Identification of immunogenic HLA-B7 "Achilles' heel" epitopes within highly conserved regions of HIV
Identification of immunogenic HLA-B7 "Achilles' heel" epitopes within highly conserved regions of HIV
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DOI：
10.1016/j.vaccine.2007.12.004
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发表时间：
2008-06-06
期刊：
影响因子：
5.5
通讯作者：
Martin, William
中科院分区：
文献类型：
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作者：
De Groot, Anne S.;Rivera, Daniel S.;Martin, William
I类人类白细胞抗原分子（HLA）的遗传多态性已被证明决定了对HIV感染的易感性以及发展为艾滋病的速度。特别是，HLA-B7超型已被证明与高病毒载量和疾病的快速进展有关。使用多平台的体内/体外方法，我们前瞻性地鉴定了45个高度保守的、推测的HLA-137限制性HIV CTL表位，并在HLA结合和ELISpot检测中对它们进行了评估。在基于细胞的HLA结合实验中，所有45个表位（100%）与HLA-137结合：28个（62%）具有高亲和力，6个（13%）具有中等亲和力，11个（24%）具有低亲和力。45个多肽中的40个（88%）刺激至少一个受试者的PBMC中的ifn - γ反应。这40个表位中有18个以前没有被描述过；另外8个表位以前未被描述为受B7限制。使用这种计算机筛选方法发现的HLA-B7限制性表位在HIV毒株和分支之间高度保守，并且自HIV-1分离株首次测序以来，在HIV基因组中保守了20多年。这项研究表明，有可能在快速突变的HIV基因组中选择广泛的包含稳定元件的HLA-137限制性表位。这些表位中免疫原性最强的将被包括在GAIA多表位疫苗中。(c) 2007 Elsevier Ltd.版权所有。
Genetic polymorphisms in class I human leukocyte antigen molecules (HLA) have been shown to determine susceptibility to HIV infection as well as the rate of progression to AIDS. In particular, the HLA-B7 supertype has been shown to be associated with high viral loads and rapid progression to disease. Using a multiplatform in sitico/in vitro approach, we have prospectively identified 45 highly conserved, putative HLA-137 restricted HIV CTL epitopes and evaluated them in HLA binding and ELISpot assays. All 45 epitopes (100%) bound to HLA-137 in cell-based HLA binding assays: 28 (62%) bound with high affinity, 6 (13%) peptides bound with medium affinity and 11 (24%) bound with tow affinity. Forty of the 45 peptides (88%) stimulated a IFN-gamma response in PBMC from at least one subject. Eighteen of these 40 epitopes have not been previously described; an additional eight epitopes have not been previously described as restricted by B7. The HLA-B7 restricted epitopes discovered using this in silico screening approach are highly conserved across strains and clades of HIV as well as conserved in the HIV genome over the 20 years since HIV-1 isolates were first sequenced. This study demonstrates that it is possible to select a broad range of HLA-137 restricted epitopes that comprise stable elements in the rapidly mutating HIV genome. The most immunogenic of these epitopes will be included in the GAIA mutti-epitope vaccine. (c) 2007 Elsevier Ltd. All rights reserved.