Loss of memory B cells during chronic HIV infection is driven by Foxo3a-and TRAIL-mediated apoptosis
Loss of memory B cells during chronic HIV infection is driven by Foxo3a-and TRAIL-mediated apoptosis
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DOI：
10.1172/jci59211
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发表时间：
2011-10-01
影响因子：
15.9
通讯作者：
Haddad, Elias K.
中科院分区：
文献类型：
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作者：
Van Grevenynghe, Julien;Cubas, Rafael A.;Haddad, Elias K.
记忆B细胞的丧失从HIV-1感染开始并持续到感染的慢性阶段。即使在接受治疗的受试者中，这些细胞也缺乏存活能力，这可能主要是艾滋病毒感染引起的局部微环境改变的结果。在这项研究中，我们发现，与由于自然免疫而控制病毒载量的受试者(精英控制者[EC])或未感染对照(HIV-)受试者相比，成功治疗(ST)受试者的记忆B细胞存活率显着降低。在ST受试者的记忆B细胞中观察到较低的存活水平是由于IL-2信号中断导致Foxo3a转录活性增加及其促凋亡靶标TRAIL表达增加的结果。值得注意的是，在ST受试者中，外源性IL-2以Foxo3a依赖的方式加入显著提高了记忆B细胞的存活率。我们进一步表明，siRNA沉默Foxo3a导致ST受试者记忆B细胞TRAIL表达和凋亡水平下降。因此，我们的结果建立了Foxo3a/TRAIL信号在记忆B细胞持续存在中的直接作用，并提供了一种在HIV感染期间记忆B细胞存活率降低的机制。这一知识可用于开发治疗性和预防性艾滋病毒疫苗。
Loss of memory B cells occurs from the onset of HIV-1 infection and persists into the chronic stages of infection. Lack of survival of these cells, even in subjects being treated, could primarily be the consequence of an altered local microenvironment induced by HIV infection. In this study we showed that memory B cell survival was significantly decreased in aviremic successfully treated (ST) subjects compared with subjects who control viral load as a result of natural immunity (elite controller [EC]) or with uninfected control (HIV-) subjects. The lower survival levels observed in memory B cells from ST subjects were the result of disrupted IL-2 signaling that led to increased transcriptional activity of Foxo3a and increased expression of its proapoptotic target TRAIL. Notably, memory B cell survival in ST subjects was significantly enhanced by the addition of exogenous IL-2 in a Foxo3a-dependent manner. We further showed that Foxo3a silencing by siRNA resulted in decreased expression of TRAIL and apoptosis levels in memory B cells from ST subjects. Our results thus establish a direct role for Foxo3a/TRAIL signaling in the persistence of memory B cells and provide a mechanism for the reduced survival of memory B cells during HIV infection. This knowledge could be exploited for the development of therapeutic and preventative HIV vaccines.