TOPOLOGICAL ANALYSIS OF HIV-1 ENVELOPE GLYCOPROTEINS

HIV-1 包膜糖蛋白的拓扑分析

• 批准号: 6373512
• 负责人: JOSEPH G SODROSKI
• 金额: $ 31.36万
• 依托单位: DANA-FARBER CANCER INST
• 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 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6373512
• 关键词: HIV envelope protein gp120; HIV envelope protein gp160; glycoprotein structure; human immunodeficiency virus 1; neutralizing antibody

DESCRIPTION (Adapted from Applicant's Abstract): The basic goal of this proposal is to understand the structural differences that exist between two highly related forms of the HIV glycoprotein that differ markedly in neutralization sensitivity through the use of chimeric env genes and antibody probes. The authors argue that the development of an effective and safe human immunodeficiency virus (HIV-1) vaccine would benefit greatly from an understanding of protective immune responses. In several animal models, including the infection of macaques with simian-human immunodeficiency viruses (SHIVs), neutralizing antibodies against the challenge virus can mediate protection. However, the applicants point out that two difficulties face the practical utilization of neutralizing antibodies for HIV-1 prophylaxis: a) the diversity of the HIV-1 envelope glycoproteins, the major target for neutralizing antibodies; and b) the relative resistance of primary HIV-1 isolates, compared with laboratory-adapted virus strains, to neutralization by antibodies. Although the major variable loops of the gp120 external envelope glycoprotein are known to contribute to these properties, understanding of the structure of these determinants lags behind that of more conserved envelope glycoprotein components. Results from the PI's laboratory have shown that in vivo passage of a SHIV bearing the envelope glycoproteins of a laboratory-adapted HIV-1 isolate, HXBc2, resulted in a virus that caused rapid CD4-positive T-lymphocyte depletion and AIDS in rhesus monkeys. A molecularly cloned virus, SHIV-HXBc2P 3.2, which contains the HIV-1 envelope glycoproteins of the passaged virus, was shown to be pathogenic in monkeys. The HXBc2P 3.2 envelope glycoproteins were markedly resistant to neutralization by soluble CD4 and several antibodies compared with the parental HXBc2 envelope glycoproteins. Thus, in vivo passage resulted in the acquisition of neutralization resistance typical of that of primary HIV-1 isolates.The specific aims of this proposal are: 1. To create recombinants between the neutralization-sensitive HXBc2 and the neutralization-resistant HXBc2P 3.2 envelope glycoproteins to map the genetic determinants of resistance to neutralization by various antibodies. 2. To compare the structures of the parental and recombinant gp120 glycoprotein monomers by antibody cross-competition analysis. To study the structure of HIV-1 envelope glycoprotein trimers by antibody cross-competition analysis, and to characterize differences between HXBc2 and HXBc2P 3.2 envelope glycoprotein trimers.

描述(改编自申请者摘要)：本报告的基本目标 建议的目的是了解两个国家之间存在的结构性差异 高度相关的HIV糖蛋白形式，在 使用嵌合env基因和抗体的中和敏感性 探测器。作者认为，有效和安全的人类的发展 免疫缺陷病毒(HIV-1)疫苗将从 了解保护性免疫反应。在几个动物模型中， 包括猕猴感染猿人免疫缺陷病毒 (SHIV)，针对挑战病毒的中和抗体可以介导 保护。然而，申请者指出， 中和抗体在HIV-1预防中的实际应用：a) HIV-1包膜糖蛋白的多样性，主要目标是 中和抗体；以及b)初级HIV-1的相对抵抗力 与实验室适应的病毒株相比，分离株对 抗体。尽管gp120外部包络的主要变量循环 糖蛋白已知对这些特性有贡献，了解 这些行列式的结构落后于更保守的包络 糖蛋白成分。来自PI实验室的结果表明，在 携带沙门氏菌包膜糖蛋白的新城疫病毒的体内传代 实验室适应的HIV-1分离株HXBc2导致了一种导致快速 恒河猴CD4阳性T淋巴细胞耗竭与艾滋病从分子上讲 含HIV-1包膜糖蛋白的克隆病毒SHIV-HXBc2P 3.2 在传代病毒中，被证明在猴子中是致病的。HXBc2P 3.2 包膜糖蛋白明显抵抗可溶性CD4的中和 并与亲本HXBc2囊膜糖蛋白进行了比较。 因此，体内传代导致获得了中和抗性。 主要HIV-1分离株的典型特征。这项提案的具体目标 1.在对中和敏感的HXBc2和 抗中和HXBc2P3.2囊膜糖蛋白的定位 抵抗各种抗体中和的遗传决定因素。2. 亲本和重组gp120糖蛋白的结构比较 抗体交叉竞争分析。研究…的结构 HIV-1包膜糖蛋白三聚体的抗体交叉竞争分析，以及 HXBc2和HXBc2P3.2包膜糖蛋白的特性差异 三聚体。