The expression of CD39 on NK cells relates to poor HIV-1 suppression in treatment-naïve HIV-1-infected individuals: Association with elevated IL-10 secretion and TIGIT co-expression

Xin Zhang; Qianqian Xu; Junyan Jin; Hongxia Yan; Xiaofan Lu; Zhen Li; Zhiying Liu; Rui Wang; Lin Yuan; Zhenglai Ma; Tong Zhang; Hao Wu; Bin Su

doi:10.1016/j.virs.2026.03.006

April 2026

. doi: 10.1016/j.virs.2026.03.006

Citation: Xin Zhang, Qianqian Xu, Junyan Jin, Hongxia Yan, Xiaofan Lu, Zhen Li, Zhiying Liu, Rui Wang, Lin Yuan, Zhenglai Ma, Tong Zhang, Hao Wu, Bin Su. The expression of CD39 on NK cells relates to poor HIV-1 suppression in treatment-naïve HIV-1-infected individuals: Association with elevated IL-10 secretion and TIGIT co-expression .VIROLOGICA SINICA, 2026, 41(2) : 293-302. http://dx.doi.org/10.1016/j.virs.2026.03.006

CD39表达于NK细胞与未抗反转录病毒治疗HIV-1感染者的病毒学抑制差有关：与IL-10分泌增加和TIGIT共表达相关

张欣 ^a ,
徐芊芊 ^a ,
晋俊艳 ^a ,
闫红霞 ^a ,
陆小凡 ^a ,
李珍 ^a ,
刘志英 ^a ,
王蕊 ^a ,
袁霖 ^a ,
马正来 ^a ,
张彤 ^a ,
吴昊 ^a ,
粟斌 ^a,b,c,,

1. 首都医科大学附属北京佑安医院, 感染中心, 中法艾滋病研究联合实验室, 艾滋病研究北京市重点实验室;
2. 首都医科大学附属北京佑安医院, 中心实验室;
3. 首都医科大学附属北京佑安医院, 科技成果转化中心

通讯作者： 粟斌, binsu@ccmu.edu.cn
收稿日期： 2025-08-16
录用日期： 2026-03-17

摘要

CD39通过减弱自然杀伤（NK）细胞对癌细胞的细胞毒性，在抗肿瘤中发挥抑制作用。然而，在未接受抗反转录病毒治疗的HIV-1感染者中，CD39表达对NK细胞的非细胞毒性功能影响尚不清楚。此项研究纳入34例急性HIV-1感染者（AHI，感染时长：1~3个月）、38例慢性HIV-1感染者（CHI，感染时长：9个月~3年）及24例HIV-1阴性健康对照（HC），探讨不同感染阶段NK细胞CD39表达在HIV-1病毒学抑制中的作用。研究采用流式细胞术分析NK细胞的免疫表型及功能特征，发现HIV-1感染后CD39在NK细胞表达显著上调，且在AHI和CHI感染者中，其阳性率均与HIV-1病毒载量呈正相关。与CD39^- NK细胞相比，CD39⁺ NK细胞的活化能力降低；在AHI感染者中，CD39⁺ NK细胞的活化水平与HIV-1病毒载量呈正相关，而与CD4⁺ T细胞计数呈负相关。在CHI感染者中，总NK细胞、CD39⁺ NK细胞及CD39^- NK细胞的白细胞介素-10（IL-10）产生能力均增强，且与HIV-1病毒载量呈正相关。此外，在AHI和CHI组中，NK细胞的总体IL-10分泌能力与CD39⁺ NK细胞频率呈正相关。在AHI和CHI感染者中，CD39⁺ NK细胞的TIGIT表达均低于CD39^- NK细胞，而CD39⁺TIGIT⁺ NK细胞亚群的IL-10分泌能力显著增强。CD39外核苷酸酶活性抑制剂POM-1可增强HIV-1感染者及健康对照者NK细胞分泌IL-10，但减弱HIV-1感染者NK细胞分泌干扰素-γ（IFN-γ）。相反，CD39阻断抗体A1可降低HIV-1感染者和健康对照者NK细胞分泌IFN-γ，但不影响分泌IL-10。综上所述，研究结果揭示了一种新的CD39⁺ NK 细胞相关机制，该机制参与了 HIV-1 病毒控制失效的过程；同时提示，CD39（单独或与 TIGIT 联合）有望成为恢复未治疗 HIV-1 感染者 NK 细胞抗病毒功能的潜在靶点。
- HIV-1感染
- , 自然杀伤细胞
- , CD39
- , 细胞因子-10
- , TIGIT

