TOPOLOGICAL ANALYSIS OF HIV-1 ENVELOPE GLYCOPROTEINS

HIV-1 包膜糖蛋白的拓扑分析

• 批准号: 6631818
• 负责人: JOSEPH G SODROSKI
• 金额: $ 33.2万
• 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/6631818
• 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（改编自申请人的摘要）：本发明的基本目标是： 建议是了解两个之间存在的结构差异， HIV糖蛋白的高度相关形式，其在以下方面显著不同： 通过使用嵌合env基因和抗体的中和敏感性 probes.作者认为，发展一个有效和安全的人类 免疫缺陷病毒（HIV-1）疫苗将大大受益于 了解保护性免疫反应。在几种动物模型中， 包括猕猴感染猴-人类免疫缺陷病毒 （SHIV），针对攻击病毒的中和抗体可以介导 保护然而，申请人指出， 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， 中和抗体;和B）原发性HIV-1的相对抗性 与实验室适应的病毒株相比， 抗体的虽然gp 120外部信封的主要变量循环 已知糖蛋白有助于这些性质，理解糖蛋白的作用， 这些决定子结构落后于更保守的包络 糖蛋白组分。PI实验室的结果表明， 携带SHIV的包膜糖蛋白的SHIV的体内传代 实验室适应HIV-1分离株HXBc 2产生了一种病毒， 恒河猴CD 4阳性T淋巴细胞耗竭与艾滋病的分子 克隆的病毒SHIV-HXBc 2 P 3.2，其含有HIV-1包膜糖蛋白 传代病毒，被证明是致病性的猴子。HXBc2P 3.2 包膜糖蛋白对可溶性CD 4 和几种抗体与亲本HXBc 2包膜糖蛋白的比较。 因此，体内传代导致获得中和抗性 主要HIV-1分离株的典型特征。 是：1.为了在中和敏感的HXBc 2和 中和抗性HXBc 2 P 3.2包膜糖蛋白，以绘制 抵抗各种抗体中和的遗传决定因素。2. 比较亲本和重组gp 120糖蛋白的结构 通过抗体交叉竞争分析确定单体。研究…的结构 通过抗体交叉竞争分析的HIV-1包膜糖蛋白三聚体，和 表征HXBc 2和HXBc 2 P 3.2包膜糖蛋白之间的差异 三聚体。