Enhanced immunogenicity of HIV-1 vaccine construct by modification of the native peptide sequence
Enhanced immunogenicity of HIV-1 vaccine construct by modification of the native peptide sequence
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DOI：
10.1073/pnas.94.20.10856
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发表时间：
1997-09-30
影响因子：
11.1
通讯作者：
Berzofsky, JA
中科院分区：
文献类型：
--
作者：
Ahlers, JD;Takeshita, T;Berzofsky, JA
病毒蛋白并非自然选择高亲和力的主要组织相容性复合体 (MHC) 结合序列；事实上，如果有任何选择，它本质上很可能是阴性的。因此，在合成肽疫苗的合理设计中应该能够增加病毒肽与MHC的结合。 HIV-1包膜蛋白前面的TI辅助肽通过替换对与MHC II类分子的肽结合产生不利影响的残基而变得更具免疫原性，用于诱导T细胞增殖到天然序列。用结合更有效的Th辅助（Th）表位与细胞毒性T淋巴细胞（CTL）决定簇的疫苗构建体免疫的小鼠产生了大大增强的CTL反应，使用II类MHC同源小鼠证实CTL反应的增强是由于类II 限制性帮助，因此，增强 T 细胞帮助是最佳诱导 CTL 的关键，并且通过修饰天然免疫原以增加与 MHC 的结合，有可能开发出增强 Th 细胞激活和 CTL 诱导的第二代疫苗构建体。
Viral proteins are not naturally selected for high affinity major histocompatibility complex (MHC) binding sequences; indeed, if there is any selection, it is;likely to be negative in nature, Thus, one should be able to increase viral peptide binding to MHC in the rational design of synthetic peptide vaccines. The TI helper peptide front the HIV-I envelope protein was made more immunogenic for inducing T cell proliferation to the native sequence by replacing a residue that exerts an adverse influence on peptide binding to an MHC class II molecule, Mice immunized with vaccine constructs combining the more potent Th helper (Th) epitope with a cytotoxic T lymphocyte (CTL) determinant developed greatly enhanced CTL responses, Use of class II MHC-congenic mice confirmed that the enhancement of CTL response was due to class II-restricted help, Thus, enhanced T cell help is key for optimal induction of CTL, and, by modification of the native immunogen to increase binding to MHC, it is possible to develop second generation vaccine constructs that enhance both Th cell activation and CTL induction.