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三结构域蛋白29（TRIM29）与HBV复制及聚乙二醇干扰素α-2b抗病毒作用的关联性分析
DOI: 10.12449/JCH241111
Association of TRIM29 with HBV replication and the antiviral effect of pegylated interferon α-2b
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摘要:
目的 三结构域蛋白29（TRIM29）参与多种疾病的发生和发展，与部分DNA和RNA病毒复制密切相关，本研究对TRIM29与HBV复制及聚乙二醇干扰素（PEG-IFN）α-2b抗病毒作用之间的关系展开初步讨论。 方法 选取2021年10月—2022年6月在贵州医科大学附属医院感染内科门诊就诊的CHB患者64例，其中未治疗患者34例（CHB组），经PEG-IFN-α- 2b治疗患者30例，体检中心30例健康志愿者作为对照（健康对照组）。收集志愿者年龄、性别、ALT、AST、TBil、DBil、HBV DNA和外周血单个核细胞（PBMC）。采用HepG2和HepG2.2.15细胞作为细胞模型，将TRIM29特异性过表达质粒或siRNA和对照转染至细胞；PEG-IFN-α-2b（0、10、100、1 000和10 000 U/mL）处理HepG2细胞和Huh7细胞；TRIM29特异性si-RNA或阴性对照联合PEG-IFN-α-2b处理HepG2.2.15细胞。ELISA检测HBsAg和HBeAg的浓度，qRT-PCR检测TRIM29和HBV RNA相对表达水平，Western Blot检测STING、p-TBK1、TBK1、pIRF3、IRF3、MX1和IFIT1蛋白表达情况，免疫共沉淀检测TRIM29与STING蛋白相互作用关系。正态分布的计量资料两组间比较采用成组t检验，多组间比较采用单因素方差分析，进一步两两比较采用LSD-t检验。计数资料两组间比较采用χ2检验或Fisher检验。 结果 CHB组患者外周血TRIM29表达明显高于健康对照组（P<0.001）。在细胞实验中，HBsAg、HBeAg和HBV RNA的表达均随TRIM29表达上调而升高，随TRIM29表达下调而降低（P值均<0.05）。TRIM29与STING互相结合，并通过蛋白酶降解STING，与对照组相比，过表达TRIM29对TBK1和IRF3总蛋白无明显变化，STING、p-TBK1和p-IRF3蛋白表达水平均降低（P值均<0.05）。处理HepG2细胞和Huh7细胞的PEG-IFN-α-2b浓度越高，TRIM29蛋白和mRNA的表达水平越低（P值均<0.01）。CHB患者在PEG-IFN-α-2b治疗期间，TRIM29 mRNA表达水平逐渐降低，且早期应答组和无应答组间差异均有统计学意义（P值均<0.05）。在等量PEG-IFN-α-2b处理下，与对照相比，敲低TRIM29后HepG2.2.15细胞的MX1和IFIT1蛋白表达水平明显增高（P值均<0.05）。在PEG-IFN-α-2b治疗早期，CHB患者PBMC中TRIM29表达逐渐降低。 结论 TRIM29靶向并降解STING，通过抑制STING-TBK1-IRF3信号通路促进HBV复制。TRIM29干扰PEG-IFN-α-2b的抗病毒作用，CHB患者PBMC中TRIM29的表达水平可能作为预测患者对PEG-IFN-α-2b治疗应答的指标。 Abstract:Objective To preliminarily investigate the association of TRIM29 with HBV replication and the antiviral effect of pegylated interferon α-2b （PEG-IFN-α-2b）， since TRIM29 protein is involved in the development and progression of a variety of diseases and is closely associated with the replication of some DNA and RNA viruses. Methods A total of 64 chronic hepatitis B （CHB） patients who attended the outpatient service of Department of Infectious Diseases， The Affiliated Hospital of Guizhou Medical University， from October 2021 to June 2022 were enrolled， among whom there were 34 treatment-naïve patients and 30 patients treated with PEG-IFN-α-2b， and 30 healthy volunteers in Physical Examination Center were enrolled as controls. Related data were collected， including age， sex， alanine aminotransferase， aspartate aminotransferase， total bilirubin， direct bilirubin， HBV DNA， and peripheral blood mononuclear cells （PBMCs）. HepG2 and HepG2.2.15 cells were used as cell models and were transfected with TRIM29-specific overexpressed plasmid or siRNA and control plasmid. HepG2 cells and Huh7 cells were treated with PEG-IFN-α-2b （0， 10， 100， 1 000， and 10 000 U/mL）， and HepG2.2.15 cells were treated with TRIM29-specific siRNA or negative control combined with PEG-IFN-α-2b. ELISA was used to measure the concentrations of HBsAg and HBeAg； qRT-PCR was used to measure the relative expression levels of TRIM29 and HBV RNA； Western blot was used to measure the protein expression levels of STING， p-TBK1， TBK1， pIRF3， IRF3， MX1， and IFIT1； co-immunoprecipitation assay was used to observe the interaction between TRIM29 and STING protein. