Engineering immunogenic consensus T helper epitopes for a cross-clade HIV vaccine
Engineering immunogenic consensus T helper epitopes for a cross-clade HIV vaccine
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DOI：
10.1016/j.ymeth.2004.06.003
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发表时间：
2004-12-01
期刊：
影响因子：
4.8
通讯作者：
Martin, W
中科院分区：
文献类型：
--
作者：
De Groot, AS;Bishop, EA;Martin, W
由于HIV T细胞表位序列的可变性，开发将刺激广泛的HIV特异性T细胞应答的疫苗是困难的，这反过来又是由于HIV-1的高突变率和随之而来的毒株多样性。我们使用EpiMatrix T细胞表位作图工具的新II类版本和Conservatrix从18，313个HIV-1 env序列的数据库中选择高度保守和混杂的II类HLA限制性T细胞表位。选择标准为：（1）由Conservatrix测量的HIV-1株的数量;（2）EpiMatrix评分;和（3）混杂性（肽中含有的独特MHC基序的数量）。使用另一种称为EpiAssembler的疫苗设计工具，一组新的重叠的、保守的和免疫原性的HIV-1肽被工程化，产生扩展的“免疫原性共有”序列。20-23个氨基酸长的免疫原性共有肽的每个重叠9聚体在大量（范围893-2254）个体HIV-1毒株中是保守的，尽管新的肽不代表任何单一的HIV毒株。我们合成了九个代表性的肽。通过ELISpot（γ-干扰素）测定，使用从34名健康的长期非进展者（LT）或中度进展者（MP）供体获得的外周血单核细胞（PBMC）（感染的中位数年数= 8.88，中位数CD 4 T细胞= 595，中位数VL = 1044），评价T辅助细胞对肽的应答。测试了9种肽，其中8种在使用来自LT/MP受试者的PBMC的ELISpot测定中得到确认。这些表位通过9个原始肽的集合中的保守性和EpiMatrix评分1、2、3、5、7、11和14进行排名。这些肽中的五种被选择用于包含在表位驱动的交叉进化枝HIV-1疫苗（GAIA疫苗）中。这些数据证实了生物信息学工具在选择和构建新型“免疫原性共有序列”T细胞表位用于全球相关的HIV疫苗方面的实用性。(C)2004年由Elsevier Inc.出版
Developing a vaccine that will stimulate broad HIV-specific T cell responses is difficult because of the variability in HIV T cell epitope sequences, which is in turn due to the high mutation rate and consequent strain diversity of HIV-1. We used a new Class II version of the EpiMatrix T cell epitope-mapping tool and Conservatrix to select highly conserved and promiscuous Class II HLA-restricted T cell epitopes from a database of 18,313 HIV-1 env sequences. Criteria for selection were: (1) number of HIV-1 strains represented as measured by Conservatrix; (2) EpiMatrix score; and (3) promiscuity (number of unique MHC motifs contained in the peptide). Using another vaccine design tool called the EpiAssembler, a new set of overlapping, conserved and immunogenic HIV-1 peptides were engineered creating extended "immunogenic consensus" sequences. Each overlapping 9-mer of the 20-23 amino acid long immunogenic consensus peptides was conserved in a large number (range 893-2254) of individual HIV-1 strains, although the novel peptides were not representative of any single strain of HIV. We synthesized nine representative peptides. T helper cell responses to the peptides were evaluated by ELISpot (gamma-interferon) assay, using peripheral blood monocytes (PBMC) obtained from 34 healthy long term non-progressor (LT) or moderate-progressor (MP) donors (median years infected = 8.88, median CD4 T cells = 595, median VL = 1044). Nine peptides were tested, of which eight were confirmed in ELISpot assays using PBMC from the LT/MP subjects. These epitopes were ranked by Conservation and EpiMatrix score 1, 2, 3, 5, 7, 11, and 14 out of the set of 9 original peptides. Five of these peptides were selected for inclusion in an epitope-driven cross-clade HIV-1 vaccine (the GAIA vaccine). These data confirm the utility of bioinformatics tools to select and construct novel "immunogenic consensus sequence" T cell epitopes for a globally relevant vaccine against HIV. (C) 2004 Published by Elsevier Inc.