Impaired Processing and Presentation of Cytotoxic-T-Lymphocyte (CTL) Epitopes Are Major Escape Mechanisms from CTL Immune Pressure in Human Immunodeficiency Virus Type 1 Infection
Impaired Processing and Presentation of Cytotoxic-T-Lymphocyte (CTL) Epitopes Are Major Escape Mechanisms from CTL Immune Pressure in Human Immunodeficiency Virus Type 1 Infection
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DOI：
10.1128/jvi.78.3.1324-1332.2004
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发表时间：
2004-02
影响因子：
5.4
通讯作者：
Y. Yokomaku;H. Miura;H. Tomiyama;A. Kawana-Tachikawa;M. Takiguchi;A. Kojima;Y. Nagai;A. Iwamoto;Z. Matsuda;K. Ariyoshi
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文献类型：
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作者：
Y. Yokomaku;H. Miura;H. Tomiyama;A. Kawana-Tachikawa;M. Takiguchi;A. Kojima;Y. Nagai;A. Iwamoto;Z. Matsuda;K. Ariyoshi
摘要研究人类免疫缺陷病毒1型（HIV-1）逃避细胞毒性T淋巴细胞（CTL）的机制对于了解HIV-1感染的发病机制和开发有效的疫苗至关重要。为了研究已知CTL表位的加工和呈递，我们通过采用水泡性口炎病毒G蛋白假型化的env/nef缺失的HIV-1载体制备了内源性表达6个野毒株gag基因的EB病毒转化的B细胞，然后测试它们对Gag表位特异性CTL系或克隆的识别。我们观察到A*0201限制性Gag CTL表位SLYNTVATL的两个场变体SLFNTVAVL和SVYNTVATL，以及A24限制性Gag CTL表位KYKLKHIVW的三个场变体KYRLKHLVW、QYRLKHIVW和RYRLKHLVW，逃脱了CTL系的杀伤，尽管当对应于这些变体序列的合成肽被外源加载到靶细胞上时，它们被识别。因此，它们的逃逸可能是由于在受感染细胞中表位的加工和呈递期间发生的变化。负责这种逃逸模式的突变位于表位区域而不是侧翼区域，并且这种突变不影响病毒复制。这些结果表明，受损的抗原加工和呈递经常发生在HIV-1野外分离株中，因此是使HIV-1能够逃避CTL识别的主要机制之一。我们强调在内源性表达系统中检测HIV-1变异体的重要性。
ABSTRACT Investigating escape mechanisms of human immunodeficiency virus type 1 (HIV-1) from cytotoxic T lymphocytes (CTLs) is essential for understanding the pathogenesis of HIV-1 infection and developing effective vaccines. To study the processing and presentation of known CTL epitopes, we prepared Epstein-Barr virus-transformed B cells that endogenously express the gag gene of six field isolates by adopting an env/nef-deletion HIV-1 vector pseudotyped with vesicular stomatitis virus G protein and then tested them for the recognition by Gag epitope-specific CTL lines or clones. We observed that two field variants, SLFNTVAVL and SVYNTVATL, of an A*0201-restricted Gag CTL epitope SLYNTVATL, and three field variants, KYRLKHLVW, QYRLKHIVW, and RYRLKHLVW, of an A24-restricted Gag CTL epitope KYKLKHIVW escaped from being killed by the CTL lines, despite the fact that they were recognized when the synthetic peptides corresponding to these variant sequences were exogenously loaded onto the target cells. Thus, their escape is likely due to the changes that occur during the processing and presentation of epitopes in the infected cells. Mutations responsible for this mode of escape were located within the epitope regions rather than the flanking regions, and such mutations did not influence the virus replication. The results suggest that the impaired antigen processing and presentation often occur in HIV-1 field isolates and thus are one of the major mechanisms that enable HIV-1 to escape from CTL recognition. We emphasize the importance of testing HIV-1 variants in an endogenous expression system.