Identification of sequential viral escape mutants associated with altered T-cell responses in a human immunodeficiency virus type 1-infected individual
Identification of sequential viral escape mutants associated with altered T-cell responses in a human immunodeficiency virus type 1-infected individual
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DOI：
10.1128/jvi.77.23.12430-12440.2003
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发表时间：
2003-12-01
影响因子：
5.4
通讯作者：
Goudsmit, J
中科院分区：
文献类型：
--
作者：
Geels, MJ;Cornelissen, M;Goudsmit, J
人类自然感染人类免疫缺陷病毒1型（HIV-1）的病毒血症的控制与病毒特异性T细胞反应有关。然而，关于成功控制HIV-1感染所需的CD 8（+）细胞毒性T淋巴细胞（CTL）应答的程度以及CTL表位逃逸在多大程度上可以解释病毒载量的升高和最终疾病的进展，仍然有很多未知数。在这项研究中，我们选择通过全长基因组序列的复制能力的生物克隆预测的CTL表位内发生的修改，并确定是否改变导致表位逃避CTL识别监测。通过对一个病毒载量升高的个体在4年内产生的59个HIV-1生物克隆的广泛分析，我们确定了5个CD 8（+）CTL表位在基因组中的位置。在p17、gp 120、gp 41、Nef和逆转录酶基因内鉴定了固定突变。使用γ干扰素ELIspot测定，我们确定了四个固定突变的五个表位的T细胞反应性对野生型表位的完全丧失和对突变表位的反应性的部分丧失。这些结果表明，在疾病进展过程中，患者体内CTL逃逸的顺序积累，表明需要T细胞表位的多种组合来控制病毒血症。
Control of viremia in natural human immunodeficiency virus type 1 (HIV-1) infection in humans is associated with a virus-specific T-cell response. However, still much is unknown with regard to the extent of CD8(+) cytotoxic T-lymphocyte (CTL) responses required to successfully control HIV-1 infection and to what extent CTL epitope escape can account for rises in viral load and ultimate progression to disease. In this study, we chose to monitor through full-length genome sequence of replication-competent biological clones the modifications that occurred within predicted CTL epitopes and to identify whether the alterations resulted in epitope escape from CTL recognition. From an extensive analysis of 59 biological HIV-1 clones generated over a period of 4 years from a single individual in whom the viral load was observed to rise, we identified the locations in the genome of five CD8(+) CTL epitopes. Fixed mutations were identified within the p17, gp120, gp41, Nef, and reverse transcriptase genes. Using a gamma interferon ELIspot assay, we identified for four of the five epitopes with fixed mutations a complete loss of T-cell reactivity against the wild-type epitope and a partial loss of reactivity against the mutant epitope. These results demonstrate the sequential accumulation of CTL escape in a patient during disease progression, indicating that multiple combinations of T-cell epitopes are required to control viremia.