人乳头瘤病毒免疫逃逸机制研究进展

doi:10.12280/gjfckx.20250229

摘要/Abstract

摘要：

免疫逃逸是人乳头瘤病毒（human papilloma virus，HPV）持续性感染、促进宫颈癌等相关恶性肿瘤进展的核心致病机制之一。在分子生物学层面，HPV的基因组区域在侵袭和感染宿主细胞中发挥关键作用；在机体免疫应答层面，HPV通过抑制自然杀伤细胞、巨噬细胞和树突状细胞等固有免疫核心效应细胞的功能，同时干扰T淋巴细胞介导的适应性免疫应答，导致免疫效应细胞功能耗竭并诱导免疫耐受状态。值得注意的是，HPV还能通过改变阴道局部微生态平衡引发免疫调节与菌群稳态的交互失衡，构建有利于病毒持续存在的免疫抑制微环境。深入解析这些机制对于研发有效的HPV防治策略具有重要意义，有望为HPV相关疾病的预防、诊断和治疗提供新的思路和靶点。

关键词: 乳头状瘤病毒科, 肿瘤逃逸, 免疫, 先天, 适应性免疫, 乳杆菌属, 持续感染, 生物学特性

Abstract:

Immune evasion is one of the core pathogenic mechanisms for the persistent infection of human papilloma virus (HPV) and the progression of related malignancies such as cervical cancer. At the molecular biological level, the genomic regions of HPV play a crucial role in invading and infecting host cells. At the level of the host immune response, HPV inhibits the functions of innate immune core effector cells such as natural killer cells, macrophages, and dendritic cells, and at the same time interferes with the T -lymphocyte-mediated adaptive immune response, ultimately leading to the functional exhaustion of immune effector cells and inducing an immune tolerance state. Notably, HPV can also disrupt the local vaginal microecological balance, causing an interactive imbalance between immune regulation and microbial homeostasis, and creating an immunosuppressive microenvironment conducive to the persistence presence of the virus. In-depth anaysis of these mechanisms is of great significance for the development of effective prevention and treatment strategies for HPV, and is expected to provide new ideas and targets for the prevention, diagnosis, and treatment of HPV-related diseases.

Key words: Papillomaviridae, Tumor escape, Immunity, innate, Adaptive immunity, Lactobacillus, Persistent infection, Biological characteristics

李祖雯, 郭洁, 宋殿荣. 人乳头瘤病毒免疫逃逸机制研究进展[J]. 国际妇产科学杂志, 2025, 52(4): 420-424.

LI Zu-wen, GUO Jie, SONG Dian-rong. Research Progress on the Immune Evasion Mechanism of Human Papilloma Virus[J]. Journal of International Obstetrics and Gynecology, 2025, 52(4): 420-424.

