Viral Adaptation to Host Immune Responses Occurs in Chronic Hepatitis B Virus (HBV) Infection, and Adaptation Is Greatest in HBV e Antigen-Negative Disease
Viral Adaptation to Host Immune Responses Occurs in Chronic Hepatitis B Virus (HBV) Infection, and Adaptation Is Greatest in HBV e Antigen-Negative Disease
复制标题
DOI：
10.1128/jvi.05308-11
复制
发表时间：
2012-01-01
影响因子：
5.4
通讯作者：
Lewin, Sharon R.
中科院分区：
文献类型：
--
作者：
Desmond, Christopher P.;Gaudieri, Silvana;Lewin, Sharon R.
B型肝炎病毒（HBV）特异性T细胞应答在HBV感染的自然史中是重要的。已知的HBV特异性T细胞表位的数量有限，并且尚不清楚慢性HBV感染中是否发生病毒进化。我们的目的是确定新的HBV T细胞表位，通过检查HBV序列变异和人类白细胞抗原（HLA）类型之间的关系，在一个大型的前瞻性临床队列的亚洲慢性HBV感染患者招募在澳大利亚和中国（n = 119）。对未经治疗的个体进行高分辨率4位数HLA I类和II类分型和全长HBV测序（52%为基因型B，48%为基因型C，63%为HBV e抗原[ HBeAg]阳性）。在HBV基因组的41个位点上，HLA类型和HBV序列变异之间存在统计学显著相关性（n = 49）。使用预测程序，我们确定了含有这些多态性的肽和相关HLA类型之间的结合得分。在可以测试的区域中，HLA结合被预测为14/18（78%）。我们确定了几个HLA相关的多态性，涉及可能已知的锚残基，导致改变预测的结合评分。一些HLA相关的多态性属于已知的T细胞表位与匹配的HLA限制。增强的病毒适应（定义为相关HLA和逃逸氨基酸的存在）与HBeAg阴性疾病独立相关（P = 0.003）。因此，在慢性HBV感染中，特别是在HBeAg阴性的疾病中，HBV似乎受到免疫压力。
Hepatitis B virus (HBV)-specific T-cell responses are important in the natural history of HBV infection. The number of known HBV-specific T-cell epitopes is limited, and it is not clear whether viral evolution occurs in chronic HBV infection. We aimed to identify novel HBV T-cell epitopes by examining the relationship between HBV sequence variation and the human leukocyte antigen (HLA) type in a large prospective clinic-based cohort of Asian patients with chronic HBV infection recruited in Australia and China (n = 119). High-resolution 4-digit HLA class I and II typing and full-length HBV sequencing were undertaken for treatment-naive individuals (52% with genotype B, 48% with genotype C, 63% HBV e antigen [ HBeAg] positive). Statistically significant associations between HLA types and HBV sequence variation were identified (n = 49) at 41 sites in the HBV genome. Using prediction programs, we determined scores for binding between peptides containing these polymorphisms and associated HLA types. Among the regions that could be tested, HLA binding was predicted for 14/18 (78%). We identified several HLA-associated polymorphisms involving likely known anchor residues that resulted in altered predicted binding scores. Some HLA-associated polymorphisms fell within known T-cell epitopes with matching HLA restriction. Enhanced viral adaptation (defined as the presence of the relevant HLA and the escaped amino acid) was independently associated with HBeAg-negative disease (P = 0.003). Thus, HBV appears to be under immune pressure in chronic HBV infection, particularly in HBeAg-negative disease.