Immune profile and mitochondrial alterations driven by age and HIV infection: Associations with T-cell senescence in people with HIV receiving suppressive antiretroviral therapy

Junyan Jin; Xin Zhang; Qianqian Xu; Wei Xia; Hongxia Yan; Hao Wu; Christiane Moog; Tong Zhang; Bin Su

doi:10.1016/j.virs.2026.05.001

June 2026

. doi: 10.1016/j.virs.2026.05.001

Citation: Junyan Jin, Xin Zhang, Qianqian Xu, Wei Xia, Hongxia Yan, Hao Wu, Christiane Moog, Tong Zhang, Bin Su. Immune profile and mitochondrial alterations driven by age and HIV infection: Associations with T-cell senescence in people with HIV receiving suppressive antiretroviral therapy .VIROLOGICA SINICA, 2026, 41(3) : 561-573. http://dx.doi.org/10.1016/j.virs.2026.05.001

年龄和HIV感染驱动的免疫特征及线粒体改变：与接受抑制性抗反转录病毒治疗的HIV感染者T细胞衰老的关联

晋俊艳a ^a,b ,
张欣 ^a,b ,
徐芊芊 ^a,b ,
夏炜 ^a,b ,
闫红霞a ^a,b ,
吴昊 ^a,b ,
Moog Christiane ^b,c ,
张彤 ^a,b,, ,
粟斌 ^a,b,d,e,,

a. 艾滋病研究北京市重点实验室, 感染性疾病临床与研究中心, 首都医科大学附属北京佑安医院, 北京 100069, 中国;
b. 中法艾滋病研究联合实验室, 首都医科大学附属北京佑安医院, 北京 100069, 中国;
c. 法国国家健康与医学研究院 (INSERM) UMR_S 1109, 斯特拉斯堡精准医学跨学科主题研究所 (ITI) Transplantex NG, 医学院, OMICARE 大学医院联合会, 斯特拉斯堡转化医学联合会 (FMTS), 斯特拉斯堡大学, 斯特拉斯堡 67000, 法国;
d. 中心实验室, 首都医科大学附属北京佑安医院, 北京 100069, 中国;
e. 科技成果转化中心, 首都医科大学附属北京佑安医院, 北京 100069, 中国

通讯作者： 张彤, zt_doc@ccmu.edu.cn; 粟斌, binsu@ccmu.edu.cn
收稿日期： 2026-01-11
录用日期： 2026-05-09

摘要

抗逆转录病毒治疗（ART）显著延长了HIV感染者（PWH）的预期寿命，使得人群老龄化与免疫衰老成为突出的临床重点问题。T细胞衰老与线粒体功能障碍相关，并介导衰老相关的免疫重塑，但HIV感染与衰老如何共同塑造CD4⁺和CD8⁺ T细胞免疫特征及线粒体重塑，目前尚不明确。本横断面研究纳入61例接受抑制性ART≥12个月的HIV感染者，以及61例年龄、性别相匹配的HIV阴性男男性行为者，并按年龄分为青年组（≤35岁）与老年组（≥50岁）。采用多参数流式细胞术分析CD4⁺和CD8⁺ T细胞的分化、干性、激活/耗竭、代谢表型，以及线粒体质量与膜电位。研究结果显示，衰老与HIV感染共同参与了T细胞重塑，表现为终末分化表型扩增，而具有干性、稳态及共刺激分子的CD4⁺和CD8⁺ T细胞亚群减少；其标志为CD57、CX3CR1表达上调，CD45RA⁺CD31⁺、FOXO1及CD28表达下调。值得注意的是，青年HIV感染者呈现类似衰老的CD4⁺ T细胞表型，其CD57、CX3CR1和TIGIT表达水平高于同年龄段HIV阴性者。与之相对，与HIV感染相关的CD8⁺ T细胞紊乱（KLRG1、NKG2C、CD95）在老年HIV感染者中更为显著。HIV感染者的总CD4⁺、CD8⁺ T细胞及类衰老T细胞均出现线粒体质量与膜电位升高，在老年感染者的CD8⁺ T细胞中尤为明显。另外，在感染者CD4⁺ T细胞中，KLRG1、CX3CR1表达与年龄呈正相关，与CD4⁺ T细胞计数及CD4/CD8比值呈负相关；而CD8⁺ T细胞中FOXO1表达与年龄、终末分化标志物及ART治疗时长呈负相关。总体而言，年龄是T细胞免疫衰老的主要驱动因素，而HIV感染可调控并加剧上述改变。线粒体应激、FOXO1下调与免疫网络重塑共同支持HIV相关免疫衰老的多因素模型，这可能与感染者免疫重建异质性相关。此研究为延缓HIV感染者免疫衰老提供了潜在干预靶点。
- HIV感染
- , 衰老
- , 免疫衰老
- , T细胞
- , 线粒体功能障碍