参考文献 44

[1]	Demarco M, Hyun N, Carter-Pokras O, et al. A study of type-specific HPV natural history and implications for contemporary cervical cancer screening programs[J]. EClinicalMedicine, 2020, 22:100293. doi: 10.1016/j.eclinm.2020.100293.
[2]	Baedyananda F, Chaiwongkot A, Varadarajan S, et al. HPV16 E1 dysregulated cellular genes involved in cell proliferation and host DNA damage: A possible role in cervical carcinogenesis[J]. PLoS One, 2021, 16(12):e0260841. doi: 10.1371/journal.pone.0260841.
[3]	Prabhakar AT, Morgan IM. A new role for human papillomavirus 16 E2: Mitotic activation of the DNA damage response to promote viral genome segregation[J]. Tumour Virus Res, 2024, 18:200291. doi: 10.1016/j.tvr.2024.200291.
[4]	Piirsoo A, Kala M, Sankovski E, et al. Uncovering the Role of the E1 Protein in Different Stages of Human Papillomavirus 18 Genome Replication[J]. J Virol, 2020, 94(20):e00674-00620. doi: 10.1128/JVI.00674-20.
[5]	Kuehner F, Wong M, Straub E, et al. Mus musculus papillomavirus 1 E8^E2 represses expression of late protein E4 in basal-like keratinocytes via NCoR/SMRT-HDAC3 co-repressor complexes to enable wart formation in vivo[J]. mBio, 2023, 14(4):e0069623. doi: 10.1128/mbio.00696-23.
[6]	Yajid AI, Zakariah MA, Mat Zin AA, et al. Potential Role of E4 Protein in Human Papillomavirus Screening: a Review[J]. Asian Pac J Cancer Prev, 2017, 18(2):315-319. doi: 10.22034/APJCP.2017.18.2.315.
[7]	Miyauchi S, Kim SS, Jones RN, et al. Human papillomavirus E5 suppresses immunity via inhibition of the immunoproteasome and STING pathway[J]. Cell Rep, 2023, 42(5):112508. doi: 10.1016/j.celrep.2023.112508.
[8]	Song Y, Wu X, Xu Y, et al. HPV E7 inhibits cell pyroptosis by promoting TRIM21-mediated degradation and ubiquitination of the IFI16 inflammasome[J]. Int J Biol Sci, 2020, 16(15):2924-2937. doi: 10.7150/ijbs.50074. pmid: 33061806
[9]	陈玉梅, 栗宁, 薛明岩, 等. 人乳头瘤病毒58型(HPV58)主要衣壳蛋白L1的可溶性表达及应用[J]. 细胞与分子免疫学杂志, 2022, 38(6):553-558.
[10]	宋丹, 史茜, 侯向前, 等. HPV-16 URR突变对病毒早期启动子活性影响的研究[J]. 中国癌症杂志, 2017, 27(2):109-114. doi: 10.19401/j.cnki.1007-3639.2017.02.005.
[11]	von Knebel Doeberitz M. Prigge ES. Role of DNA methylation in HPV associated lesions[J]. Papillomavirus Res, 2019, 7:180-183. doi: 10.1016/j.pvr.2019.03.005. pmid: 30978415
[12]	胡绍雯, 朱惠芳. NK细胞在肿瘤免疫治疗中的研究进展[J]. 中国免疫学杂志, 2023, 39(6):1318-1325. doi: 10.3969/j.issn.1000-484X.2023.06.043.
[13]	Bahadorian D, Mollazadeh S, Mirazi H, et al. Regulatory NK cells in autoimmune disease[J]. Iran J Basic Med Sci, 2023, 26(6):609-616. doi: 10.22038/IJBMS.2023.68653.14969. pmid: 37275764
[14]	Nie Y, Liu D, Yang W, et al. Increased expression of TIGIT and KLRG1 correlates with impaired CD56bright NK cell immunity in HPV16-related cervical intraepithelial neoplasia[J]. Virol J, 2022, 19(1):68. doi: 10.1186/s12985-022-01776-4.
[15]	Pagni RL, Souza P, Pegoraro R, et al. Interleukin-6 and indoleamine-2,3-dioxygenase as potential adjuvant targets for Papillomavirus-related tumors immunotherapy[J]. Front Immunol, 2022, 13:1005937. doi: 10.3389/fimmu.2022.1005937.
