获得性免疫缺陷综合征患者免疫重建不良研究进展

doi:10.16138/j.1673-6087.2026.01.01

摘要/Abstract

摘要：

尽管高效抗逆转录病毒治疗（highly active antiretroviral therapy, HAART）可实现长期稳定的病毒学抑制，仍有部分获得性免疫缺陷综合征患者治疗后CD4⁺T细胞计数恢复不佳，通常称为免疫无应答（immune non-response, INR）或免疫重建不良。目前，INR缺乏统一的国际定义和判定阈值，不同研究报道的发病率差异显著。INR与多种因素相关，但关键机制尚未明确，临床上亦缺乏有效的治疗方案。本文系统梳理获得性免疫缺陷综合征相关研究中INR的定义、影响因素及治疗措施，旨在为后续研究提供参考，并为开发针对INR的有效治疗策略奠定基础。

关键词: 人类免疫缺陷病毒, 获得性免疫缺陷综合征, 免疫无应答, 高效抗逆转录病毒治疗, CD4⁺T细胞, 流行病学

Abstract:

Although highly active antiretroviral therapy (HAART) can achieve long-term and stable viral suppression, some patients with acquired immunodeficiency syndrome still exhibit poor recovery of CD4⁺ T cell counts after treatment. This condition is commonly referred to as immune non-response (INR). Currently, there is no unified international definition or diagnostic threshold for INR, and the incidence rates reported in different studies vary significantly. INR is associated with multiple factors, but its key mechanisms remain unclear, and effective clinical treatment strategies are still lacking. This article systematically reviews the definitions, influencing factors, and therapeutic approaches for INR in acquired immunodeficiency syndrome-related research, aiming to provide a reference for subsequent studies and lay a foundation for the development of effective treatment strategies for INR.

Key words: human immunodeficiency virus, acquired immunodeficiency syndrome, immune non-response, highly active antiretroviral therapy, CD4⁺ T cells, epidemiology

中图分类号:

R512.91

齐青松, 田美娜, 于瑶. 获得性免疫缺陷综合征患者免疫重建不良研究进展[J]. 内科理论与实践, 2026, 21(01): 3-11.

QI Qingsong, TIAN Meina, YU Yao. Research progress on immunological non-response in acquired immunodeficiency syndrome patients[J]. Journal of Internal Medicine Concepts & Practice, 2026, 21(01): 3-11.

