The CD4 Binding Site on HIV gp120 as a Vaccine Antigen

作为疫苗抗原的 HIV gp120 上的 CD4 结合位点

• 批准号: 6450263
• 负责人: MARTIN TEINTZE
• 金额: $ 20.77万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6450263
• 关键词: AIDS vaccines; CD4 molecule; HIV envelope protein gp120; X ray crystallography; affinity chromatography; antibody neutralization test; enzyme linked immunosorbent assay; high performance liquid chromatography; human immunodeficiency virus; laboratory mouse; laboratory rabbit; monoclonal antibody; neutralizing antibody; nuclear magnetic resonance spectroscopy; peptide library; recombinant proteins; recombinant virus; synthetic peptide; vaccine development

DESCRIPTION: (Provided by Applicant) Design of an effective vaccine against HIV must take into account the high degree of variability in the sequence of the envelope proteins that has been observed in clinical isolates, and the high mutation rate of the virus. The envelope glycoprotein gp120 and its precursor gp160 have been ineffective against clinical isolates of HIV when used as vaccine candidates. HIV-neutralizing antibodies are elicited primarily against the third variable (V3) loop of the sequence. Late in HIV infection, however, neutralizing antibodies with broader strain specificity are produced which appear to be directed at the three-dimensional shape of the CD4 binding site. Our hypothesis is that this part of gp120 will make a more effective vaccine antigen than the whole protein. We therefore want to construct recombinant or synthetic molecules that display this conformation-dependent structure. Our immediate goals are to: 1) find peptide structures that can mimic the sites that the neutralizing antibodies bind to; 2) display these peptides on the capsid protein of a plant virus that can be expressed and assembled in yeast, and determine which constructs can bind anti-HIV antibodies; 3) synthesize the peptide sequences and determine their three-dimensional structures when bound to the antibodies; 4) immunize mice and rabbits with the recombinant plant virus protein or synthetic peptide-protein conjugates and determine whether HIV-neutralizing antibodies are produced. The information obtained from X-ray crystallography of the recombinant viruses and peptide-antibody complexes will be used to design better antigens that can elicit a more effective immune response to the virus.

描述：（由申请人提供）有效的艾滋病毒疫苗设计 必须考虑到序列的高度可变性 已在临床分离株中观察到的包膜蛋白，以及高 病毒的突变率。包膜糖蛋白 gp120 及其前体 当用作 gp160 时，gp160 对临床分离的 HIV 无效。 候选疫苗。 HIV 中和抗体主要针对 序列的第三个变量 (V3) 循环。然而，在艾滋病毒感染晚期， 产生具有更广泛菌株特异性的中和抗体， 似乎是针对 CD4 结合位点的三维形状。 我们的假设是 gp120 的这一部分将制成更有效的疫苗 抗原高于全蛋白。因此，我们想要构建重组或 显示这种构象依赖性结构的合成分子。我们的 近期目标是：1）找到可以模拟这些位点的肽结构 中和抗体结合； 2) 将这些肽展示在 植物病毒的衣壳蛋白，可以在酵母中表达和组装， 并确定哪些构建体可以结合抗HIV抗体； 3）综合 肽序列并确定其结合时的三维结构 抗体； 4) 用重组植物免疫小鼠和兔子 病毒蛋白或合成肽-蛋白缀合物并确定是否 产生 HIV 中和抗体。从X射线获得的信息 重组病毒和肽-抗体复合物的晶体学将 用于设计更好的抗原，从而引发更有效的免疫 对病毒的反应。