The expression of CD39 on NK cells relates to poor HIV-1 suppression in treatment-naïve HIV-1-infected individuals: Association with elevated IL-10 secretion and TIGIT co-expression

Xin Zhang ^a ,
Qianqian Xu ^a ,
Junyan Jin ^a ,
Hongxia Yan ^a ,
Xiaofan Lu ^a ,
Zhen Li ^a ,
Zhiying Liu ^a ,
Rui Wang ^a ,
Lin Yuan ^a ,
Zhenglai Ma ^a ,
Tong Zhang ^a ,
Hao Wu ^a ,
Bin Su ^a,b,c,,

a. Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China;
b. Central Laboratory, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China;
c. The Scientific and Technological Achievement Transformation Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China

Corresponding author: Bin Su, binsu@ccmu.edu.cn
Received Date: 16 August 2025
Accepted Date: 17 March 2026

Abstract

CD39 exerts an inhibitory effect on tumour progression by impairing the cytotoxic capacity of natural killer (NK) cells against cancer cells. However, the impact of CD39 expression on the non-cytolytic functions of NK cells in treatment-naïve human immunodeficiency virus type 1 (HIV-1)-infected individuals remains poorly understood. In this study, thirty-four individuals with acute HIV-1 infection (AHI), thirty-eight with chronic HIV-1 infection (CHI), and twenty-four HIV-1-negative healthy controls (HC) were enrolled to explore the role of CD39 expression on NK cells in HIV-1 suppression at different infection stages. Flow cytometry was employed to analyze the immune phenotype and functional characteristics of NK cells. We found that CD39 expression on NK cells was significantly upregulated following HIV-1 infection, and its positive rate was positively associated with HIV-1 viral load in both AHI and CHI individuals. Compared with CD39^- NK cells, CD39⁺ NK cells exhibited reduced activation; in AHI individuals, the activation level of CD39⁺ NK cells was positively associated with HIV-1 viral load but inversely correlated with CD4⁺ T-cell counts. In CHI individuals, the interleukin-10 (IL-10)-producing capacity of total NK cells, CD39⁺ NK cells, and CD39^- NK cells was enhanced and positively correlated with HIV-1 viral load. Additionally, across the AHI and CHI groups, the overall IL-10-secreting ability of NK cells was positively correlated with the frequency of CD39⁺ NK cells. In both AHI and CHI individuals, CD39⁺ NK cells showed lower T-cell immunoglobulin and ITIM domain (TIGIT) expression than CD39^- NK cells, while the CD39⁺TIGIT⁺ NK cell subset displayed significantly stronger IL-10-secreting capacity. POM-1, an inhibitor of CD39 ectonucleotidase activity, could enhance IL-10 secretion by NK cells in both HIV-1-infected individuals and the majority of healthy controls, but attenuate interferon-γ (IFN-γ) secretion by NK cells in HIV-1-infected individuals. In contrast, the CD39-blocking antibody A1 reduced IFN-γ secretion without affecting IL-10 secretion by NK cells in both HIV-1-infected individuals and healthy controls. Our findings reveal a novel CD39⁺ NK cell-associated mechanism that contributes to ineffective HIV-1 control, and suggest that CD39, alone or combined with TIGIT, may serve as a promising target to restore antiviral NK cell function in treatment-naïve individuals living with HIV-1.
- HIV-1 infection
- , Natural killer cells (NK cells)
- , CD39
- , IL-10
- , T-cell immunoreceptor with Ig and ITIM domain (TIGIT)

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Electronic Supplementary Material

10.1016j.virs.2026.03.006-ESM.doc