参考文献 65

[1]	Guedes MCS, Lopes-Araujo HF, Dos Santos KF, et al. How to properly define immunological nonresponse to antiretroviral therapy in people living with HIV? an integrative review[J]. Front Immunol, 2025, 16:1535565. doi: 10.3389/fimmu.2025.1535565
[2]	Zhang W, Ruan L. Recent advances in poor HIV immune reconstitution: what will the future look like?[J]. Front Microbiol, 2023, 14:1236460. doi: 10.3389/fmicb.2023.1236460
[3]	Yang X, Su B, Zhang X, et al. Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: challenges of immunological non-responders[J]. J Leukoc Biol, 2020, 107(4):597-612. doi: 10.1002/JLB.4MR1019-189R
[4]	Yan L, Xu K, Xiao Q, et al. Cellular and molecular insights into incomplete immune recovery in HIV/AIDS patients[J]. Front Immunol, 2023, 14:1152951. doi: 10.3389/fimmu.2023.1152951
[5]	Zhou J, Sirisanthana T, Kiertiburanakul S, et al. Trends in CD4 counts in HIV-infected patients with HIV viral load monitoring while on combination antiretroviral treatment: results from the TREAT Asia HIV Observational Database[J]. BMC Infect Dis, 2010, 10:361. doi: 10.1186/1471-2334-10-361
[6]	Mutoh Y, Nishijima T, Inaba Y, et al. Incomplete recovery of CD4 cell count, CD4 percentage, and CD4/CD8 ratio in patients with human immunodeficiency virus infection and suppressed viremia during long-term antiretroviral therapy[J]. Clin Infect Dis, 2018, 67(6):927-933. doi: 10.1093/cid/ciy176
[7]	Kelley CF, Kitchen CM, Hunt PW, et al. Incomplete peripheral CD4⁺ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment[J]. Clin Infect Dis, 2009, 48(6):787-794.
[8]	O'Connor JL, Smith CJ, Lampe FC, et al. Failure to achieve a CD4⁺ cell count response on combination antiretroviral therapy despite consistent viral load suppression[J]. AIDS, 2014, 28(6):919-924. doi: 10.1097/QAD.0000000000000165
[9]	王立洋, 唐诗, 闻颖. 艾滋期HIV患者HAART后免疫重建不良的基线相关因素分析[J]. 实用医学杂志, 2021, 37(23):3047-3051.
	Wang LY, Tang S, Wen Y. Baseline related factors of suboptimal immune responders after antiretroviral therapy in HIV patients during AIDS[J]. The Journal of Practical Medicine, 2021, 37(23):3047-3051.
[10]	Rb-Silva R, Goios A, Kelly C, et al. Definition of immunological nonresponse to antiretroviral therapy: a systematic review[J]. J Acquir Immune Defic Syndr, 2019, 82(5):452-461. doi: 10.1097/QAI.0000000000002157
[11]	中华医学会感染病学分会艾滋病学组, 中国疾病预防控制中心. 中国艾滋病诊疗指南（2024版）[J]. 中国预防医学杂志, 2024, 25(12):1469-1497.
	Acquired Immunodeficiency Syndrome Professional Group of Society of Infectious Diseases of Chinese Medical Association, Chinese Center for Disease Control and Prevention. Chinese guideline for diagnosis and treatment of human immunodeficiency virus infection/acquired immunodeficiency syndrome (2024 edition)[J]. Chin Prev Med, 2024, 25(12):1469-1497.
[12]	Byakwaga H, Murray JM, Petoumenos K, et al. Evolution of CD4⁺ T cell count in HIV-1-infected adults receiving antiretroviral therapy with sustained long-term virological suppression[J]. AIDS Res Hum Retroviruses, 2009, 25(6):756-776. doi: 10.1186/1758-2652-11-s1-p70
[13]	Young J, Psichogiou M, Meyer L, et al. CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE[J]. PLoS Med, 2012, 9(3):e1001194. doi: 10.1371/journal.pmed.1001194
[14]	Fan L, Li P, Yu A, et al. Prevalence of and prognosis for poor immunological recovery by virally suppressed and aged HIV-infected patients[J]. Front Med (Lausanne), 2023, 10:1259871. doi: 10.3389/fmed.2023.1259871
[15]	van Lelyveld SF, Gras L, Kesselring A, et al. Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort[J]. AIDS, 2012, 26(4):465-474. doi: 10.1097/QAD.0b013e32834f32f8
[16]	Aksak-Wąs BJ, Kowalska JD, Ząbek P, et al. Immune restoration affects 10-year survival in people living with HIV/AIDS[J]. HIV Med, 2023, 24(3):325-334.