[16]	Coyle KM, Hawke LG, Ormiston ML. Addressing Natural Killer Cell Dysfunction and Plasticity in Cell-Based Cancer Therapeutics[J]. Cancers(Basel), 2023, 15(6):1743. doi: 10.3390/cancers15061743.
[17]	Wei Y, Wu P, Cao C. 563P Single-cell profiling analysis reveals that AIF1-induced M2-to-M1 transition of macrophages suppresses the expression of HPV oncogenes and the progression of cervical carcinoma[J]. Ann Oncol, 2022, 33(Suppl 7):S805-S806. doi: 10.1016/j.annonc.2022.07.691.
[18]	何玲, 刘喜平, 陈光顺, 等. 半夏泻心汤抑制巨噬细胞M2型极化增敏PD-1单抗治疗肝细胞癌[J]. 中药药理与临床, 2024-11-15 15:50.[2025-04-29]. https://doi.org/10.13412/j.cnki.zyyl.20241115.003. doi: 10.13412/j.cnki.zyyl.20241115.003.
[19]	Chen XJ, Han LF, Wu XG, et al. Clinical Significance of CD163+ and CD68+ Tumor-associated Macrophages in High-risk HPV-related Cervical Cancer[J]. J Cancer, 2017, 8(18):3868-3875. doi: 10.7150/jca.21444.
[20]	Chen X, Liu Y, Luo X, et al. HPV16 E6-induced M2 macrophage polarization in the cervical microenvironment via exosomal miR-204-5p[J]. Sci Rep, 2024, 14(1):23725. doi: 10.1038/s41598-024-74399-0. pmid: 39390116
[21]	牛佳欣, 曾菊, 张聪, 等. 树突状细胞在头颈部鳞状细胞癌免疫作用研究进展[J]. 临床与实验病理学杂志, 2025, 41(1):81-85,92. doi: 10.13315/j.cnki.cjcep.2025.01.013.
[22]	Dai W, Gui L, Du H, et al. The association of cervicovaginal Langerhans cells with clearance of human papillomavirus[J]. Front Immunol, 2022, 13:918190. doi: 10.3389/fimmu.2022.918190.
[23]	Da Silva DM, Woodham AW, Naylor PH, et al. Immunostimulatory Activity of the Cytokine-Based Biologic, IRX-2, on Human Papillomavirus-Exposed Langerhans Cells[J]. J Interferon Cytokine Res, 2016, 36(5):291-301. doi: 10.1089/jir.2015.0115.
[24]	Maleka MN, Mbita Z, Morafo V. Regulation of Granzymes A and B by High-Risk HPV: Impact on Immune Evasion and Carcinogenesis[J]. Viruses, 2025, 17(2):221. doi: 10.3390/v17020221.
[25]	云红叶, 林莉香, 于欣荣, 等. 尖锐湿疣外周血HPV16抗原特异性CD8+CTL表型及其与HPV DNA的关系[J]. 中华医院感染学杂志, 2022, 32(3):453-457. doi: 10.11816/cn.ni.2022-210500.
[26]	Ferrall L, Lin KY, Roden R, et al. Cervical Cancer Immunotherapy: Facts and Hopes[J]. Clin Cancer Res, 2021, 27(18):4953-4973. doi: 10.1158/1078-0432.CCR-20-2833. pmid: 33888488
[27]	Luo X, Donnelly CR, Gong W, et al. HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING[J]. J Clin Invest, 2020, 130(4):1635-1652. doi: 10.1172/JCI129497. pmid: 31874109
[28]	Kamrani A, Asghari KM, Zafarani Y, et al. The role of probiotics in restoring the Th1 to Th2 ratio in women experiencing recurrent implantation failure; a double-blind randomized clinical trial[J]. Hum Immunol, 2025, 86(1):111220. doi: 10.1016/j.humimm.2024.111220.
[29]	沈丽, 薛平莉, 朱燕娜. HPV感染及其基因型与宫颈病变患者病灶微环境Th1/Th2平衡及疾病进展的关系[J]. 中华医院感染学杂志, 2022, 32(16):2510-2514. doi: 10.11816/cn.ni.2022-211722.