Immune profile and mitochondrial alterations driven by age and HIV infection: Associations with T-cell senescence in people with HIV receiving suppressive antiretroviral therapy

Junyan Jin ^a,b ,
Xin Zhang ^a,b ,
Qianqian Xu ^a,b ,
Wei Xia ^a,b ,
Hongxia Yan ^a,b ,
Hao Wu ^a,b ,
Christiane Moog ^b,c ,
Tong Zhang ^a,b,, ,
Bin Su ^a,b,d,e,,

a. Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China;
b. Sino-French Joint Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China;
c. Laboratoire d'ImmunoRhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1109, Institut Thématique Interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, 67000, France;
d. Central Laboratory, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China;
e. The Scientific and Technological Achievement Transformation Center, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China

Corresponding author: Tong Zhang, zt_doc@ccmu.edu.cn Bin Su, binsu@ccmu.edu.cn
Received Date: 11 January 2026
Accepted Date: 09 May 2026

Abstract

Antiretroviral therapy (ART) has significantly extended the life expectancy of people with HIV (PWH), rendering population ageing and immunosenescence prominent clinical priorities. T-cell senescence is linked to mitochondrial dysfunction and drives age-related immune remodelling, yet how HIV infection and ageing jointly shape CD4⁺ and CD8⁺ T-cell immunophenotypes and mitochondrial remodelling remains unclear. This cross-sectional study included 61 PWH on suppressive ART for ≥ 12 months and 61 age- and sex-matched HIV-negative men who have sex with men, stratified into younger (≤ 35 years) and older (≥ 50 years) groups. Multiparameter flow cytometry was used to profile CD4⁺ and CD8⁺ T-cell differentiation, stemness, activation/exhaustion, and metabolic phenotypes, together with mitochondrial mass and membrane potential. We found that ageing and HIV infection were associated with T-cell remodelling, characterized by expanded late-differentiated phenotypes and reduced stem-like, homeostatic and costimulatory CD4⁺ and CD8⁺ T-cell subsets, as indicated by upregulated CD57 and CX3CR1 and downregulated CD45RA⁺CD31⁺, FOXO1, and CD28. Notably, younger PWH had an ageing-like CD4⁺ T-cell profile, with higher CD57, CX3CR1 and TIGIT expression than younger HIV-negative individuals. In contrast, HIV-related CD8⁺ T-cell perturbations (KLRG1, CXCR3, NKG2C and CD95) were more pronounced in older PWH. PWH exhibited increased mitochondrial mass and membrane potential in both total and senescent-like CD4⁺ and CD8⁺ T cells, particularly in CD8⁺ T cells from older PWH. In CD4⁺ T cells, KLRG1 and CX3CR1 expression correlated positively with age, and inversely with CD4⁺ T-cell counts and CD4/CD8 ratio. By contrast, FOXO1 expression in CD8⁺ T cells was inversely associated with age, late-differentiation markers, and ART duration in PWH. Overall, age is a major driver of T-cell immunosenescence, and HIV infection modulates and exacerbates these alterations. Mitochondrial stress, FOXO1 downregulation and immune network remodelling support a multifaceted model of HIV-associated immune ageing that may contribute to heterogeneous immune reconstitution in PWH, highlighting potential targets to mitigate immune ageing.
- HIV infection
- , Ageing
- , Immunosenescence
- , T cells
- , Mitochondrial dysfunction

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