[17]	Li CX, Li YY, He LP, et al. The predictive role of CD4⁺ cell count and CD4/CD8 ratio in immune reconstitution outcome among HIV/AIDS patients receiving antiretroviral therapy: an eight-year observation in China[J]. BMC Immunol, 2019, 20(1):31. doi: 10.1186/s12865-019-0311-2
[18]	向靖, 陈洋, 汪俊华, 等. 艾滋病抗病毒治疗患者免疫重建不良预测模型的构建与验证[J]. 中国艾滋病性病, 2025, 31(9):967-973. doi: 10.13419/j.cnki.aids.2025.09.08
	Xiang J, Chen Y, Wang JH, et al. Construction and validation of a predictive model for poor immune reconstitution in patients receiving HIV antiretroviral therapy[J]. Chin J AIDS STD, 2025, 31(9):967-973. doi: 10.13419/j.cnki.aids.2025.09.08
[19]	隆素素, 席娜娜, 左宗力, 等. 2005-2013年成都市艾滋病抗病毒治疗的免疫学效果及影响因素分析[J]. 中国卫生统计, 2016, 33(6):944-946..
	Long SS, Xi NN, Zuo ZL, et al. Immunological outcomes and associated factors of anti-retroviral therapy for HIV/AIDS in Chengdu from 2005 to 2013[J]. Chinese Journal of Health Statistics, 2016, 33(6):944-946..
[20]	黄跃兴, 陈冰莹, 强华. HIV/AIDS患者抗病毒治疗后免疫重建不良发生情况及影响因素研究[J]. 中国艾滋病性病, 2025, 31(10):1126-1129. doi: 10.13419/j.cnki.aids.2025.10.13
	Huang YX, Chen BY, Qiang H. Incidence and influencing factors of immunological non-responder among HIV/AIDS patients with antiretroviral therapy[J]. Chin J AIDS STD, 2025, 31(10):1126-1129. doi: 10.13419/j.cnki.aids.2025.10.13
[21]	He L, Pan X, Dou Z, et al. The factors related to CD4⁺ T-cell recovery and viral suppression in patients who have low CD4⁺ T cell counts at the initiation of HAART: a retrospective study of the national HIV treatment sub-database of Zhejiang province, China, 2014[J]. PLoS One, 2016, 11(2):e0148915. doi: 10.1371/journal.pone.0148915
[22]	宋爽, 蒋运兰, 李滔, 等. HIV/AIDS患者抗逆转录病毒治疗后免疫重建不良患病率的Meta分析[J]. 中国艾滋病性病, 2024, 30(11):1211-1218. doi: 10.13419/j.cnki.aids.2024.11.22
	Song S, Jiang YL, Li T, et al. The prevalence of immune reconstitution dysfunction following antiretroviral therapy in HIV/AIDS patients: a meta-analysis[J]. Chin J AIDS STD, 2024, 30(11):1211-1218. doi: 10.13419/j.cnki.aids.2024.11.22
[23]	Kroeze S, Ondoa P, Kityo CM, et al. Suboptimal immune recovery during antiretroviral therapy with sustained HIV suppression in sub-Saharan Africa[J]. AIDS, 2018, 32(8):1043-1051. doi: 10.1097/QAD.0000000000001801
[24]	Han WM, Ubolyam S, Apornpong T, et al. Characteristics of suboptimal immune response after initiating antiretroviral therapy among people living with HIV with a pre-treatment CD4⁺ T cell count <200 cells/mm³ in Thailand[J]. J Virus Erad, 2020, 6(3):100005. doi: 10.1016/j.jve.2020.100005
[25]	Karuppusamy KV, Demosthenes JP, Venkatesan V, et al. The CCR5 gene edited CD34⁺CD90⁺ hematopoietic stem cell population serves as an optimal graft source for HIV gene therapy[J]. Front Immunol, 2022, 13:792684. doi: 10.3389/fimmu.2022.792684
[26]	Tsukamoto T. Hematopoietic Stem/Progenitor cells and the pathogenesis of HIV/AIDS[J]. Front Cell Infect Microbiol, 2020, 10:60. doi: 10.3389/fcimb.2020.00060
[27]	Yuan Y, Zhou C, Yang Q, et al. HIV-1 Tat protein inhibits the hematopoietic support function of human bone marrow mesenchymal stem cells[J]. Virus Res, 2019, 273:197756. doi: 10.1016/j.virusres.2019.197756
[28]	Li T, Wu N, Dai Y, et al. Reduced thymic output is a major mechanism of immune reconstitution failure in HIV-infected patients after long-term antiretroviral therapy[J]. Clin Infect Dis, 2011, 53(9):944-951. doi: 10.1093/cid/cir552
[29]	Ferrando-Martinez S, De Pablo-Bernal RS, De Luna-Romero M, et al. Thymic function failure is associated with human immunodeficiency virus disease progression[J]. Clin Infect Dis, 2017, 64(9):1191-1197. doi: 10.1093/cid/cix095
[30]	Briceño O, Chávez-Torres M, Peralta-Prado A, et al. Associations between recent thymic emigrants and CD4⁺ T-cell recovery after short-term antiretroviral therapy initiation[J]. AIDS, 2020, 34(4):501-511. doi: 10.1097/QAD.0000000000002458
[31]	Rb-Silva R, Nobrega C, Azevedo C, et al. Thymic function as a predictor of immune recovery in chronically HIV-infected patients initiating antiretroviral therapy[J]. Front Immunol, 2019, 10:25. doi: 10.3389/fimmu.2019.00025