[30]	Lin W, Niu Z, Zhang H, et al. Imbalance of Th1/Th2 and Th17/Treg during the development of uterine cervical cancer[J]. Int J Clin Exp Pathol, 2019, 12(9):3604-3612.
[31]	王岚, 唐娟, 庾广聿, 等. 阴道灌洗液中炎症因子与CD4+和CD8+T细胞在高级别宫颈鳞状上皮内病变与早期宫颈癌发病中的作用研究[J]. 中国肿瘤临床, 2024, 51(7):337-341. doi: 10.12354/j.issn.1000-8179.2024.20240349.
[32]	唐志坚, 赵超, 李明珠, 等. 高危型人乳头瘤病毒感染的不同级别子宫颈病变患者细胞免疫状态分析[J]. 中国实用妇科与产科杂志, 2023, 39(10):1024-1029. doi: 10.19538/j.fk2023100113.
[33]	Bonin-Jacob CM, Almeida-Lugo LZ, Puga M, et al. IL-6 and IL-10 in the serum and exfoliated cervical cells of patients infected with high-risk human papillomavirus[J]. PLoS One, 2021, 16(3):e0248639. doi: 10.1371/journal.pone.0248639.
[34]	Aghbash PS, Hemmat N, Baradaran B, et al. The effect of Wnt/β-catenin signaling on PD-1/PDL-1 axis in HPV-related cervical cancer[J]. Oncol Res, 2022, 30(3):99-116. doi: 10.32604/or.2022.026776. pmid: 37305016
[35]	Chen X, He H, Xiao Y, et al. CXCL10 Produced by HPV-Positive Cervical Cancer Cells Stimulates Exosomal PDL1 Expression by Fibroblasts via CXCR3 and JAK-STAT Pathways[J]. Front Oncol, 2021, 11:629350. doi: 10.3389/fonc.2021.629350.
[36]	姜英, 周红. 高危型HPV阳性宫颈癌细胞中YAP1与Wnt/β-catenin信号通路的关系及生物学意义[J]. 病毒学报, 2022, 38(4):889-895. doi: 10.13242/j.cnki.bingduxuebao.004158.
[37]	许涵洁, 陈钰, 陈道桢. 乳杆菌抗宫颈病变的机制研究进展[J]. 南京医科大学学报(自然科学版), 2020, 40(6):927-932,936. doi: 10.7655/NYDXBNS20200629.
[38]	Lebeau A, Bruyere D, Roncarati P, et al. HPV infection alters vaginal microbiome through down-regulating host mucosal innate peptides used by Lactobacilli as amino acid sources[J]. Nat Commun, 2022, 13(1):1076. doi: 10.1038/s41467-022-28724-8. pmid: 35228537
[39]	López-Filloy M, Cortez FJ, Gheit T, et al. Altered Vaginal Microbiota Composition Correlates With Human Papillomavirus and Mucosal Immune Responses in Women With Symptomatic Cervical Ectopy[J]. Front Cell Infect Microbiol, 2022, 12:884272. doi: 10.3389/fcimb.2022.884272.
[40]	鲍亚玲, 贾维宁, 杨子娇. 高危型HPV感染患者阴道微生态特点及miR-155、miR-222表达水平的相关性分析[J]. 中国病原生物学杂志, 2024, 19(6):648-652. doi: 10.13350/j.cjpb.240606.
[41]	Avsaroglu E, Kaleli B, Kilic D, et al. A Decrease in Lactobacilli in the Vaginal Microbiota Is Independently Associated With HPV Persistence in Women With High-Risk HPV Infection[J]. Cureus, 2023, 15(12):e50907. doi: 10.7759/cureus.50907.
[42]	So KA, Yang EJ, Kim NR, et al. Changes of vaginal microbiota during cervical carcinogenesis in women with human papillomavirus infection[J]. PLoS One, 2020, 15(9):e0238705. doi: 10.1371/journal.pone.0238705.
[43]	Liu J, Song J, Yang Q, et al. Correlation between Lactobacillus and expression of E-cadherin, β-catenin, N-cadherin, and Vimentin in postmenopausal cervical lesions[J]. Ann Palliat Med, 2022, 11(1):135-145. doi: 10.21037/apm-21-3581. pmid: 35144405
[44]	Wang X, Zhang Y, Xiao J, et al. Effect of Vaginal Microecological Disorders on the Increased Risk of Abnormal Cervical Cytology Among Women With Human Immunodeficiency Virus in China[J]. J Infect Dis, 2024, 230(1):61-66. doi: 10.1093/infdis/jiae058.