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目的 :探讨重庆地区乙型肝炎病毒(hepatitis B virus,HBV)疫苗免疫失败儿童患者体内病毒表面抗原(surface gene)基因主要亲水区(major hydrophilic region,MHR)及a决定簇变异情况。方法:收集乙型肝炎病毒疫苗免疫保护失败患儿及未接种疫苗的乙型肝炎病毒感染患儿血清样本,通过扩增HBV S基因并测序,与相应基因型的标准序列进行比对分析。结果:243例免疫保护失败患儿体内病毒a决定簇突变检出率明显高于20例未经疫苗免疫组患儿(31.7%vs.10.0%,P=0.044);免疫失败组儿童体内病毒MHR突变率数值也高于未接种组儿童,在统计学上差异不显著(49.8%vs.30.0%,P=0.106)。在疫苗免疫失败儿童病例中,MHR和a决定簇突变发生与病毒低水平复制相关:突变组患儿DNA滴度均明显低于无突变组患儿(log106.9±1.8vs.log107.7±1.8,P=0.000;log107.1±1.6 vs.log107.6±1.9,P=0.000)。免疫失败儿童病例中,MHR突变组儿童谷丙转氨酶(alanine aminotransferase,ALT)数值也明显高于未突变组(67.1±58.8 vs.56.5±51.8,P=0.018)。在243例疫苗免疫保护失败儿童体内病毒MHR区域中共检出145个变异氨基酸,热点变异类型主要包括I110L(6例)、K122R(15例)、T126A(18例)、I126T(14例)、M133L(7例)、G145R(6例)及Y161F(12例)等。进一步分析各类型突变与临床表型间差异,发现含G145R及Y161F突变病例体内血清病毒DNA水平明显低于无突变组(log106.8±1.1 vs.log107.5±1.8,P=0.048;log105.0±2.6 vs.log107.3±1.8,P=0.000)。结论:疫苗免疫保护失败儿童病例体内病毒a决定簇及MHR具有较高的突变率,且该区段的突变与病毒较低的复制水平及及较高的ALT相关。
Objective: To investigate the variation of major hydrophilic region (MHR) and a-determinant of viral surface gene in children with failed immunocompromised hepatitis B virus vaccine in Chongqing. Methods: Serum samples from children with unhealthy hepatitis B virus infection and unvaccinated children with hepatitis B virus infection were collected. The HBV S gene was amplified and sequenced, and compared with the corresponding standard genotypes. Results: The detection rate of the mutation of virus a in 243 children with immune protection failure was significantly higher than that in 20 children without vaccine immunization (31.7% vs. 10.0%, P = 0.044). In children with immune failure, the virus MHR The mutation rate was also higher in unvaccinated children, with no statistically significant difference (49.8% vs. 30.0%, P = 0.106). In children with failed vaccine immunization, mutations in the MHR and a determinants were associated with low levels of viral replication: DNA titres in the mutated group were significantly lower than those in the non-mutated group (log106.9 ± 1.8 vs. rs107.7 ± 1.8, P = 0.000; log107.1 ± 1.6 vs. log107.6 ± 1.9, P = 0.000). Children with immunocompromised children also had significantly higher alanine aminotransferase (ALT) values than those who did not (67.1 ± 58.8 vs.56.5 ± 51.8, P = 0.018). A total of 145 variant amino acids were detected in the virus MHR region of 243 children with failed immune protection. The types of hot spot mutations included I110L (6 cases), K122R (15 cases), T126A (18 cases), I126T (14 cases), M133L (7 cases), G145R (6 cases) and Y161F (12 cases). Further analysis of the differences between the various types of mutations and clinical phenotypes found that the serum levels of the virus DNA in the G145R and Y161F mutant cases were significantly lower than those in the non-mutant group (log106.8 ± 1.1 vs.log107.5 ± 1.8, P = 0.048; log105. 0 ± 2.6 vs. log 107.3 ± 1.8, P = 0.000). CONCLUSIONS: The viral a determinant and MHR in children with failed vaccine immunoprotection have a high mutation rate and the mutation in this segment is associated with a lower replication level of the virus and with a higher ALT.