乙型肝炎病毒包膜区和核心区CTL抗原表位变异对感染慢性化及疾病转归的影响

Impact of CTL epitope mutations of hepatitis B virus envelope protein and core protein on chronicity and disease prognosis in patients with hepatitis B

目的探讨HBV包膜区和核心区细胞毒性T淋巴细胞（CTL）抗原表位变异的规律及对疾病发展转归的影响。方法本研究选择无症状HBsAg携带者（ASC）38例，慢性乙型肝炎（CHB）35例，乙型肝炎肝硬化（Lc）23例。采用DNA测序法检测HBV包膜区和核心区病毒序列及表位变异情况，并分析其与临床转归的关系。结果在人组患者中，HBV包膜区CTL抗原表位41～49、88～96、97～108、172-180和185～194变异率分别为48个（55．2％）、13个（14．9％）、11个（12．6％）、9个（10．3％）和6个（6．9％）；HBVCTL41～49位变异率在CHB和肝硬化患者中的变异率分别为60．0％和65．2％，显著高于ASCE31．6％，P〈0．05]；HBV核心区CTL抗原表位18～27和91～95的变异率分别为18个（56．2％）和14个（43．8％），HBVCTLl8～27位的变异率在慢性乙型肝炎和肝硬化患者中分别为20．0％和30．4％，显著高于ASC[10．5％，P〈O．05]；多变量分析表明，HBV核心区CTL4149的变异是预示HBV感染后患者肝内炎症活动、慢性乙型肝炎病程进展、迁延并发生肝炎肝硬化的独立危险因素。结论HBVCTL变异是HBV感染慢性化的重要原因，预示病情将进展或加重。

Objective To investigate the impact of cytotoxic T lymphocyte （CTL） epitope mutation of HBV envelope and core protein on disease progress in patients with hepatitis B. Methods 38 individuals with asymptomatic HBsAg carrier,35 patients with chronic hepatitis B and 23 with liver cirrhosis were recruited in this study. Gene sequencing analysis of HBV core region and envelope region was carried out in all enrolled patients to unveil any possible CTL epitope mutation. Results The mutation rates of locus 41~49,88-96,97~108,172~180 and 185~194 of CTL epitope in HBV envelope region were 48（55.2%）,13（14.9%）,11（12.6%）,9（10.3%） and 6 （6.9%）,respectively;60% of mutation at locus 41-49 in patients with chronic hepatitis B and 65.2% in with liver cirrhosis were significantly higher than 31.6% in asymptomatic HBsAg carriers（P〈0.05）;the mutation rates at 18~27 and 91-95 locus of CTL epitope in HBV core region were 56.2% and 43.8% ,respectively;the mutation rates at locus 18-27 were also higher in patients with CHB （20.0%） and LC （30.4%） than that in asymptomatie HBsAg carriers （10.5% ,P〈0.05 ）;Multivariate analysis showed that locus 41--49 mutation was an independent risk factor for the progress of CHB to LC. Conclusion CTL epitope mutation of HBV is a significant cause for the chronicity of hepatitis B virus infection.