Altering effects of antigenic variations in HIV-1 on antiviral effectiveness of HIV-specific CTLs
Altering effects of antigenic variations in HIV-1 on antiviral effectiveness of HIV-specific CTLs
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DOI：
10.4049/jimmunol.178.9.5513
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发表时间：
2007-05-01
影响因子：
4.4
通讯作者：
Takiguchi, Masafumi
中科院分区：
文献类型：
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作者：
Ueno, Takamasa;Idegami, Yuka;Takiguchi, Masafumi
HIV-1从已建立的CTL应答中的突变逃逸正变得越来越明显。然而，目前尚不清楚HIV-1的抗原变异是否可能对HIV特异性CTL的不同抗病毒效力产生额外影响。在此，我们的特点是HIV-1感染的慢性期对Pol，Env和Nef的最佳表位HLA-B*35提出的HIV特异性CTL反应。我们在Pol和Nef表位内发现了CTL逃逸变体，这些变体影响TCR的识别，尽管Env表位内没有突变。肽-HLA四聚体复合物的分析显示，在变体病毒的支配下产生了对Nef变体特异性的CD 8 T细胞。变体特异性细胞能够杀死靶细胞并产生抗病毒细胞因子，但表现出体外Ag特异性增殖受损，而野生型特异性细胞具有强效活性。此外，对Pol变体特异性的克隆型CD 8 T细胞显示增殖减少，而Env特异性的细胞没有功能异质性。两者合计，我们的数据表明，抗原变异，废除TCR识别不仅导致逃脱既定的CTL反应，但最终也产生了另一个子集的变体特异性CTL具有降低的抗病毒活性，导致在慢性HIV感染的抗病毒免疫反应的额外的负面影响。
The mutational escape of HIV-1 from established CTL responses is becoming evident. However, it is not yet clear whether antigenic variations of HIV-1 may have an additional effect on the differential antiviral effectiveness of HIV-specific CTLs. Herein, we characterized HIV-specific CTL responses toward Pol, Env, and Nef optimal epitopes presented by HLA-B*35 during a chronic phase of HIV-1 infection. We found CTL escape variants within Pol and Nef epitopes that affected recognition by TCRs, although there was no mutation within the Env epitope. An analysis of peptide-HLA tetrameric complexes revealed that CD8 T cells exclusively specific for the Nef variant were generated following domination by the variant viruses. The variant-specific cells were capable of killing target cells and producing antiviral cytokines but showed impaired Ag-specific proliferation ex vivo, whereas wild-type specific cells had potent activities. Moreover, clonotypic CD8 T cells specific for the Pol variant showed diminished proliferation, whereas Env-specific ones had no functional heterogeneity. Taken together, our data indicate that antigenic variations that abolished TCR recognition not only resulted in escape from established CTL responses but also eventually generated another subset of variant-specific CTLs having decreased antiviral activity, causing an additional negative effect on antiviral immune responses during a chronic HIV infection.