SHIV/HIV Env-Antibody Coevolution as a Guide to Iterative Vaccine Design

SHIV/HIV 包膜抗体协同进化作为迭代疫苗设计的指南

• 批准号: 9316783
• 负责人: GEORGE M SHAW
• 金额: $ 334.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-07 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316783
• 关键词: Address; Animal Model; Antibodies; Antigens; Autologous; B-Lymphocytes; Binding; Bioinformatics; Biological Models; Biology; Cell Lineage; Development; Epitopes; Event; Evolution; Genes; HIV; HIV-1; HIV-1 vaccine; Hand; Human; Individual; Infection; Lead; Macaca; Macaca mulatta; Maps; Memory B-Lymphocyte; Methods; Molecular; Molecular Conformation; Pathway interactions; Pattern; Polysaccharides; Population Dynamics; Receptors, Antigen, B-Cell; Reproducibility; Research; Research Personnel; Research Project Grants; System; Talents; Testing; Time; Vaccine Design; Vaccine Research; Viral; Viral Antibodies; Virus; Work; base; design; env Glycoproteins; human subject; humanized mouse; immunogenicity; innovation; iterative design; neutralizing antibody; novel; novel strategies; novel vaccines; response; simian human immunodeficiency virus; statistics; vaccine candidate; vaccine development; vaccinology

SUMMARY Despite decades of HIV-1 vaccine research, there are no examples of immunogens or candidate vaccines that consistently elicit potent broadly neutralizing antibodies (bNAbs). Most examples of bNAbs come from natural HIV-1 infection of humans, but even then, they develop only after several years of infection and in only a subset of individuals. Nonetheless, the finding that humans have the potential to make potent bNAbs has spurred intensive research to identify the target epitopes of these antibodies and their developmental pathways from unmutated germline B cell receptor (BCR) to mature bNAb. Recently, research has focused on the coevolutionary pathways of bNAbs and HIV-1 Env sequences that elicit them in hopes of inferring particular Env sequences that can be developed into immunogens that engage and stimulate germline and intermediate ancestor BCRs. This strategy has been championed by investigators pursuing both “B cell lineage design” and “reverse vaccinology” approaches to vaccine development. We propose that a major roadblock to rational HIV- 1 vaccine design is the lack of an animal model where the induction of bNAbs can be achieved in a consistent and reproducible manner such that the molecular events responsible for bNAb elicitation can be deciphered and used to guide iterative HIV-1 vaccine design. This HIVRAD application proposes a novel hypothesis and an integrated research plan – supported by promising new discoveries in SHIV biology, virus-Ab coevolution, and B lineage vaccine design – to overcome this critical roadblock. We hypothesize that: (i) primary HIV-1 Env glycoproteins, if presented in their native conformation as persistently replicating SHIVs to outbred, genetically diverse rhesus macaques (RMs), will lead to consistent patterns of virus-Ab coevolution that recapitulate those patterns observed in humans infected by HIV-1 strains bearing homologous Envs; (ii) SHIVs containing primary HIV-1 Envs that in humans elicited bNabs, will bind orthologous germline and intermediate ancestor BCRs in RMs, and lead to the development of autologous and heterologous tier 2 neutralizing antibodies; and (iii) by identifying RM germline and intermediate ancestor BCRs that evolve to achieve neutralization breadth, together with their cognate SHIV Env immunogens (“immunotypes”), we will have in hand for the first time a reproducible experimental system in which to iteratively design, test and guide the development of novel vaccine candidates based on both B lineage design and reverse vaccinology platforms. To test this hypothesis, we propose three highly inter-related research projects and three cores: Project 1 - Env Evolution and Neutralizing Antibody Elicitation in SHIV Infected Rhesus Macaques and in Humans Infected by HIV-1 Strains bearing Homologous Envs (Shaw); Project 2 - Population Dynamics of Neutralizing B-Cell Responses in SHIV- infected Macaques (Kelsoe); Project 3 - Immunogen Design of HIV Sequential Envelopes Derived from SHIV- infected Macaques (Haynes). These projects will be enabled by Core A - Administrative (Shaw); Core B - Viral and Antibody Gene Sequencing (Hahn); and Core C - Bioinformatics and Statistics (Korber).

概括 尽管 HIV-1 疫苗研究已进行了数十年，但尚无免疫原或候选疫苗的例子 持续引发有效的广泛中和抗体（bNAb）。 bNAb 的大多数例子都来自天然 人类感染了 HIV-1，但即便如此，它们也只有在感染几年后才会出现，而且只需要很短的时间。 个体的子集。尽管如此，人类有潜力制造有效的 bNAb 的发现已经 激发了深入研究以确定这些抗体的目标表位及其发育途径 从未突变的种系 B 细胞受体 (BCR) 到成熟的 bNAb。最近，研究主要集中在 bNAb 和 HIV-1 Env 序列的共同进化途径引发它们，希望推断出特定的 Env 序列可开发成免疫原，参与并刺激种系和中间体 祖先 BCR。这一策略得到了追求“B 细胞谱系设计”和 疫苗开发的“反向疫苗学”方法。我们提出理性艾滋病毒的一个主要障碍是 1 疫苗设计缺乏可以一致地诱导 bNAb 的动物模型 和可重复的方式，以便可以破译负责 bNAb 引发的分子事件 并用于指导迭代 HIV-1 疫苗设计。该 HIVRAD 应用提出了一个新的假设 一项综合研究计划——由 SHIV 生物学、病毒-抗体协同进化方面有前景的新发现支持， B 谱系疫苗设计——克服这一关键障碍。我们假设： (i) 原发性 HIV-1 包膜 糖蛋白，如果以它们的天然构象呈现，作为持续复制的 SHIV 进行远交，在遗传上 不同的恒河猴（RM）将导致一致的病毒-抗体共同进化模式，从而概括了这些 在感染带有同源 Env 的 HIV-1 毒株的人类中观察到的模式； (ii) SHIV 含有 在人类中引发 bNab 的初级 HIV-1 包膜将结合直系同源种系和中间祖先 RM 中的 BCR，并导致自体和异源 2 级中和抗体的发展；和 (iii) 通过识别 RM 种系和中间祖先 BCR，这些 BCR 进化以实现中和广度， 连同其同源 SHIV 包膜免疫原（“免疫型”），我们将首次掌握 可重复的实验系统，在其中迭代设计、测试和指导新颖的开发 基于 B 谱系设计和反向疫苗学平台的候选疫苗。为了检验这个假设， 我们提出了三个高度相关的研究项目和三个核心：项目 1 - Env Evolution 和 在感染 SHIV 的恒河猴和感染 HIV-1 菌株的人类中诱导中和抗体 轴承同源环境（Shaw）；项目 2 - SHIV 中和 B 细胞反应的群体动态 - 受感染的猕猴（Kelsoe）；项目 3 - 来自 SHIV 的 HIV 序列包膜的免疫原设计 - 感染猕猴（海恩斯）。这些项目将由核心 A - 行政（Shaw）启动；核心 B - 病毒 和抗体基因测序（Hahn）；和核心 C - 生物信息学和统计学 (Korber)。