Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance
Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance
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DOI：
10.1038/ni.1728
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发表时间：
2009-06-01
影响因子：
30.5
通讯作者：
Iversen, Astrid K. N.
中科院分区：
文献类型：
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作者：
Tenzer, Stefan;Wee, Edmund;Iversen, Astrid K. N.
虽然感染人类免疫缺陷病毒1型的人体内的细胞毒性T淋巴细胞（ctl）可以潜在地靶向多个病毒表位，但相同的少数是重复识别的。我们在这里表明，人类免疫缺陷病毒1型组相关抗原蛋白p17和p24区域的CTL免疫优势与表位丰度相关，这受到蛋白酶体消化谱、对转运蛋白TAP的亲和力和内质网氨基肽酶ERAAP介导的修剪的强烈影响，并受到HLA亲和力的适度影响。结构和功能分析表明，蛋白酶体切割的“偏好”调节了含有表位肽的数量和长度，从而影响T细胞的反应速度和克隆性。切割模式受到侧翼和表位内ctl逃逸突变的影响。我们的分析表明，抗原加工塑造了CTL反应等级，病毒进化改变了裂解模式，并为体外疫苗优化提供了策略。
Although cytotoxic T lymphocytes (CTLs) in people infected with human immunodeficiency virus type 1 can potentially target multiple virus epitopes, the same few are recognized repeatedly. We show here that CTL immunodominance in regions of the human immunodeficiency virus type 1 group-associated antigen proteins p17 and p24 correlated with epitope abundance, which was strongly influenced by proteasomal digestion profiles, affinity for the transporter protein TAP, and trimming mediated by the endoplasmatic reticulum aminopeptidase ERAAP, and was moderately influenced by HLA affinity. Structural and functional analyses demonstrated that proteasomal cleavage 'preferences' modulated the number and length of epitope-containing peptides, thereby affecting the response avidity and clonality of T cells. Cleavage patterns were affected by both flanking and intraepitope CTL-escape mutations. Our analyses show that antigen processing shapes CTL response hierarchies and that viral evolution modifies cleavage patterns and suggest strategies for in vitro vaccine optimization.