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and a one-way analysis of variance was used for comparison between multiple groups， with the least significant difference t-test for further comparison between two groups； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. Results The CHB patients had a significantly higher expression level of TRIM29 in peripheral blood than the healthy controls （P<0.001）. In cell experiments， the expression levels of HBsAg， HBeAg， and HBV RNA increased with the upregulation of TRIM29 expression and decreased with downregulation of TRIM29 expression （P<0.05）. TRIM29 bound to STING and degraded STING via protease， and compared with the control group， there were no significant changes in the total protein levels of TBK1 and IRF3 after overexpression of TRIM29， while there were significant reductions in the expression levels of STING， p-TBK1， and p-IRF3 （P<0.05）. The protein and mRNA expression levels of TRIM29 decreased with the increase in the concentration of PEG-IFN-α-2b for the treatment of HepG2 and Huh7 cells （P<0.01）. During the treatment with PEG-IFN-α-2b， the CHB patients had a gradual reduction in the mRNA expression level of TRIM29， and there was a significant difference between the early response group and the non-response group （P<0.05）. In the context of treatment with an equal volume of PEG-IFN-α-2b， compared with the control group， there were significant increases in the protein expression levels of Mx1 and IFIT1 in HepG2.2.15 cells after TRIM29 knockdown （P<0.05）. There was a gradual reduction in the expression of TRIM29 in CHB patients during the early stage of PEG-IFN-α-2b treatment. Conclusion TRIM29 targets and degrades STING and promotes HBV replication by inhibiting the STING-TBK1-IRF3 signaling pathway. TRIM29 interferes with the antiviral effect of PEG-IFN-α-2b， and the expression level of TRIM29 in PBMCs of CHB patients may be used as an indicator for predicting the response of patients to PEG-IFN-α-2b therapy. -
Key words:
- Hepatitis B Virus /
- Tripartite Motif-Containing Protein 29 /
- PEG-IFNα /
- Signaling Pathway
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抗病毒治疗是慢性乙型肝炎(CHB)的关键措施，其中恩替卡韦(ETV) 是治疗HBV的一线核苷(酸)类似物(NAs) 之一。尽管其他研究曾报道了长期ETV治疗CHB的疗效和安全性，但其在中国慢性CHB(主要为基因型B和C)患者中的临床数据仍然有限。
马来酸ETV是正大天晴药业股份有限公司开发的ETV衍生物，多中心、随机、双盲双模拟、阳性药物对照临床研究显示其治疗48周时与原研ETV在治疗CHB时等效，基于上述结果，国家食品药品管理局已经批准其上市。作为此项研究的主要研究者，北京大学第一医院于岩岩教授对其长期疗效和安全性进行了进一步研究：此前已经报告144周的马来酸ETV治疗中国慢性CHB(主要为基因型B和C)患者有效而且安全。更长疗程的药物治疗效果和安全性如何，尚无知晓。
2022年7月6日于岩岩教授团队在线发表研究论文，旨在更新马来酸ETV治疗中国患者240周疗程的病毒学、血清学和生化结果。CHB受试者被随机分配接受0.5 mg/d ETV(A组)或0.5 mg/d马来酸ETV(B组)治疗48周，此后所有受试者从第49周开始接受0.5 mg/d马来酸ETV治疗。定期对患者进行随访，监测血清HBV标志物、肝生化等指标，记录不良事件(AE)。主要终点是治疗结束时每组HBV DNA的下降。次要终点包括治疗结束时HBV DNA不可测(＜20 IU/mL) 的比率、HBeAg消失率、HBeAg血清转化率和血清ALT复常率。137例(A组71例) HBeAg阳性CHB患者和46例(A组21例)HBeAg阴性CHB患者完成了240周的治疗和随访。两组的基线特征可比。在HBeAg阳性CHB组，240周时两组的HBV DNA较基线下降平均值可比(A：6.67 log10 IU/mL vs B：6.74 log10 IU/mL；P＞0.05)，血清HBV DNA不可测率(A：91.55% vs B：87.88%；P＞0.05)、HBeAg血清学转换率(A：26.98% vs B：20.97%；P＞0.05)和ALT复常率(A：87.32% vs B：83.61%；P＞0.05)均在组间可比。在HBeAg阴性CHB组，240周时两组的HBV DNA较基线下降平均值可比(A：6.05 log10 IU/mL vs B：6.10 log10 IU/mL；P＞0.05)，血清HBV DNA不可测比例(A：100% vs B：100%)和ALT复常率(A：90.91% vs B：95.45%)(P＞0.05)也可比。在耐药方面，HBeAg阴性CHB组耐药率为0；HBeAg阳性CHB组144周时耐药率1.16%，此后直至240周新增1例ETV耐药。安全性方面，没有因为AE导致停药，无肝癌或死亡病例。
总之，作为国产抗HBV药物代表之一的马来酸ETV，长期治疗中国CHB(主要是基因型B或C)是安全有效的。
摘译自XU JH, FAN YN, YU YY, et al. 240-week entecavir maleate treatment in Chinese chronic hepatitis B predominantly genotype B or C[J]. J Viral Hepat, 2022, 29(10): 862-867. DOI: 10.1111/jvh.13724.
