TOPOLOGICAL ANALYSIS OF HIV-1 ENVELOPE GLYCOPROTEINS

HIV-1 包膜糖蛋白的拓扑分析

• 批准号: 2887144
• 负责人: JOHN P MOORE
• 金额: $ 25.49万
• 依托单位: AARON DIAMOND AIDS RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887144
• 关键词: HIV envelope protein gp120; HIV envelope protein gp160; epitope mapping; glycoprotein structure; human immunodeficiency virus 1; tissue /cell culture

DESCRIPTION : (Adapted from applicant's abstract) The envelope glycoproteins are the principal targets for humoral immunity against HIV-1 infection, and are therefore a major focus of vaccine development. Although the envelope glycoproteins can be expressed as recombinant proteins that are immunogenic, it appears that these proteins are insufficient to provide protective immunity to HIV-1 infection. One contributing factor is the inability of envelope glycoproteins to elicit antibodies able to neutralize primary HIV-1 isolates with significant potency, despite their ability to induce antibodies able to neutralize T-cell line adapted strains. Despite the presence of neutralizing antibody epitopes on the recombinant proteins, the inefficiency with which antibodies against these epitopes are generated in humans may compromise the practical efficacy of these immunogens. Understanding the basis of these observations would facilitate the design of a new generation of immunogens that might better elicit antibodies effective against primary HIV-1 isolates. The principal investigator's approach to the problem is to gain a better understanding of the structure of the envelope glycoproteins, to learn how key neutralizing antibody epitopes are presented on these proteins. The methods he has chosen probe the topology of both monomeric and oligomeric forms of gp120 and gp160 with monoclonal antibodies against continuous and discontinuous epitopes that he is able to partially or totally define. He will study not only the envelope glycoproteins of T-cell line-adapted strains that were used in the first generation of subunit vaccines, but also proteins derived from primary isolates. As well as gp120 monomers, he will investigate the conformation of soluble gp160 molecules that contain the gp120 moiety linked to the ectodomain of gp41, because proteins of this type are under consideration as vaccine immunogens. He will also study the conformation of the envelope glycoproteins in their most native forms on the surfaces of virions and virus-infected cells. These studies are aimed at increasing our understanding of the antigenicity and immunogenicity of key viral proteins involved in the generation of humoral immunity against HIV-1, and may provide information to facilitate the development of new generations of HIV vaccines with improved performance.

描述：（改编自申请人的摘要）信封 糖蛋白是抗体液免疫的主要靶标 HIV-1感染，因此是疫苗开发的主要重点。 尽管信封糖蛋白可以表示为重组 免疫原性的蛋白质，看来这些蛋白质是 不足以提供对HIV-1感染的保护性免疫。 一 促成因素是信封糖蛋白无法引起的因素 能够中和具有显着的原代HIV-1分离株的抗体 效力，尽管它们能够诱导能够中和的抗体 T细胞线适应应变。 尽管存在中和 重组蛋白上的抗体表位，效率低下 人类产生了针对这些表位的哪些抗体 损害了这些免疫原子的实际功效。 理解 这些观察的基础将促进新的设计 产生可能会更好地引起抗体有效的免疫原子 针对原发性HIV-1分离株。 主要研究者的方法 解决问题是更好地理解 包膜糖蛋白，了解钥匙中和抗体表位如何 在这些蛋白质上呈现。 他选择了探测的方法 GP120和GP160的单体和寡聚形式的拓扑结构 抗连续和不连续表位的单克隆抗体 他能够部分或完全定义。 他不仅会学习 T细胞线适应菌株的包膜糖蛋白用于 第一代亚基疫苗，但也源自 主要分离株。 除GP120单体外，他还将调查 包含GP120部分的可溶性GP160分子的构象 与gp41的外生域相关，因为这种类型的蛋白质在下面 考虑为疫苗免疫原。 他还将研究构象 在表面上最本地形式的信封糖蛋白的 病毒体和病毒感染的细胞。 这些研究针对 提高我们对抗原性和免疫原性的理解 与体液免疫产生有关的关键病毒蛋白 反对HIV-1，并可能提供信息以促进发展 新一代的艾滋病毒疫苗具有改善的性能。