Wu Jia-Feng, Tai Chi-San, Chang Kai-Chi, Chen Ting-Wei, Chen Huey-Ling, Ni Yen-Hsuan, Hsu Hong-Yuan, Chang Mei-Hwei
Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
JHEP Rep. 2024 Mar 8;6(5):101061. doi: 10.1016/j.jhepr.2024.101061. eCollection 2024 May.
BACKGROUND & AIM: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) attenuates cytotoxic T lymphocyte (CTL) activation. This study was performed to examine the relationships between genotypes/haplotypes, hepatitis B surface antigen (HBsAg), and hepatitis B core-related antigen (HBcrAg) levels, and their potential impact on the clinical course of chronic HBV infection.
We recruited 145 treatment-naïve patients with genotype B or C chronic HBV infection who were initially hepatitis B e-antigen (HBeAg)-positive and had been followed from a mean age of 7.08 years for a total of 4,787 person-years in the study cohort. We also recruited another 69 treatment-naïve adults with genotype B or C chronic HBV infection as a validation cohort. We assessed the gene single nucleotide polymorphisms rs4553808 (-A1661G)/rs5742909 (-C318T) in both cohorts, and the serum HBsAg and HBcrAg levels in the study cohort.
promoter haplotypes were associated with HBsAg and HBcrAg levels at 10 and 15 years of age in the study cohort. Patients with the AA/CC haplotype showed earlier spontaneous HBeAg seroconversion (hazard ratio = 1.58; = 0.02), and a more rapid annual decline in the serum HBsAg level than other patients (0.09 0.03 log IU/ml/year, = 0.02). The AA/CC haplotype was also predictive of HBeAg seroconversion in the validation cohort ( = 0.01).
Chronic HBV-infected patients with a AA/CC haplotype had lower serum HBsAg and HBcrAg levels in childhood and earlier spontaneous HBeAg seroconversion.
The role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in chronic HBV-infected children has not been studied previously. In a very long-term cohort followed from childhood to adulthood, we showed that haplotypes are associated with HBV biomarker levels in childhood and are correlated with the clinical course of chronic HBV infection. CTLA-4 pathway may serve as a future target for the development of therapeutic agents against HBV infection.
细胞毒性T淋巴细胞相关蛋白4（CTLA-4）可减弱细胞毒性T淋巴细胞（CTL）的激活。本研究旨在探讨基因型/单倍型、乙型肝炎表面抗原（HBsAg）和乙型肝炎核心相关抗原（HBcrAg）水平之间的关系，以及它们对慢性HBV感染临床病程的潜在影响。
我们招募了145例未经治疗的B或C基因型慢性HBV感染患者，这些患者最初为乙型肝炎e抗原（HBeAg）阳性，在研究队列中从平均7.08岁开始随访，共随访4787人年。我们还招募了另外69例未经治疗的B或C基因型慢性HBV感染成人作为验证队列。我们评估了两个队列中的基因单核苷酸多态性rs4553808（-A1661G）/rs5742909（-C318T），以及研究队列中的血清HBsAg和HBcrAg水平。
在研究队列中，启动子单倍型与10岁和15岁时的HBsAg和HBcrAg水平相关。AA/CC单倍型的患者显示出更早的自发HBeAg血清学转换（风险比=1.58；P=0.02），并且血清HBsAg水平的年下降速度比其他患者更快（0.09±0.03 log IU/ml/年，P=0.02）。AA/CC单倍型在验证队列中也可预测HBeAg血清学转换（P=0.01）。
具有AA/CC单倍型的慢性HBV感染患者在儿童期血清HBsAg和HBcrAg水平较低，且自发HBeAg血清学转换较早。
细胞毒性T淋巴细胞相关蛋白4（CTLA-4）在慢性HBV感染儿童中的作用此前尚未得到研究。在一个从儿童期到成年期的长期队列中，我们表明单倍型与儿童期的HBV生物标志物水平相关，并与慢性HBV感染的临床病程相关。CTLA-4通路可能成为未来开发抗HBV感染治疗药物的靶点。
