schwartz, Olivier
中科院分区：
文献类型：
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作者：
Ayinde, Diana;Bruel, Timothee;Schwartz, Olivier
单核细胞来源的树突状细胞（MDDC）通过主要组织相容性复合物I类（MHC-I）分子提呈内源性和外源性病毒肽来刺激CD 8（+）细胞毒性T淋巴细胞（CTL）。MDDC对HIV-1的敏感性较差，部分原因是存在SAMHD 1，SAMHD 1是一种细胞酶，可消耗细胞内脱氧核苷三磷酸（dNTP）并降解病毒RNA。Vpx是一种HIV-1中不存在的HIV-2/SIVsm蛋白，通过诱导SAMHD 1的降解来拮抗SAMHD 1。SAMHD 1对适应性细胞免疫应答的影响仍然缺乏特征。在这里，我们问SAMHD 1是否调节MHC-I限制的HIV-1抗原呈递。将未经处理的MDDC或用Vpx预处理的MDDC暴露于HIV-1，并通过监测HIV-1 Gag特异性CTL克隆的活化来检查抗原呈递。SAMHD 1耗竭强烈增强MDDC的生产性感染以及内源性HIV-1抗原呈递。延时显微镜分析表明，在SAMHD 1的情况下，CTL迅速杀死感染的MDDC。我们还报告说，各种传播/创始人（T/F）HIV-1株感染MDDC差，因此，没有刺激CTL。水泡性口炎病毒糖蛋白（VSV-G）的T/F假型缓解了病毒进入和诱导抗原呈递的封锁，只有在没有SAMHD 1。此外，通过使用另一个CTL克隆，主要是识别传入的HIV-1抗原，我们证明，SAMHD 1不影响外源性病毒抗原呈递。总之，我们的研究结果表明，SAMHD 1的抗病毒活性的影响抗原呈递DC，突出了限制因素和适应性免疫反应之间存在的联系。IMPORTANCEUpon病毒感染，DC可能会提出抗原来自传入的病毒材料在没有生产性感染的DC或新合成的病毒蛋白。在HIV的情况下，DC的生产性感染在试验后的早期步骤被阻断。这是由于SAMHD 1的存在，SAMHD 1是一种细胞酶，可消耗细胞内dNTP水平并抑制病毒逆转录。我们发现，SAMHD 1在DC中的耗竭强烈刺激来自新产生的病毒蛋白的病毒抗原的呈递，导致HIV-1特异性细胞毒性T淋巴细胞（CTL）的激活。我们进一步显示在真实的时间，增强的CTL激活导致被感染的DC的杀伤。我们的研究结果表明，SAMHD 1的抗病毒活性不仅影响HIV复制，而且影响DC的抗原呈递。他们强调了限制因素和适应性免疫反应之间存在的联系。
Monocyte-derived dendritic cells (MDDC) stimulate CD8(+) cytotoxic T lymphocytes (CTL) by presenting endogenous and exogenous viral peptides via major histocompatibility complex class I (MHC-I) molecules. MDDC are poorly susceptible to HIV-1, in part due to the presence of SAMHD1, a cellular enzyme that depletes intracellular deoxynucleoside triphosphates (dNTPs) and degrades viral RNA. Vpx, an HIV-2/SIVsm protein absent from HIV-1, antagonizes SAMHD1 by inducing its degradation. The impact of SAMHD1 on the adaptive cellular immune response remains poorly characterized. Here, we asked whether SAMHD1 modulates MHC-I-restricted HIV-1 antigen presentation. Untreated MDDC or MDDC pretreated with Vpx were exposed to HIV-1, and antigen presentation was examined by monitoring the activation of an HIV-1 Gag-specific CTL clone. SAMHD1 depletion strongly enhanced productive infection of MDDC as well as endogenous HIV-1 antigen presentation. Time-lapse microscopy analysis demonstrated that in the absence of SAMHD1, the CTL rapidly killed infected MDDC. We also report that various transmitted/founder (T/F) HIV-1 strains poorly infected MDDC and, as a consequence, did not stimulate CTL. Vesicular stomatitis virus glycoprotein (VSV-G) pseudotyping of T/F alleviated a block in viral entry and induced antigen presentation only in the absence of SAMHD1. Furthermore, by using another CTL clone that mostly recognizes incoming HIV-1 antigens, we demonstrate that SAMHD1 does not influence exogenous viral antigen presentation. Altogether, our results demonstrate that the antiviral activity of SAMHD1 impacts antigen presentation by DC, highlighting the link that exists between restriction factors and adaptive immune responses.IMPORTANCEUpon viral infection, DC may present antigens derived from incoming viral material in the absence of productive infection of DC or from newly synthesized viral proteins. In the case of HIV, productive infection of DC is blocked at an early postentry step. This is due to the presence of SAMHD1, a cellular enzyme that depletes intracellular levels of dNTPs and inhibits viral reverse transcription. We show that the depletion of SAMHD1 in DCs strongly stimulates the presentation of viral antigens derived from newly produced viral proteins, leading to the activation of HIV-1-specific cytotoxic T lymphocytes (CTL). We further show in real time that the enhanced activation of CTL leads to killing of infected DCs. Our results indicate that the antiviral activity of SAMHD1 not only impacts HIV replication but also impacts antigen presentation by DC. They highlight the link that exists between restriction factors and adaptive immune responses.