Structure-Based Characterization of gp120 Non-V3 Variable Loop Epitopes

gp120 非 V3 可变环表位的基于结构的表征

• 批准号: 7737804
• 负责人: TIMOTHY J CARDOZO
• 金额: $ 62.59万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7737804
• 关键词: Address; Antigens; Conserved Sequence; Epitopes; Goals; HIV Envelope Protein gp120; HIV vaccine; Methods; Outcome; Research; Research Project Grants; Structure; Surface; V3 Loop; Vaccines; Virus; Work; base; design; innovation; meetings; neutralizing antibody; novel

DESCRIPTION (provided by applicant): We propose unconventional, unique and exceptionally novel methods to uncover the structure of broadly neutralizeable epitopes in the variable loops of gp120. This work challenges the standard paradigm that the variable loops of gp120 are too dynamic and variable to have conserved epitopes useful in a vaccine. We were able to devise a novel computational de-noising approach to the sequence and structural variability in these loops and have a high likelihood of identifying the first broadly neutralizing antibodies targeting epitopes in V1, V2 V4 and/or V5. We are confident of attaining this significant outcome based on our preliminary results with the V3 loop. The research group and the proposed research is uniquely suited to the stated goals of the HIT-IT initiative, rather than a conventional research grant (R01) application. This is because we have a proven track record of this kind of innovation targeting the V3 loop, and because the research addresses a problem that is both crucial to an HIV vaccine and simultaneously thought currently to be too challenging to address. All prior failed HIV vaccines have targeted sequence conserved and non-gp120 determinants in the virus. This is primarily because the dynamic, sequence variable surface loops of gp120 are considered too challenging to dissect for hidden broadly neutralizing antibody epitopes. This research proposes a highly innovative tactic to meet this challenge and produce the first structure-based design of immunogens mimicking broadly neutralizing epitopes in the variable loops V1, V2, V4 and V5.

描述（由申请人提供）：我们提出了非常规，独特和异常新颖的方法，以揭示GP120变量循环中可广泛中和的表位的结构。这项工作挑战了标准范式，即GP120的可变回路太动态和可变，无法保守的表位对疫苗有用。我们能够为这些循环中的序列和结构变异性设计一种新型的计算降价方法，并具有很高的可能性，即鉴定靶向V1，V2 V4和/或V5中的第一个广泛中和抗体的可能性。我们有信心根据V3循环的初步结果获得这一重大结果。研究小组和拟议的研究非常适合HIT-IT计划的既定目标，而不是传统的研究赠款（R01）应用程序。这是因为我们对针对V3循环的这种创新有了可靠的记录，并且该研究解决了一个对艾滋病毒疫苗至关重要的问题，并且同时认为目前难以解决。所有先前的失败的HIV疫苗均在病毒中靶向保守的序列和非GP120决定因素。这主要是因为GP120的动态，序列变量的表面环被认为太具有挑战性了，无法剖析隐藏的广泛中和抗体表位。这项研究提出了一种高度创新的策略，以应对这一挑战，并产生第一个基于结构的免疫原子设计，模仿可变回路V1，V2，V4和V5中广泛中和表位。