[32]	Scherpenisse M, Kootstra NA, Bakker M, et al. Cell-associated HIV-1 unspliced-to-multiply-spliced RNA ratio at 12 weeks of ART predicts immune reconstitution on therapy[J]. mBio, 2021, 12(2):e00099-21. doi: 10.1128/mbio.00099-21
[33]	Lv T, Cao W, Li T. HIV-related immune activation and inflammation: current understanding and strategies[J]. J Immunol Res, 2021, 2021:7316456
[34]	Henrick BM, Yao XD, Rosenthal KL, et al. HIV-1 structural proteins serve as PAMPs for TLR2 heterodimers significantly increasing infection and innate immune activation[J]. Front Immunol, 2015, 6:426. doi: 10.3389/fimmu.2015.00426
[35]	Younas M, Psomas C, Reynes J, et al. Immune activation in the course of HIV-1 infection: causes, phenotypes and persistence under therapy[J]. HIV Med, 2016, 17(2):89-105. doi: 10.1111/hiv.12310
[36]	Zevin AS, McKinnon L, Burgener A, et al. Microbial translocation and microbiome dysbiosis in HIV-associated immune activation[J]. Curr Opin HIV AIDS, 2016, 11(2):182-190. doi: 10.1097/COH.0000000000000234
[37]	Marchetti G, Tincati C, Silvestri G. Microbial translocation in the pathogenesis of HIV infection and AIDS[J]. Clin Microbiol Rev, 2013, 26(1):2-18. doi: 10.1128/CMR.00050-12
[38]	Huang L, Deng J, Lang R, et al. Enriched LPS staining within the germinal center of a lymph node from an HIV-infected long-term nonprogressor but not from progressors[J]. J Immunol Res, 2020, 2020:7471380. doi: 10.1155/2020/7471380
[39]	Lu L, Wang J, Yang Q, et al. The role of CD38 in HIV infection[J]. AIDS Res Ther, 2021, 18(1):11. doi: 10.1186/s12981-021-00330-6
[40]	Cockerham LR, Jain V, Sinclair E, et al. Programmed death-1 expression on CD4⁺ and CD8⁺ T cells in treated and untreated HIV disease[J]. AIDS, 2014, 28(12):1749-1758. doi: 10.1097/QAD.0000000000000314
[41]	Vos WAJW, Navas A, Meeder EMG, et al. HIV immunological non-responders are characterized by extensive immunosenescence and impaired lymphocyte cytokine production capacity[J]. Front Immunol, 2024, 15:1350065. doi: 10.3389/fimmu.2024.1350065
[42]	Freeman ML, Mudd JC, Shive CL, et al. CD8 T-cell expansion and inflammation linked to CMV coinfection in ART-treated HIV infection[J]. Clin Infect Dis, 2016, 62(3):392-396. doi: 10.1093/cid/civ840
[43]	Looke KJ, Elmes JAR, Gottlieb SL, et al. Effect of HSV-2 infection on subsequent HIV acquisition:an updated systematic review and meta-analysis[J]. Lancet Infect Dis, 2017, 17(12):1303-1316.
[44]	Retamal-Díaz AR, Kalergis AM, Bueno SM, et al. A herpes simplex virus type 2 deleted for glycoprotein D enables dendritic cells to activate CD4⁺ and CD8⁺ T cells[J]. Front Immunol, 2017, 8:904. doi: 10.3389/fimmu.2017.00904
[45]	Rubbo PA, Tuaillon E, Nagot N, et al. HIV-1 infection impairs HSV-specific CD4⁺ and CD8⁺ T-cell response by reducing Th1 cytokines and CCR5 ligand secretion[J]. J Acquir Immune Defic Syndr, 2011, 58(1):9-17. doi: 10.1097/QAI.0b013e318224d0ad
[46]	Margolick JB, Bream JH, Nilles TL, et al. Relationship between T-cell responses to CMV, markers of inflammation, and frailty in HIV-uninfected and HIV-infected men in the multicenter AIDS cohort study[J]. J Infect Dis, 2018, 218(2):249-258. doi: 10.1093/infdis/jiy005
[47]	Fiseha T, Ebrahim H, Ebrahim E, et al. CD4⁺ cell count recovery after initiation of antiretroviral therapy in HIV-infected Ethiopian adults[J]. PLoS One, 2022, 17(3):e0265740. doi: 10.1371/journal.pone.0265740
[48]	Zhu J, Huang H, Wang M, et al. High baseline body mass index predicts recovery of CD4⁺ T lymphocytes for HIV/AIDS patients receiving long-term antiviral therapy[J]. PLoS One, 2022, 17(12):e0279731. doi: 10.1371/journal.pone.0279731
