Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, United States of America ; Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey, United States of America.
PLoS One. 2013 Sep 6;8(9):e72205. doi: 10.1371/journal.pone.0072205. eCollection 2013.
The development of an effective AIDS vaccine has been a formidable task, but remains a critical necessity. The well conserved membrane-proximal external region (MPER) of the HIV-1 gp41 glycoprotein is one of the crucial targets for AIDS vaccine development, as it has the necessary attribute of being able to elicit antibodies capable of neutralizing diverse isolates of HIV.
METHODOLOGY/PRINCIPLE FINDINGS: Guided by X-ray crystallography, molecular modeling, combinatorial chemistry, and powerful selection techniques, we designed and produced six combinatorial libraries of chimeric human rhinoviruses (HRV) displaying the MPER epitopes corresponding to mAbs 2F5, 4E10, and/or Z13e1, connected to an immunogenic surface loop of HRV via linkers of varying lengths and sequences. Not all libraries led to viable chimeric viruses with the desired sequences, but the combinatorial approach allowed us to examine large numbers of MPER-displaying chimeras. Among the chimeras were five that elicited antibodies capable of significantly neutralizing HIV-1 pseudoviruses from at least three subtypes, in one case leading to neutralization of 10 pseudoviruses from all six subtypes tested.
Optimization of these chimeras or closely related chimeras could conceivably lead to useful components of an effective AIDS vaccine. While the MPER of HIV may not be immunodominant in natural infection by HIV-1, its presence in a vaccine cocktail could provide critical breadth of protection.
开发有效的艾滋病疫苗一直是一项艰巨的任务，但仍是一项至关重要的需求。HIV-1 gp41 糖蛋白的高度保守的膜近端外区（MPER）是艾滋病疫苗开发的关键目标之一，因为它具有能够引发能够中和多种 HIV 分离株的抗体的必要属性。
方法/原理发现：受 X 射线晶体学、分子建模、组合化学和强大的选择技术的指导，我们设计并生产了六种嵌合人类鼻病毒（HRV）的组合文库，展示了与 mAb 2F5、4E10 和/或 Z13e1 对应的 MPER 表位，通过不同长度和序列的接头连接到 HRV 的免疫原性表面环上。并非所有文库都能产生具有所需序列的可行嵌合病毒，但组合方法允许我们检查大量展示 MPER 的嵌合体。在这些嵌合体中，有五种能够显著中和来自至少三种亚型的 HIV-1 假病毒的抗体，在一种情况下，导致对所有六种亚型测试的 10 个假病毒的中和。
对这些嵌合体或密切相关的嵌合体进行优化，可能会成为有效艾滋病疫苗的有用成分。虽然 HIV 的 MPER 在 HIV-1 自然感染中可能不是免疫优势，但它在疫苗鸡尾酒中的存在可以提供关键的广泛保护。
