Antigenic characteristics of rhinovirus chimeras designed in silico for enhanced presentation of HIV-1 gp41 epitopes [corrected].
Antigenic characteristics of rhinovirus chimeras designed in silico for enhanced presentation of HIV-1 gp41 epitopes [corrected].
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DOI：
10.1016/j.jmb.2010.01.064
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发表时间：
2010-04-02
影响因子：
5.6
通讯作者：
Levy RM
中科院分区：
文献类型：
--
作者：
Lapelosa M;Arnold GF;Gallicchio E;Arnold E;Levy RM
研制有效的艾滋病疫苗仍然是防治人体免疫缺陷病毒（艾滋病毒）/艾滋病最有希望的长期战略。在这里，我们报告了从人类鼻病毒组合文库中分离的候选疫苗的良好抗原特性，这些候选疫苗显示HIV-1的gp41糖蛋白的ELDKWA表位。该库的设计原则来自于分子建模计算的应用，并结合我们之前获得的显示eldkwa嵌合体的知识，包括迄今为止获得的具有最佳2f5结合特性的嵌合体的知识。分子模型计算确定了影响表位能力的能量和结构因素，这些因素能够适应eldkwa结合的互补决定区域，广泛中和人单抗2F5。通过竞争性免疫选择从文库中分离出单个病毒，采用ELISA和荧光猝灭实验进行检测。使用这两种技术获得的解离常数显示，一些新分离的嵌合体与2F5的结合比以前鉴定的嵌合鼻病毒具有更大的亲和力。对这两种嵌合体的分子动力学模拟证实，它们的HIV插入部分预先组织了结合，这在很大程度上是它们相应的结合亲和力增加的原因。该研究表明，将基于结构的实验与计算建模方法相结合，可以提高选择具有首选抗原特征的疫苗成分设计的几率。获得的结果还证实了HRV作为HIV表位呈递载体的灵活性，以及这一平台在开发抗艾滋病疫苗成分方面的潜力。
The development of an effective AIDS vaccine remains the most promising long-term strategy to combat human immunodeficiency virus (HIV)/AIDS. Here, we report favorable antigenic characteristics of vaccine candidates isolated from a combinatorial library of human rhinoviruses displaying the ELDKWA epitope of the gp41 glycoprotein of HIV-1. The design principles of this library emerged from the application of molecular modeling calculations in conjunction with our knowledge of previously obtained ELDKWA-displaying chimeras, including knowledge of a chimera with one of the best 2F5-binding characteristics obtained to date. The molecular modeling calculations identified the energetic and structural factors affecting the ability of the epitope to assume conformations capable of fitting into the complementarity determining region of the ELDKWA-binding, broadly neutralizing human mAb 2F5. Individual viruses were isolated from the library following competitive immunoselection and were tested using ELISA and fluorescence quenching experiments. Dissociation constants obtained using both techniques revealed that some of the newly isolated chimeras bind 2F5 with greater affinity than previously identified chimeric rhinoviruses. Molecular dynamics simulations of two of these same chimeras confirmed that their HIV inserts were partially preorganized for binding, which is largely responsible for their corresponding gains in binding affinity. The study illustrates the utility of combining structure-based experiments with computational modeling approaches for improving the odds of selecting vaccine component designs with preferred antigenic characteristics. The results obtained also confirm the flexibility of HRV as a presentation vehicle for HIV epitopes and the potential of this platform for the development of vaccine components against AIDS.
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影响因子：
3
作者：
Gallicchio, Emilio;Levy, Ronald M.;Parashar, Manish
通讯作者：
Parashar, Manish
影响因子：
5.4
作者：
Arnold, Gail Ferstandig;Velasco, Paola K.;Arnold, Eddy
通讯作者：
Arnold, Eddy
影响因子：
2.9
作者：
Felts, AK;Harano, Y;Levy, RM
通讯作者：
Levy, RM
影响因子：
3.8
作者：
Matyas, Gary R.;Wieczorek, Lindsay;Alving, Carl R.
通讯作者：
Alving, Carl R.
影响因子：
3.7
作者：
Hinz, Andreas;Schoehn, Guy;Weissenhorn, Winfried
通讯作者：
Weissenhorn, Winfried