The Effect of Latency Reversal Agents on Primary CD8+ T Cells: Implications for Shock and Kill Strategies for Human Immunodeficiency Virus Eradication.
The Effect of Latency Reversal Agents on Primary CD8+ T Cells: Implications for Shock and Kill Strategies for Human Immunodeficiency Virus Eradication.
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DOI：
10.1016/j.ebiom.2016.04.019
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发表时间：
2016-06
期刊：
影响因子：
11.1
通讯作者：
Blankson JN
中科院分区：
文献类型：
--
作者：
Walker-Sperling VE;Pohlmeyer CW;Tarwater PM;Blankson JN
休克和杀伤策略涉及使用小分子诱导静息CD 4 + T细胞中的病毒转录（休克），然后免疫介导清除再活化的细胞（杀伤），已被提议作为消除潜伏感染的CD 4 + T细胞的方法。组蛋白脱乙酰酶（HDAC）抑制剂罗米地辛和蛋白激酶C（PKC）激动剂苔藓抑素-1的组合在体外逆转潜伏期方面非常有效。然而，我们发现，原代HIV-1特异性CD 8 + T细胞不能消除用这些药物重新激活的自体静息CD 4 + T细胞。我们检验了这两种药物影响原发性CD 8 + T细胞功能的假设，发现两种药物对来自未接受抗逆转录病毒治疗而控制病毒复制的患者（精英抑制者/控制者）的HIV特异性CD 8 + T细胞的抑制能力具有抑制作用。这种抑制作用是多因素叠加的。这些抑制作用没有看到与prostratin，另一种PKC激动剂，无论是单独或与JQ 1，含溴结构域蛋白4抑制剂组合。我们的研究结果表明，由于其对原代CD 8 + T细胞的不利影响，一些LRA可能会导致免疫抑制，因此在休克和杀伤策略中应谨慎使用。潜伏逆转剂可以重新激活潜伏感染细胞中的HIV-1表达。来自HIV-1感染患者的CD 8 T细胞不能清除再活化的潜伏感染细胞。这一发现可以部分解释为我们的数据显示潜伏期逆转剂影响CD 8 + T细胞的功能。潜伏感染的CD 4 + T细胞是HIV-1感染治愈的主要障碍。消除这些细胞的一种策略涉及用小分子（潜伏期逆转剂或LRA）诱导病毒转录，这将导致免疫系统识别这些细胞。我们在这里表明，CD 8 + T细胞不能消除CD 4 + T细胞从HIV-1感染的患者与LRA刺激后。我们的数据表明，这可能部分是因为一些LRA影响CD 8 + T细胞的功能。因此，选择不引起免疫抑制的LRA将是至关重要的。
Shock and kill strategies involving the use of small molecules to induce viral transcription in resting CD4 + T cells (shock) followed by immune mediated clearance of the reactivated cells (kill), have been proposed as a method of eliminating latently infected CD4 + T cells. The combination of the histone deacetylase (HDAC) inhibitor romidepsin and protein kinase C (PKC) agonist bryostatin-1 is very effective at reversing latency in vitro. However, we found that primary HIV-1 specific CD8 + T cells were not able to eliminate autologous resting CD4 + T cells that had been reactivated with these drugs. We tested the hypothesis that the drugs affected primary CD8 + T cell function and found that both agents had inhibitory effects on the suppressive capacity of HIV-specific CD8 + T cells from patients who control viral replication without antiretroviral therapy (elite suppressors/controllers). The inhibitory effect was additive and multi-factorial in nature. These inhibitory effects were not seen with prostratin, another PKC agonist, either alone or in combination with JQ1, a bromodomain-containing protein 4 inhibitor. Our results suggest that because of their adverse effects on primary CD8 + T cells, some LRAs may cause immune-suppression and therefore should be used with caution in shock and kill strategies. Latency reversal agents can reactivate HIV-1 expression in latently infected cells. CD8 T cells from HIV-1 infected patients did not eliminate reactivated latently infected cells. This finding can partially be explained by our data showing that latency reversal agents affect the function of CD8 + T cells. Latently infected CD4 + T cells are a major barrier to the cure of HIV-1 infection. One strategy of eliminating these cells involves inducing viral transcription with small molecules (latency reversal agents or LRAs) which would result in the recognition of these cells by the immune system. We show here that CD8 + T cells were not able to eliminate CD4 + T cells from HIV-1-infected patients following stimulation with LRAs. Our data suggests that this may be partially because some LRAs affect the function of CD8 + T cells. Thus it will be critical to select LRAs that do not cause immune suppression.