Evolution and transmission of stable CTL escape mutations in HIV infection
Evolution and transmission of stable CTL escape mutations in HIV infection
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DOI：
10.1038/35085576
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发表时间：
2001-07-19
期刊：
影响因子：
64.8
通讯作者：
Walker, BD
中科院分区：
文献类型：
--
作者：
Goulder, PJR;Brander, C;Walker, BD
越来越多的证据表明，细胞毒性T淋巴细胞（CTLs）介导了强大的抗HIV - 1活性（1 - 3）；然而，这种免疫压力对病毒传播和进化的影响尚未确定。在此，我们研究在人类白细胞抗原（HLA）- B27表达情况下的母婴传播，选择进行分析是因为它与成人感染中免疫抑制的延长有关（4）。在成人中，一个主要且高度保守的B27限制性Gag CTL表位发生突变会导致识别丧失和疾病进展（4 - 6）。在表达HLA - B27且在围产期传播HIV - 1的母亲中，我们记录了在这个主要的Gag表位中编码CTL逃逸变体的病毒的传播，这些变体不再与B27结合。她们受感染的婴儿针对一个原本为次要的B27限制性表位，且无法抑制HIV复制。在没有最初选择该突变的进化压力的情况下，这些CTL逃逸变体保持稳定，没有回复突变。这些数据表明，随着疫情的发展，与抑制病毒血症相关的表位中的CTL逃逸突变将会累积，因此对疫苗设计具有重要意义。
Increasing evidence indicates that potent anti-HIV-1 activity is mediated by cytotoxic T lymphocytes (CTLs)(1-3); however, the effects of this immune pressure on viral transmission and evolution have not been determined. Here we investigate mother-child transmission in the setting of human leukocyte antigen (HLA)-B27 expression, selected for analysis because it is associated with prolonged immune containment in adult infection(4). In adults, mutations in a dominant and highly conserved B27-restricted Gag CTL epitope lead to loss of recognition and disease progression(4-6). In mothers expressing HLA-B27 who transmit HIV-1 perinatally, we document transmission of viruses encoding CTL escape variants in this dominant Gag epitope that no longer bind to B27. Their infected infants target an otherwise subdominant B27-restricted epitope and fail to contain HIV replication. These CTL escape variants remain stable without reversion in the absence of the evolutionary pressure that originally selected the mutation. These data suggest that CTL escape mutations in epitopes associated with suppression of viraemia will accumulate as the epidemic progresses, and therefore have important implications for vaccine design.