Interdisciplinary Analysis of HIV-Specific CD8+ T Cell Responses against Variant Epitopes Reveals Restricted TCR Promiscuity
Interdisciplinary Analysis of HIV-Specific CD8+ T Cell Responses against Variant Epitopes Reveals Restricted TCR Promiscuity
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DOI：
10.4049/jimmunol.0903516
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发表时间：
2010-05-01
影响因子：
4.4
通讯作者：
Karlsson, Annika C.
中科院分区：
文献类型：
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作者：
Hoof, Ilka;Perez, Carina L.;Karlsson, Annika C.
HIV-1特异性CTL应答在限制病毒复制中起关键作用。CTL应答对影响病毒识别的病毒逃逸突变敏感。虽然CTL已被证明识别表位变体，但这种交叉反应性的程度尚未在遗传多样性的HIV-1感染患者队列中进行定量研究。本研究采用一种新的生物信息学结合预测方法，旨在根据患者的HLA基因型和自体病毒序列定量解释表位特异性CTL应答的模式。从26名研究受试者中获得覆盖HIV-Gag、Pol和Nef区域内预测和测试的HLA I类限制性表位（肽）的序列，得到1492个患者特异性肽对。发现在ELISPOT测定中识别的表位与未引起应答的表位相比，与自体病毒显著更相似。所呈现的表位中的单个取代使CTL应答的机会降低了40%。序列相似性对交叉识别的影响通过测试针对六个选定表位的多个变体的免疫应答来证实。表位中心位置的取代特别可能导致识别的废除。总之，所呈现的数据证明了HIV-1特异性CTL在识别变体表位中的高度限制的混杂性。此外，我们的研究结果表明，生物信息学预测方法是有用的，以研究复杂的模式表现出的HIV-1感染的患者队列的CTL反应，并确定新的治疗或疫苗的方法的最佳目标。免疫学杂志，2010，184：5383-5391。
HIV-1 specific CTL responses play a key role in limiting viral replication. CTL responses are sensitive to viral escape mutations, which influence recognition of the virus. Although CTLs have been shown to recognize epitope variants, the extent of this cross-reactivity has not been quantitatively investigated in a genetically diverse cohort of HIV-1 infected patients. Using a novel bioinformatic binding prediction method, we aimed to explain the pattern of epitope-specific CTL responses based on the patients' HLA genotype and autologous virus sequence quantitatively. Sequences covering predicted and tested HLA class I-restricted epitopes (peptides) within the HIV-Gag, Pol, and Nef regions were obtained from 26 study subjects resulting in 1492 patient-specific peptide pairs. Epitopes that were recognized in ELISPOT assays were found to be significantly more similar to the autologous virus than those that did not elicit a response. A single substitution in the presented epitope decreased the chance of a CTL response by 40%. The impact of sequence similarity on cross-recognition was confirmed by testing immune responses against multiple variants of six selected epitopes. Substitutions at central positions in the epitope were particularly likely to result in abrogation of recognition. In summary, the presented data demonstrate a highly restricted promiscuity of HIV-1 specific CTL in the recognition of variant epitopes. In addition, our results illustrate that bioinformatic prediction methods are useful to study the complex pattern of CTL responses exhibited by an HIV-1 infected patient cohort and for identification of optimal targets for novel therapeutic or vaccine approaches. The Journal of Immunology, 2010, 184: 5383-5391.