[49]	Pereira LMS, França EDS, Costa IB, et al. HLA-B13, B35 and B*39 alleles are closely associated with the lack of response to ART in HIV infection: a cohort study in a population of northern Brazil[J]. Front Immunol, 2022, 13:829126. doi: 10.3389/fimmu.2022.829126
[50]	Logerot S, Rancez M, Charmeteau-de Muylder B, et al. HIV reservoir dynamics in HAART-treated poor immunological responder patients under IL-7 therapy[J]. AIDS, 2018, 32(6):715-720. doi: 10.1097/QAD.0000000000001752
[51]	Harper J, Huot N, Micci L, et al. IL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques[J]. Nat Commun, 2021, 12(1):2866. doi: 10.1038/s41467-021-23189-7
[52]	Tripiciano A, Picconi O, Moretti S, et al. Anti-Tat immunity defines CD4⁺ T-cell dynamics in people living with HIV on long-term cART[J]. EBioMedicine, 2021, 66:103306. doi: 10.1016/j.ebiom.2021.103306
[53]	Gupta RK, Abdul-Jawad S, McCoy LE, et al. HIV-1 remission following CCR5delta32/delta32 haematopoietic stem-cell transplantation[J]. Nature, 2019, 568(7751):244-248. doi: 10.1038/s41586-019-1027-4
[54]	Tebas P, Jadlowsky JK, Shaw PA, et al. CCR5-edited CD4⁺ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication[J]. J Clin Invest, 2021, 131(7):e144486. doi: 10.1172/JCI144486
[55]	Beccari MV, Mogle BT, Sidman EF, et al. Ibalizumab, a novel monoclonal antibody for the management of multidrug-resistant HIV-1 infection[J]. Antimicrob Agents Chemother, 2019, 63(6):e00110-19. doi: 10.1128/aac.00110-19
[56]	Fan L, Hu Y, Li R, et al. Enhanced immune reconstitution with albuvirtide in HIV-infected immunological non-responders[J]. Front Cell Infect Microbiol, 2024, 14:1397743. doi: 10.3389/fcimb.2024.1397743
[57]	Hemsworth JC, Hekmat S, Reid G. Micronutrient supplemented probiotic yogurt for HIV-infected adults taking HAART in London, Canada[J]. Gut Microbes, 2012, 3(5):414-419. doi: 10.4161/gmic.21248
[58]	d'Ettorre G, Rossi G, Scagnolari C, et al. Probiotic supplementation promotes a reduction in T-cell activation, an increase in Th17 frequencies, and a recovery of intestinal epithelium integrity and mitochondrial morphology in ART-treated HIV-1-positive patients[J]. Immun Inflamm Dis, 2017, 5(3):244-260. doi: 10.1002/iid3.160
[59]	Carter GM, Esmaeili A, Shah H, et al. Probiotics in human immunodeficiency virus infection: a systematic review and evidence synthesis of benefits and risks[J]. Open Forum Infect Dis, 2016, 3(4):ofw164. doi: 10.1093/ofid/ofw164
[60]	Khoruts A, Sadowsky MJ. Understanding the mechanisms of faecal microbiota transplantation[J]. Nat Rev Gastroenterol Hepatol, 2016, 13(9):508-516. doi: 10.1038/nrgastro.2016.98
[61]	Elopre L, Rodriguez M. Fecal microbiota therapy for recurrent Clostridium difficile infection in HIV-infected persons[J]. Ann Intern Med, 2013, 158(10):779-780. doi: 10.7326/0003-4819-158-10-201305210-00021
[62]	Ding X, Fan L, Xu L, et al. Incomplete immune reconstitution and traditional Chinese medicine in patients with HIV/AIDS: challenges and perspectives[J]. Infect Drug Resist, 2024, 17:5827-5838. doi: 10.2147/IDR.S497083
[63]	Cao W, Liu X, Han Y, et al. (5R)-5-hydroxytriptolide for HIV immunological non-responders receiving ART: a randomized, double-blinded, placebo-controlled phase Ⅱ study[J]. Lancet Reg Health West Pac, 2023, 34:100724. doi: 10.1016/j.lanwpc.2023.100724
[64]	许琪华, 吴雪, 郑海鹏, 等. 青蒿琥酯对HAART后免疫重建不良HIV/AIDS患者免疫功能和肠道菌群影响的研究[J]. 中医药学报, 2022, 50(12):54-59. doi: 10.19664/j.cnki.1002-2392.220274
	Xu QH, Wu X, Zheng HP, et al. Effect of artesunate on immune function and gut microbiota in HIV/AIDS patients with immune non-response after HAART[J]. Acta Chinese Medicine and Pharmacology, 2022, 50(12):54-59. doi: 10.19664/j.cnki.1002-2392.220274
[65]	邹雯, 王健, 高国建, 等. 益气健脾颗粒联合HAART治疗对艾滋病免疫无应答患者TLR4和TLR9的影响[J]. 中华中医药杂志, 2019, 34(9):4426-4428.
	Zou W, Wang J, Gao GJ, et al. Effects of TLR4 and TLR9 in immunological unresponsiveness AIDS patients treated with Yiqi Jianpi Granules combined with HAART[J]. CJTCMP, 2019, 34(9):4426-4428.