HIV-1 Vpr- and Reverse Transcription-Induced Apoptosis in Resting Peripheral Blood CD4 T Cells and Protection by Common Gamma-Chain Cytokines.
HIV-1 Vpr- and Reverse Transcription-Induced Apoptosis in Resting Peripheral Blood CD4 T Cells and Protection by Common Gamma-Chain Cytokines.
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HIV-1 Vpr 和逆转录诱导静息外周血 CD4 T 细胞凋亡以及常见伽马链细胞因子的保护。
DOI：
10.1128/jvi.01770-15
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发表时间：
2016
影响因子：
5.4
通讯作者：
Levy,DavidN
中科院分区：
文献类型：
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作者：
Trinité,Benjamin;Chan,ChiN;Lee,CarolineS;Levy,DavidN
HIV-1感染通过各种已知和未知的机制导致CD 4 T细胞区室的进行性消耗。在体内，HIV-1感染活化和静息的CD 4 T细胞，但在体外，在没有任何刺激的情况下，来自外周血的静息CD 4 T细胞对感染具有抵抗力。这种抗性通常归因于不能有效支持诸如逆转录（RT）的过程的细胞内环境，从而导致感染失败。在此，我们发现HIV-1在体外感染静止的CD 4 T细胞后，会导致大量的细胞死亡，导致感染失败，而在体内，淋巴和粘膜组织中的各种微环境刺激为HIV-1的复制提供了支持。例如，常见的γ-链细胞因子（CGCC），如白细胞介素-7（IL-7），使静息的CD 4 T细胞允许HIV-1感染而不诱导T细胞活化。在这里，我们发现CGCC主要通过阻止HIV-1触发细胞凋亡来允许生产性感染，这可以通过细胞色素的早期释放和半胱天冬酶3/7的激活来证明。细胞死亡是由逆转录产物和病毒携带的Vpr蛋白触发的，CGCC阻断了这两种机制。当HIV-1 RT效率被SIVmac 239 Vpx蛋白增强时，仍然观察到细胞死亡，这表明逆转录的速度和其完成的效率对该系统中HIV-1诱导的细胞死亡贡献很小。这些结果表明，HIV-1感染在静息CD 4 T细胞中的主要限制在于这些细胞在HIV-1感染的早期阶段存活的能力。重要的是，HIV-1感染的主要后果是CD 4 T细胞的破坏。在这里，我们表明，病毒体相关的Vpr蛋白和逆转录过程的交付是每个足以触发从外周血中分离的静息CD 4 T细胞的凋亡。虽然这两种机制以前已经在各种细胞类型中描述过，但我们首次显示了它们在诱导静息CD 4 T细胞耗竭中的协同作用。重要的是，我们发现，细胞因子如IL-7和IL-4，在HIV-1复制位点特别活跃，保护静息CD 4 T细胞免受这些细胞病变效应的影响，主要是通过这种保护，而不是通过增强特定的复制步骤，它们促进了生产性感染。这项研究为理解HIV-1感染和T细胞耗竭的早期步骤提供了重要的新见解。
HIV-1 infection leads to the progressive depletion of the CD4 T cell compartment by various known and unknown mechanisms.In vivo, HIV-1 infects both activated and resting CD4 T cells, butin vitro, in the absence of any stimuli, resting CD4 T cells from peripheral blood are resistant to infection. This resistance is generally attributed to an intracellular environment that does not efficiently support processes such as reverse transcription (RT), resulting in abortive infection. Here, we show thatin vitroHIV-1 infection of resting CD4 T cells induces substantial cell death, leading to abortive infection.In vivo, however, various microenvironmental stimuli in lymphoid and mucosal tissues provide support for HIV-1 replication. For example, common gamma-chain cytokines (CGCC), such as interleukin-7 (IL-7), render resting CD4 T cells permissible to HIV-1 infection without inducing T cell activation. Here, we find that CGCC primarily allow productive infection by preventing HIV-1 triggering of apoptosis, as evidenced by early release of cytochromecand caspase 3/7 activation. Cell death is triggered both by products of reverse transcription and by virion-borne Vpr protein, and CGCC block both mechanisms. When HIV-1 RT efficiency was enhanced by SIVmac239 Vpx protein, cell death was still observed, indicating that the speed of reverse transcription and the efficiency of its completion contributed little to HIV-1-induced cell death in this system. These results show that a major restriction on HIV-1 infection in resting CD4 T cells resides in the capacity of these cells to survive the early steps of HIV-1 infection.IMPORTANCEA major consequence of HIV-1 infection is the destruction of CD4 T cells. Here, we show that delivery of virion-associated Vpr protein and the process of reverse transcription are each sufficient to trigger apoptosis of resting CD4 T cells isolated from peripheral blood. While these 2 mechanisms have been previously described in various cell types, we show for the first time their concerted effect in inducing resting CD4 T cell depletion. Importantly, we found that cytokines such as IL-7 and IL-4, which are particularly active in sites of HIV-1 replication, protect resting CD4 T cells from these cytopathic effects and, primarily through this protection, rather than through enhancement of specific replicative steps, they promote productive infection. This study provides important new insights for the understanding of the early steps of HIV-1 infection and T cell depletion.