Phenotypic and epigenetic profiles of circulating NK cells in spontaneous HIV-1 controllers.

IF 10.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-09-29 DOI:10.1016/j.ebiom.2025.105948

Alisa Huber, Albert L Groenendijk, Adriana Navas, Nadira Vadaq, Suzanne D E Ruijten, Vasiliki Matzaraki, Ezio T Fok, Aysel Gurbanova, Wilhelm A J W Vos, Marc J T Blaauw, Louise E van Eekeren, Maartje C P Jacobs-Cleophas, Janneke Stalenhoef, Marvin Berrevoets, Renate van der Molen, Arnold van der Meer, Marien I de Jonge, Joost H A Martens, Casper Rokx, Annelies Verbon, Jan van Lunzen, Hans J P M Koenen, Mihai G Netea, Andre J A M van der Ven, Leo A B Joosten, Jéssica C Dos Santos

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引用次数: 0

Abstract

Background: NK cells play a key role in eliminating HIV-infected cells, but it is unclear whether there are specific NK cell receptor signatures in spontaneous HIV controllers.

Methods: We conducted a cross-sectional analysis of circulating NK cell phenotypes in people living with HIV (PLHIV), divided into spontaneous HIV controllers (HIC), normal progressors on antiretroviral therapy (non-HIC), and first-degree HIV-negative family members. Using supervised and unsupervised flow cytometry, we assessed NK cell markers and receptors. We performed an epigenetic analysis of H3K4me3 chromatin enrichment in NK cells from both HIC and non-HIC and measured IFNγ, Perforin and CD107a expression in NK cells upon stimulation with IL-2/IL-15, K562 cells, and IFNα. Additionally, we conducted a genome-wide association study (GWAS) and quantitative trait locus (QTL) mapping using data from HIC and non-HIC part of the 2000HIV study.

Findings: HIV controllers had higher levels of CD56^bright NK cells and increased expression of NKp46, NKp30, and DNAM-1. The genetic association between protective MHC class I alleles and the NK cell receptor KIR2DL2/3 supports a genetic predisposition to HIV control. Unsupervised clustering identified an HIV-induced NK cell population, separate from CMV-induced NK cells. Epigenetic analysis revealed greater H3K4me3 marks in genes involved in immune response pathways, including IFNα, IL-15, and IL-2. The memory-like NK cell subpopulation was characterised by elevated expression of NKG2C and ILT2, with reduced KIR2DL2/3 in HIC. These memory NK cells were more responsive to stimulation with IFNα, resulting in increased production of IFNγ in HIC.

Interpretation: These results suggest that spontaneous HIV control is associated with an NK cell memory phenotype, shaped by HIV infection, epigenetic modifications, and genetic factors.

Funding: The authors are part of the 2000HIV study, which is supported by ViiV Healthcare.

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自发性HIV-1控制者循环NK细胞的表型和表观遗传特征。

背景：NK细胞在消灭HIV感染细胞中发挥关键作用，但目前尚不清楚在自发HIV控制者中是否存在特异性NK细胞受体信号。方法：我们对HIV感染者（PLHIV）的循环NK细胞表型进行了横断面分析，分为自发性HIV控制者（HIC），抗逆转录病毒治疗的正常进展者（non-HIC）和一级HIV阴性家庭成员。使用监督和无监督流式细胞术，我们评估NK细胞标记物和受体。我们进行了HIC和非HIC NK细胞中H3K4me3染色质富集的表观遗传学分析，并测量了IL-2/IL-15、K562细胞和IFNα刺激下NK细胞中IFNγ、Perforin和CD107a的表达。此外，我们利用2000HIV研究的HIC和非HIC部分的数据进行了全基因组关联研究（GWAS）和数量性状位点（QTL）定位。研究发现：HIV控制者具有更高水平的CD56bright NK细胞，并增加了NKp46、NKp30和DNAM-1的表达。保护性MHC I类等位基因和NK细胞受体KIR2DL2/3之间的遗传关联支持HIV控制的遗传倾向。无监督聚类鉴定了hiv诱导的NK细胞群，与cmv诱导的NK细胞分离。表观遗传学分析显示，参与免疫反应途径的基因（包括IFNα、IL-15和IL-2）的H3K4me3标记增多。记忆样NK细胞亚群的特征是NKG2C和ILT2的表达升高，而在HIC中KIR2DL2/3的表达降低。这些记忆NK细胞对IFNα刺激更敏感，导致HIC中IFNγ的产生增加。解释：这些结果表明，自发的HIV控制与NK细胞记忆表型有关，受HIV感染、表观遗传修饰和遗传因素的影响。资助：作者是由ViiV Healthcare支持的2000HIV研究的一部分。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.