HIV Vaccines Based on GP120-CD4 Mimetic Complexes

基于 GP120-CD4 模拟复合物的 HIV 疫苗

• 批准号: 7121362
• 负责人: Anthony L DeVico
• 金额: $ 6.43万
• 依托单位: UNIVERSITY OF MD BIOTECHNOLOGY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121362
• 关键词: AIDS education /prevention; AIDS therapy; AIDS vaccines; HIV envelope protein gp120; T lymphocyte; affinity chromatography; antigen antibody reaction; biomimetics; biotechnology; cellular immunity; laboratory rabbit; neutralizing antibody; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): The ultimate means for stopping the HIV epidemic is a prophylactic vaccine that blocks virus transmission in the general population. It is now accepted that such a vaccine will have to elicit anti-HIV antibody responses as well as cellular immunity to provide protection. What is desperately needed to meet this goal is an immunogen that will elicit broadly neutralizing antibodies capable of preventing (neutralizing) infection by primary HIV strains found worldwide. Our approach toward developing such an immunogen is based on the "constrained" transition state structure of gpl20 that is induced by CD4 binding. In previous studies, we showed that crosslinked gpl20-soluble CD4 complexes elicited antibodies in macaques that neutralized a wide variety of primary isolates regardless of Clade. We also showed that these "broadly neutralizing" antibodies were isolated from immune sera by affinity chromatography with a constrained single chain complex (called SCBaL/M9) containing gpl20 linked to a CD4 mimetic miniprotein (CD4M9). Thus, single chain gpl20-CD4 mimetic complexes warrant exploration as vaccine subunit immunogens to safely elicit broadly neutralizing antibodies in humans. However, in preliminary experiments SCBaL/M9 elicited broadly neutralizing antibodies less efficiently than a single chain gpl20-CD4 complex (FLSC). Such inefficiency can be logically interpreted to mean that a variable fraction of the SCBaL/M9 immunogen loses its intrachain complex and fails to present a constrained gpl20 structure. Such instability is predicted given that the CD4M9 sequence has a binding affinity for gp 120 that is only about 1% that of CD4. In agreement, other preliminary studies show that the intramolecular interactions in SCBaL/M9 are less stable than in FLSC. Accordingly, our central hypothesis, which will be evaluated in this project, is that the immunogenicity of SCBaL/M9 will be improved by sequence modifications that produce highly stabilized intramolecular complexes. In order to explore this hypothesis, Aim 1 of this project will be to design and evaluate modified versions of SCBaL/M9 for improved intrachain binding stability. Aim 2 will be to compare the immunogenicity of modified complexes versus SCBaL/M9 in rabbits. We expect these efforts to yield new candidate immunogens that can be feasibly used to elicit broadly neutralizing antibodies in a variety of vaccine contexts.

描述（由申请人提供）：阻止艾滋病毒流行的最终手段是预防性疫苗，它可以阻止病毒在普通人群中传播。现在人们普遍认为，这种疫苗必须引发抗艾滋病毒抗体反应以及细胞免疫才能提供保护。实现这一目标迫切需要一种免疫原，该免疫原将引发广泛中和抗体，从而能够预防（中和）世界范围内发现的主要艾滋病毒株的感染。 我们开发这种免疫原的方法是基于由CD4结合诱导的gp120的“受限”过渡态结构。在之前的研究中，我们表明，交联的gp120可溶性CD4复合物在猕猴中引发抗体，该抗体中和多种初级分离株，无论进化枝如何。我们还表明，这些“广泛中和”抗体是通过亲和层析从免疫血清中分离出来的，其中使用含有与CD4模拟小蛋白（CD4M9）连接的gp120的约束单链复合物（称为SCBaL/M9）。因此，单链gp120-CD4模拟复合物值得探索作为疫苗亚基免疫原以在人类中安全地引发广泛中和抗体。然而，在初步实验中，SCBaL/M9引发广泛中和抗体的效率低于单链gp120-CD4复合物(FLSC)。这种低效率可以在逻辑上解释为意味着SCBaL/M9免疫原的可变部分失去其链内复合物并且无法呈现受约束的gp120结构。鉴于 CD4M9 序列对 gp 120 的结合亲和力仅为 CD4 的约 1%，因此预测了这种不稳定性。与此一致的是，其他初步研究表明 SCBaL/M9 中的分子内相互作用不如 FLSC 中的稳定。因此，我们的中心假设（将在本项目中进行评估）是 SCBaL/M9 的免疫原性将通过产生高度稳定的分子内复合物的序列修饰来提高。为了探索这一假设，该项目的目标 1 将是设计和评估 SCBaL/M9 的修改版本，以提高链内结合稳定性。目标 2 是比较修饰复合物与 SCBaL/M9 在兔子中的免疫原性。我们期望这些努力能够产生新的候选免疫原，这些免疫原可切实用于在各种疫苗环境中引发广泛中和抗体。