(北京大学第一医院感染疾病科 徐京杭 报道)
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注： a，CHB组与健康对照组TRIM29 mRNA表达差异；b，HepG2和HepG2.2.15细胞TRIM29蛋白表达差异。
图 1 TRIM29表达水平与HBV感染的关系
Figure 1. The relationship between TRIM29 and HBV infection
注： a、c，Western Blot和qRT-PCR检测TRIM29转染效率；b、d，ELISA检测细胞培养基中HBsAg和HBeAg的浓度，qRT-PCR检测HBV RNA的相对表达水平。
图 2 过表达TRIM29对HBV复制的影响
Figure 2. Effect of TRIM29 overexpression on HBV replication and gene expression
注： a、c，Western Blot和qRT-PCR检测TRIM29特异性si-RNA转染效率；b、d，ELISA检测细胞培养基中HBsAg和HBeAg的浓度，qRT-PCR检测HBV RNA表达水平。
图 3 敲低TRIM29对HBV复制的影响
Figure 3. Effect of TRIM29 knockdown on HBV replication and gene expression
注： a，免疫共沉淀检测TRIM29和STING相互作用；b、c，qRT-PCR检测IFN-α mRNA表达水平；d、e，Western Blot检测STING、TBK1、IRF3、p-TBK1、p-IRF3蛋白水平。
图 4 TRIM29对STING-TBK1-IRF3信号通路的调控作用
Figure 4. Regulatory effect of TRIM29 on STING-TBK1-IRF3 signaling pathway
注： a、b HepG2细胞；c、d，Huh7细胞。a、c，Western Blot检测TRIM29蛋白表达水平；b、d，qRT-PCR检测TRIM29 mRNA水平。
图 5 PEG-IFN-α-2b对TRIM29表达的影响
Figure 5. Effect of PEG-IFN-α-2b on TRIM29 expression
图 6 TRIM29表达对PEG-IFN-α-2b的抗病毒作用的影响
Figure 6. Effect of TRIM29 expression on the antiviral effect of PEG-IFN-α-2b
表 1 引物序列
Table 1. List of primers
引物 序列（5'-3'） HBV RNA-F TCTTGCCTTACTTTTGGAAG HBV RNA-R AGTTCTTCTTCTAGGGGACC Hu-TRIM29-F TGCGAGCTGCATCTCAAGC Hu-TRIM29-R GGTGCTATGATTCTTGTGCTCC Hu-IFN-α-F TGACCTCAAAGCCTGTGTGATG Hu-IFN-α-R AAGTATTTCCTCACAGCCAGCAG Hu-GAPDH-F CGGATTTGGTCGTATTGGG Hu-GAPDH-R TCTCGCTCCTGGAAGATGG 
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表 2 健康对照组和CHB组患者的一般资料比较
Table 2. Comparison of clinical characteristics between healthy and CHB patients
指标 健康对照组（n=30） CHB组（n=34） 统计值 P值 年龄（岁） 38.2±10.4 33.8±5.0 t=0.451 0.328 男/女（例） 15/15 16/18 χ2=0.055 0.814 汉族/其他（例） 23/7 24/10 χ2=0.302 0.583 ALT（U/L） 19.4±4.8 17.4±4.9 t=1.702 0.094 AST（U/L） 17.3±3.3 18.4±3.3 t=-1.293 0.201 TBil（μmol/L） 6.2±3.7 8.6±2.7 t=-1.791 0.195 DBil（μmol/L） 3.4±0.8 4.6±1.6 t=-2.219 0.138
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表 3 一般临床资料
Table 3. Clinical characteristics of patients
指标 早期应答组（n=11） 早期无应答组（n=19） t值 P值 女性（例） 7 12 >0.05 年龄（岁） 26.8±4.49 29.3±7.20 -2.041 0.643 HBV DNA （log10 IU/mL） 0周 2.35±0.26 2.11±0.18 2.380 0.010 12周 1.33±0.10 1.84±0.23 2.598 <0.001 24周 1.09±0.16 1.56±0.27 -4.260 <0.001 ALT（U/L） 0周 23.64±3.70 24.09±4.00 -0.546 0.99 12周 59.78±6.30 36.25±5.73 8.127 <0.001 24周 33.66±6.74 45.68±4.96 -3.893 <0.001 TRIM29 mRNA 0周 1.57±0.43 1.32±0.75 2.07 0.047 12周 1.22±0.26 0.72±0.34 3.83 <0.001 24周 0.94±0.27 0.43±0.11 7.20 <0.001
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