Dual selection pressure by drugs and HLA class I-restricted immune responses on human immunodeficiency virus type 1 protease
Dual selection pressure by drugs and HLA class I-restricted immune responses on human immunodeficiency virus type 1 protease
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DOI：
10.1128/jvi.01547-06
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发表时间：
2007-03-01
影响因子：
5.4
通讯作者：
Harrer, Thomas
中科院分区：
文献类型：
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作者：
Mueller, Sandra M.;Schaetz, Birgit;Harrer, Thomas
为了确定人类免疫缺陷病毒I型（HIV-1）特异性CD 8（+）T细胞对HIV-1蛋白酶耐药突变发展的影响，我们分析了来自94名HIV-1阳性个体的人类白细胞抗原I类（HLA I类）分型队列的病毒蛋白酶序列。在单变量统计分析（Fisher精确检验）中，次要和主要耐药突变以及药物相关多态性与HLA I类等位基因相关。P值小于等于0.05的所有相关性均被认为是相关的，无需对多次检验进行校正。这些观察到的相关性的一个子集通过酶联免疫斑点试验进行了实验验证，允许定义10个新的表位，这些表位被来自具有适当HLA I类类型的患者的CD 8（+）T细胞识别。蛋白酶中的几种耐药相关突变作为逃逸突变;然而，来自许多患者的细胞仍然能够产生靶向逃逸突变体的CD 8（+）T细胞。这一结果可能表明，在这些患者中，靶向这些表位的CD 8（+）T细胞使用不同的T细胞受体。我们的研究结果支持HLA I类限制性免疫应答在体内塑造HIV-1蛋白酶序列中的基本作用。这一作用可能具有重要的临床意义，无论是对耐药途径的理解和针对耐药HIV-1的治疗性疫苗的设计。
To determine the influence of human immunodeficiency virus type I (HIV-1) -specific CD8(+) T cells on the development of drug resistance mutations in the HIV-1 protease, we analyzed protease sequences from viruses from a human leukocyte antigen class I (HLA class I)-typed cohort of 94 HIV-1-positive individuals. In univariate statistical analyses (Fisher's exact test), minor and major drug resistance mutations as well as drug-associated polymorphisms showed associations with HLA class I alleles. All correlations with P values of 0.05 or less were considered to be relevant without corrections for multiple tests. A subset of these observed correlations vias experimentally validated by enzyme-linked immunospot assays, allowing the definition of 10 new epitopes recognized by CD8(+) T cells from patients with the appropriate HLA class I type. Several drug resistance-associated mutations in the protease acted as escape mutations; however, cells from many patients were still able to generate CD8(+) T cells targeting the escape mutants. This result presumably indicates the usage of different T-cell receptors by CD8(+) T cells targeting these epitopes in these patients. Our results support a fundamental role for HLA class I-restricted immune responses in shaping the sequence of the HIV-1 protease in vivo. This role may have important clinical implications both for the understanding of drug resistance pathways and for the design of therapeutic vaccines targeting drug-resistant HIV-1.