The Th17/Treg ratio, IL-1RA and sCD14 levels in primary HIV infection predict the T-cell activation set point in the absence of systemic microbial translocation.
The Th17/Treg ratio, IL-1RA and sCD14 levels in primary HIV infection predict the T-cell activation set point in the absence of systemic microbial translocation.
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DOI：
10.1371/journal.ppat.1003453
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Weiss L
中科院分区：
文献类型：
--
作者：
Chevalier MF;Petitjean G;Dunyach-Rémy C;Didier C;Girard PM;Manea ME;Campa P;Meyer L;Rouzioux C;Lavigne JP;Barré-Sinoussi F;Scott-Algara D;Weiss L
肠道屏障受损和随后的微生物易位（MT）可能参与慢性免疫激活，这在HIV发病机制中起着核心作用。Th 17细胞对预防MT至关重要。该研究的目的是在原发性HIV感染（PHI）患者中研究Th 17/Treg比率，单核细胞活化和MT之间的早期关系及其对T细胞活化设定点的影响，该设定点已知可预测疾病进展。27例早期PHI患者被纳入前瞻性纵向研究，并随访6个月。在基线时，Th 17/Treg比率与表达CD 38/HLA-DR或Ki-67的活化的CD 8 T细胞的比例强烈负相关。此外，Th 17/Treg比值与病毒载量和血浆sCD 14和IL-1 RA水平呈负相关，这两种标志单核细胞活化。在未经治疗的患者中，基线时的Th 17/Treg比值与第6个月时的CD 8 T细胞活化呈负相关，定义了T细胞活化设定点（% HLA-DR+ CD 38+和%Ki-67+）。可溶性CD 14和IL-1 RA血浆水平也预测T细胞活化设定点。粘膜损伤的标志物I-FABP水平在基线时与健康对照组相似，但在第6个月时升高。在PHI期间，抗内毒素核心抗体（EndoCAb）未降低，也未检测到肽聚糖。此外，仅在基线时27例患者中的2例和M6时的另外1例患者中检测到低水平的16 S rDNA。总之，数据支持的假设，T细胞和单核细胞活化的PHI主要不是由系统MT，而是由病毒复制。此外，由早期sCD 14和IL-1 RA水平定义的“先天免疫设定点”可能是疾病进展的有力早期替代标志物，应考虑用于临床实践。广泛免疫激活在HIV疾病的发病机制中是关键的。肠粘膜屏障的损伤允许微生物植物群从肠向循环移位。易位的微生物产物与艾滋病毒复制一起促进慢性免疫激活。Th 17细胞参与上皮屏障的完整性，Th 17和调节性T细胞（T细胞）之间平衡的丧失与疾病进展有关。感染后发生的早期事件对随后的疾病进展至关重要。因此，高免疫活化设定点（在急性感染结束时建立的T细胞活化水平）是预后不良的标志。微生物易位是否有助于免疫激活设定点仍然是一个悬而未决的问题。在我们对急性感染患者的纵向前瞻性研究中，我们研究了Th 17/Treg平衡，单核细胞活化和微生物易位之间的早期关系及其对T细胞活化设定点的影响。我们证明了在急性感染时不会发生系统性微生物易位。此外，我们将IL-1 RA确定为预测免疫激活设定点的新型血浆生物标志物。该生物标志物可考虑在临床实践中用作疾病进展的替代标志物。
Impairment of the intestinal barrier and subsequent microbial translocation (MT) may be involved in chronic immune activation, which plays a central role in HIV pathogenesis. Th17 cells are critical to prevent MT. The aim of the study was to investigate, in patients with primary HIV infection (PHI), the early relationship between the Th17/Treg ratio, monocyte activation and MT and their impact on the T-cell activation set point, which is known to predict disease progression. 27 patients with early PHI were included in a prospective longitudinal study and followed-up for 6 months. At baseline, the Th17/Treg ratio strongly negatively correlated with the proportion of activated CD8 T cells expressing CD38/HLA-DR or Ki-67. Also, the Th17/Treg ratio was negatively related to viral load and plasma levels of sCD14 and IL-1RA, two markers of monocyte activation. In untreated patients, the Th17/Treg ratio at baseline negatively correlated with CD8 T-cell activation at month 6 defining the T-cell activation set point (% HLA-DR+CD38+ and %Ki-67+). Soluble CD14 and IL-1RA plasma levels also predicted the T-cell activation set point. Levels of I-FABP, a marker of mucosal damages, were similar to healthy controls at baseline but increased at month 6. No decrease in anti-endotoxin core antibody (EndoCAb) and no peptidoglycan were detected during PHI. In addition, 16S rDNA was only detected at low levels in 2 out 27 patients at baseline and in one additional patient at M6. Altogether, data support the hypothesis that T-cell and monocyte activation in PHI are not primarily driven by systemic MT but rather by viral replication. Moreover, the “innate immune set point” defined by the early levels of sCD14 and IL-1RA might be powerful early surrogate markers for disease progression and should be considered for use in clinical practice. Generalized immune activation is pivotal in the pathogenesis of HIV disease. Impairment in the gut mucosal barrier allows the translocation of microbial flora from the gut towards the circulation. Translocated microbial products, together with HIV replication, contribute to chronic immune activation. Th17 cells are involved in epithelial barrier integrity and a loss of the balance between Th17 and regulatory T cells (Tregs) has been associated with disease progression. Early events occurring following infection are crucial for the subsequent disease progression. Thus, a high immune activation set point (level of T-cell activation established at the end of acute infection) is a marker of poor prognosis. Whether microbial translocation contributes to the immune activation set point remains an outstanding question. In our longitudinal prospective study of patients with acute infection, we investigated the early relationships between the Th17/Treg balance, monocyte activation and microbial translocation and their impact on the T-cell activation set point. We demonstrated that systemic microbial translocation does not occur at the time of acute infection. Moreover, we identified IL-1RA as a novel plasma biomarker predictive of the immune activation set point. This biomarker could be considered for use in clinical practice as a surrogate marker for disease progression.
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影响因子：
3.7
作者：
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