Altered Memory Circulating T Follicular Helper-B Cell Interaction in Early Acute HIV Infection.
Altered Memory Circulating T Follicular Helper-B Cell Interaction in Early Acute HIV Infection.
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DOI：
10.1371/journal.ppat.1005777
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发表时间：
2016-07
期刊：
影响因子：
6.7
通讯作者：
RV254/SEARCH010 RV304/SEARCH 013 Study Groups
中科院分区：
文献类型：
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作者：
Muir R;Metcalf T;Tardif V;Takata H;Phanuphak N;Kroon E;Colby DJ;Trichavaroj R;Valcour V;Robb ML;Michael NL;Ananworanich J;Trautmann L;Haddad EK;RV254/SEARCH010 RV304/SEARCH 013 Study Groups
采用RV254队列研究HIV感染极早期急性期（4thG期1和2）（1/2期）和晚期急性期（4thG期3）（3期）个体的T辅助- B细胞应答和早期抗逆转录病毒治疗（ART）对T和B细胞功能的影响。为了研究这一点，研究人员检测了来自该队列的循环T滤泡辅助细胞（cTfh）的功能，并对cTfh和记忆B细胞群进行了表型分析。与1/2期相比，在3期治疗的个体中观察到cTfh细胞功能受损。cTfh/B细胞共培养3期的B细胞存活率和IgG分泌量低于1/2期。这与IL-10降低、RANTES和TNF-α升高相吻合，表明炎症在改变cTfh和B细胞反应中的作用。3期血浆病毒载量升高与cTfh介导的B细胞IgG产生减少相关，表明病毒血症增加在cTfh损伤和功能失调的体液反应中起作用。在成熟的B细胞区室中，表型扰动也很明显，最明显的是与1/2期相比，3期静息记忆B细胞减少，与较高的病毒血症相一致。我们的共培养实验也表明，内在记忆B细胞缺陷可能导致反应受损，尽管水平较低。总体而言，与1/2期相比，ctfh介导的B细胞反应在3期显著改变，与炎症增加和记忆B细胞减少相一致。这些数据表明，急性HIV感染者的早期抗逆转录病毒治疗可以预防免疫失调，同时保留cTfh功能和B细胞记忆。即使在开始抗逆转录病毒治疗（ART）后，hiv特异性T细胞记忆反应也会迅速减弱，如果治疗中断，病毒反弹也无法控制。因此，通过治疗恢复或保存记忆T细胞或B细胞，以便在抗逆转录病毒治疗停止后控制病毒复制，是非常重要的。CD4+ T细胞，特别是T滤泡辅助细胞（Tfh），通过向B细胞提供帮助，在介导抗病毒免疫中发挥重要作用，这是强大而有效的抗hiv抗体反应的关键。独特的RV254队列为分析早期急性HIV期间的免疫反应提供了最佳环境，因为该研究能够招募感染时间不到2周并在招募后约1-2天开始治疗的个体。我们旨在研究记忆循环Tfh （cTfh）细胞在急性HIV感染中促进B细胞帮助的能力，并发现与早期相比，这种相互作用在晚期功能失调，伴随着促炎细胞因子水平的增加和调节细胞因子的减少。晚期急性个体高水平血浆病毒血症与低ctfh介导的B细胞抗体产生相关记忆性B细胞显著减少，但与慢性感染者相比，抗逆转录病毒疗法可以使其恢复，与健康个体相比，慢性感染者无法使该区室正常化。总体而言，我们发现cTfh- B细胞相互作用和B细胞记忆区在晚期急性感染中发生改变，主要归因于炎症的增加和反应从辅助性向促炎性的倾斜。在急性感染的早期阶段，在免疫损伤之前确定个体进行治疗，可以保持cTfh功能和抗hiv B细胞反应，从而减少停止抗逆转录病毒治疗后病毒反弹的机会。
The RV254 cohort of HIV-infected very early acute (4thG stage 1 and 2) (stage 1/2) and late acute (4thG stage 3) (stage 3) individuals was used to study T helper- B cell responses in acute HIV infection and the impact of early antiretroviral treatment (ART) on T and B cell function. To investigate this, the function of circulating T follicular helper cells (cTfh) from this cohort was examined, and cTfh and memory B cell populations were phenotyped. Impaired cTfh cell function was observed in individuals treated in stage 3 when compared to stage 1/2. The cTfh/B cell cocultures showed lower B cell survival and IgG secretion at stage 3 compared to stage 1/2. This coincided with lower IL-10 and increased RANTES and TNF-α suggesting a role for inflammation in altering cTfh and B cell responses. Elevated plasma viral load in stage 3 was found to correlate with decreased cTfh-mediated B cell IgG production indicating a role for increased viremia in cTfh impairment and dysfunctional humoral response. Phenotypic perturbations were also evident in the mature B cell compartment, most notably a decrease in resting memory B cells in stage 3 compared to stage 1/2, coinciding with higher viremia. Our coculture assay also suggested that intrinsic memory B cell defects could contribute to the impaired response despite at a lower level. Overall, cTfh-mediated B cell responses are significantly altered in stage 3 compared to stage 1/2, coinciding with increased inflammation and a reduction in memory B cells. These data suggest that early ART for acutely HIV infected individuals could prevent immune dysregulation while preserving cTfh function and B cell memory. The HIV-specific T cell memory response diminishes rapidly even after the initiation of anti-retroviral treatment (ART), and there is no control of viral rebound if treatment is interrupted. Restoration or preservation of memory T cells or B cells with treatment, to allow for control of virus replication after ART is stopped, is therefore very important. CD4+ T cells, in particular T follicular helper (Tfh) cells, have a major role in mediating antiviral immunity by providing help to B cells, which is key to a strong and efficient anti-HIV antibody response. The unique RV254 cohort provided the best setting to analyze immune responses during very early acute HIV, as the study was able to enroll individuals that were infected for less than 2 weeks and initiated treatment approximately 1–2 days after recruitment. We aimed to study the capacity of memory circulating Tfh (cTfh) cells to promote B cell help in acute HIV infection, and found the interaction to be dysfunctional in the later stage compared to the very early stages, accompanied by increased levels of proinflammatory cytokines and a reduction in regulatory cytokines. High levels of plasma viremia correlated with low cTfh-mediated B cell antibody production in later stage acute individuals; and memory B cells were significantly decreased but could be restored with ART, compared to chronically infected individuals, who could not normalize this compartment compared to healthy individuals. Overall, we show that the cTfh- B cell interaction and B cell memory compartment is altered in late stage acute infection, mainly attributed to an increase in inflammation and skewing of the response away from helper to proinflammatory. Identifying individuals for treatment in the earliest stages of acute infection, prior to immune damage, could preserve cTfh function and the anti-HIV B cell response, therefore reducing the chances of viral rebound upon the cessation of ART.