TOPOLOGICAL ANALYSIS OF HIV-1 ENVELOPE GLYCOPROTEINS

HIV-1 包膜糖蛋白的拓扑分析

• 批准号: 2413804
• 负责人: JOHN P MOORE
• 金额: $ 23.59万
• 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 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2413804
• 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：（摘自申请人摘要）信封 糖蛋白是体液免疫的主要靶点， HIV-1感染，因此是疫苗开发的主要焦点。 尽管包膜糖蛋白可以重组表达， 免疫原性蛋白质，似乎这些蛋白质是 不足以提供对HIV-1感染的保护性免疫。 一 促成因素是包膜糖蛋白不能引起 能够中和主要HIV-1分离株的抗体， 效力，尽管它们能够诱导能够中和 T细胞系适应菌株。 尽管存在中和 重组蛋白上的抗体表位， 在人中产生的针对这些表位的抗体可以 从而损害这些免疫原的实际功效。 理解 这些观察的基础将有助于设计一个新的 产生的免疫原，可能更好地引发抗体有效 抗HIV-1病毒的能力 首席研究员的方法 问题的关键是要更好地了解 包膜糖蛋白，了解关键中和抗体表位 呈现在这些蛋白质上。 他所选择的方法， 单体和寡聚体形式的gp 120和gp 160的拓扑结构， 针对连续和不连续表位的单克隆抗体， 他能够部分或全部地定义。 他不仅要学习 T细胞系适应菌株的包膜糖蛋白， 第一代亚单位疫苗，还有来自 主要分离物。 以及gp 120单体，他将研究 含有gp 120部分的可溶性gp 160分子的构象 连接到gp 41的胞外域，因为这种类型的蛋白质在 考虑作为疫苗免疫原。 他还将研究 表面上最天然形式的包膜糖蛋白 病毒体和病毒感染细胞的细胞。 这些研究旨在 增加我们对抗原性和免疫原性的理解， 参与产生体液免疫的关键病毒蛋白 抗HIV-1，并可能提供信息，以促进发展 新一代艾滋病毒疫苗的性能得到改善。