Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation.
Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation.
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早期急性HIV感染期间艺术的起源可保留粘膜TH17功能并逆转与HIV相关的免疫激活。
DOI：
10.1371/journal.ppat.1004543
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发表时间：
2014-12
期刊：
影响因子：
6.7
通讯作者：
RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups
中科院分区：
文献类型：
--
作者：
Schuetz A;Deleage C;Sereti I;Rerknimitr R;Phanuphak N;Phuang-Ngern Y;Estes JD;Sandler NG;Sukhumvittaya S;Marovich M;Jongrakthaitae S;Akapirat S;Fletscher JL;Kroon E;Dewar R;Trichavaroj R;Chomchey N;Douek DC;O Connell RJ;Ngauy V;Robb ML;Phanuphak P;Michael NL;Excler JL;Kim JH;de Souza MS;Ananworanich J;RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups
粘液Th 17细胞在维持肠道上皮完整性方面发挥重要作用，从而防止微生物移位。慢性HIV感染的特征是粘膜Th 17细胞耗竭、微生物易位和随后的免疫激活，尽管抗逆转录病毒治疗（ART）与死亡率增加相关，但这些细胞仍然升高。然而，HIV感染后Th 17耗竭何时发生尚不清楚。我们分析了42例急性HIV感染（AHI）受试者（Fiebig（F）I-V期）的粘膜Th 17细胞，感染的中位持续时间为16天，早期开始ART的短期影响。Th 17细胞被定义为IL-17+ CD 4 + T细胞，其功能通过IL-22、IL-2和IFNγ的共表达来评估。虽然在FI/II期间是完整的，但在FIII期间观察到粘膜Th 17细胞数量和功能的耗竭，这与局部和全身免疫活化标志物相关。在FI/II开始的ART防止了Th 17细胞数量和功能的丧失，而在FIII开始恢复了Th 17细胞数量，但没有恢复其多功能性。此外，FI/II早期开始ART完全逆转了最初观察到的粘膜和全身免疫激活。与此相反，在AHI后期治疗的患者维持升高的黏膜和全身CD 8 + T细胞激活后开始的ART。这些数据支持在急性HIV感染的早期阶段的Th 17细胞的损失，并强调在早期AHI的ART启动研究应进一步探讨，以评估黏膜Th 17功能保存的潜在机制。持续的全身免疫激活是慢性HIV感染的标志，也是疾病进展的独立预测因子。潜在的机制尚未完全理解，但认为与Th 17细胞的损失有关，导致粘膜屏障的破坏和随后的微生物易位。然而，目前尚不清楚这些事件何时发生在HIV感染中，因为迄今为止唯一可用的数据来自SIV模型。我们评估了早期急性HIV感染中Th 17耗竭、微生物易位和随后的免疫激活的动力学以及早期启动ART对这些事件的影响。我们发现，Th 17细胞数量和功能的崩溃，伴随着局部和全身免疫激活，已经发生在急性HIV感染期间。然而，早期开始ART保留了Th 17的数量和功能，并完全逆转了任何最初的HIV相关免疫激活。这些研究结果表明，HIV感染早期事件的重要性，为慢性免疫激活和急性HIV感染期间的早期和积极治疗奠定了基础。
Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, microbial translocation and subsequent immune-activation, which remain elevated despite antiretroviral therapy (ART) correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown. We analyzed mucosal Th17 cells in 42 acute HIV infection (AHI) subjects (Fiebig (F) stage I-V) with a median duration of infection of 16 days and the short-term impact of early initiation of ART. Th17 cells were defined as IL-17+ CD4+ T cells and their function was assessed by the co-expression of IL-22, IL-2 and IFNγ. While intact during FI/II, depletion of mucosal Th17 cell numbers and function was observed during FIII correlating with local and systemic markers of immune-activation. ART initiated at FI/II prevented loss of Th17 cell numbers and function, while initiation at FIII restored Th17 cell numbers but not their polyfunctionality. Furthermore, early initiation of ART in FI/II fully reversed the initially observed mucosal and systemic immune-activation. In contrast, patients treated later during AHI maintained elevated mucosal and systemic CD8+ T-cell activation post initiation of ART. These data support a loss of Th17 cells at early stages of acute HIV infection, and highlight that studies of ART initiation during early AHI should be further explored to assess the underlying mechanism of mucosal Th17 function preservation. Persistent systemic immune activation is a hallmark of chronic HIV infection and an independent predictor of disease progression. The underlying mechanism is not yet completely understood but thought to be associated with the loss of Th17 cells leading to the disruption of the mucosal barrier and subsequent microbial translocation. However, it remains unclear when these events take place in HIV infection, as the only data available to date are from SIV models. We evaluated the kinetics of Th17 depletion, microbial translocation and subsequent immune activation in early acute HIV infection and the effect of early initiated ART on these events. We discovered that a collapse of Th17 cell number and function, accompanied by local and systemic immune activation, occurs already during acute HIV infection. However, early initiation of ART preserved Th17 number and function and fully reversed any initial HIV-related immune activation. These findings argue for the importance of early events during HIV infection setting the stage for chronic immune activation and for early and aggressive treatment during acute HIV infection.
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影响因子：
5.4
作者：
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DOI：
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