Background

HIV infection promotes the expansion of immunosuppressive regulatory T-cells (Tregs), contributing to immune dysfunction, tissue fibrosis and disease progression. Early antiretroviral treatment (ART) upon HIV infection improves CD4 count and decreases immune activation. However, Treg dynamics and their epigenetic regulation following early ART initiation remain understudied.

Methods

Treg subsets were characterized by flow cytometry in 103 individuals, including untreated HIV-infected participants in acute and chronic phases, ART-treated in early infection, elite controllers (ECs), immunological controllers (ICs), and HIV-uninfected controls. The methylation status of six regulatory regions of the foxp3 gene was assessed using MiSeq technology.

Findings

Total Treg frequency increased overtime during HIV infection, which was normalized in early ART recipients. Tregs in untreated individuals expressed higher levels of activation and immunosuppressive markers (CD39, and LAP(TGF-β1)), which remained unchanged following early ART. Expression of gut migration markers (CCR9, Integrin-β7) by Tregs was elevated during untreated HIV infection, while they declined with the duration of ART but not upon early ART initiation. Notably, gut-homing Tregs expressing LAP(TGF-β1) and CD39 remained higher despite early treatment. Additionally, the increase in LAP(TGF-β1)⁺ Tregs overtime were consistent with higher demethylation of conserved non-coding sequence (CNS)-1 in the foxp3 gene. Remarkably, LAP(TGF-β1)-expressing Tregs in ECs were significantly higher than in uninfected subjects, while the markers of Treg activation and gut migration were not different.

Interpretation

Early ART initiation was unable to control the levels of immunosuppressive Treg subsets and their gut migration potential, which could ultimately contribute to gut tissue fibrosis and HIV disease progression.

Funding

This study was funded by the Canadian Institutes of Health Research (CIHR, grant MOP 142294) and in part by the AIDS and Infectious Diseases Network of the Réseau SIDA et maladies infectieuses du Fonds de recherche du Québec-Santé (FRQ-S).

中文翻译：

---

急性 HIV 感染开始抗逆转录病毒治疗后调节性 T 细胞的动力学和表观遗传特征

背景

HIV 感染会促进免疫抑制性调节性 T 细胞 (Tregs) 的扩增，从而导致免疫功能障碍、组织纤维化和疾病进展。HIV 感染后的早期抗逆转录病毒治疗 (ART) 可提高 CD4 计数并降低免疫激活。然而，早期 ART 启动后的 Treg 动力学及其表观遗传调控仍未得到充分研究。

方法

Treg 亚群通过流式细胞术对 103 名个体进行了表征，包括急性期和慢性期未经治疗的 HIV 感染参与者、早期感染接受 ART 治疗、精英控制者 (ECs)、免疫控制者 (ICs) 和未感染 HIV 的控制者。使用 MiSeq 技术评估了foxp3基因的六个调节区域的甲基化状态。

发现

在 HIV 感染期间，总 Treg 频率增加，这在早期 ART 接受者中正常化。未经治疗的个体中的 Tregs 表达更高水平的激活和免疫抑制标志物（CD39 和 LAP（TGF-β1）），在早期 ART 后保持不变。在未经治疗的 HIV 感染期间，Tregs 的肠道迁移标志物（CCR9、整合素-β7）的表达升高，而它们随着 ART 的持续时间而下降，但在早期 ART 开始时没有。值得注意的是，尽管早期治疗，表达 LAP（TGF-β1）和 CD39 的肠道归巢 Tregs 仍然较高。此外，LAP（TGF-β1）^{+ Tregs 超时的增加与}foxp3中保守非编码序列（CNS）-1 的更高去甲基化一致基因。值得注意的是，内皮细胞中表达 LAP（TGF-β1）的 Tregs 显着高于未感染受试者，而 Treg 激活和肠道迁移的标志物没有差异。

解释

早期 ART 开始无法控制免疫抑制性 Treg 亚群的水平及其肠道迁移潜力，这最终可能导致肠道组织纤维化和 HIV 疾病进展。

资金

这项研究由加拿大卫生研究院 (CIHR, 拨款 MOP 142294) 和部分由Réseau SIDA et maladies infectieuses du Fonds de recherche du Québec-Santé (FRQ-S) 的艾滋病和传染病网络资助。