HIV-1 Q23.17 Env: Engineering a novel immunogen to elicit broadly neutralizing antibodies

HIV-1 Q23.17 Env：设计一种新型免疫原以引发广泛中和抗体

基本信息

批准号：
10624301
负责人：
GEORGE M SHAW
金额：
$ 116.18万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-23 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624301
关键词：
Acceleration Affinity Amino Acid Substitution Animal Model Animals Antibodies Antibody Response Antibody-mediated protection Antigens Apical Autologous B-Lymphocytes Binding Binding Sites Biological Chemicals Chronic Clinical Trials Data Development Engineering Epitopes Event Exhibits Frequencies Grant HIV-1 HIV-1 vaccine Human Immunogenetics Immunologics Knock-in Mouse Laboratories Macaca mulatta Mature B-Lymphocyte Modeling Molecular Monkeys Mutagenesis Mutation Pathway interactions Pattern Peptides Polysaccharides Prevalence Primates Regimen Reproducibility Reverse engineering Rhesus Science Scientific Advances and Accomplishments Structure Testing Time Translating Vaccination Vaccine Design Vaccine Research Vaccines Variant Viral Virus design immunogenicity innovation insertion/deletion mutation nanoparticle delivery neutralizing antibody novel pre-clinical response simian human immunodeficiency virus transmission process vaccine trial vaccinology

项目摘要

PROJECT SUMMARY In humans, neutralizing antibodies elicited by HIV-1 coevolve with viral Envs in distinctive patterns, in some cases acquiring substantial breadth. We found that primary HIV-1 Envs, when expressed by simian-human immunodeficiency viruses (SHIVs) in 22 rhesus macaques (RMs), elicited patterns of Env-Ab coevolution strikingly similar to those in humans (Science 371:eabd2638, 2021). This included conserved immunogenetic, structural and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2-apex mode of recognition like that of human bNAbs PGT145 and PCT64. We subsequently expanded this study to include 150 RMs infected by SHIVs bearing any of 15 different primary HIV-1 Envs; 24 (16%) of these animals developed bNAbs targeting conserved V2 apex, V3 glycan, CD4bs or fusion peptide epitopes. The V2 apex was the most common bNAb epitope targeted in RMs. We concluded that Env-Ab coevolution in RMs recapitulates developmental features of human bNAbs and may serve to guide and accelerate HIV-1 immunogen design for humans. From these preclinical data, we identified HIV-1 Q23.17 Env as the immunogen that most consistently elicited V2 apex bNAbs. Here, we propose to elucidate the Env-Ab coevolutionary pathways by which HIV-1 Q23.17 Env selectively primes, boosts and affinity-matures V2 apex bNAb responses and to translate these findings into an all-SOSIP Env trimer vaccine regimen consisting of a germline-targeted Q23.17 Env prime followed by boosts with lineage-designed Q23.17 Env “imunotypes” capable of affinity-maturing B cells to achieve breadth. Specific aims are: (i) to decipher molecular pathways of Env-Ab coevolution in SHIV.Q23.17 infected RMs that lead to the development of V2 apex bNAbs, including the identification of inferred germline bNAb precursors and lineage intermediates and corresponding Env immunotypes that bind to them; (ii) to use mammalian display saturation mutagenesis to generate Q23.17 Env variants that exhibit enhanced binding affinity to multiple rhesus germline V2 apex bNAb B cell precursors and to engineer these Envs as nanoparticle-delivered SOSIP trimers; (iii) to test the immunogenicity of germline- targeted and lineage-designed Q23.17 Env SOSIP trimers in V2 apex bNAb UCA knockin mice and outbred RMs and to advance the most promising combinations to a proof-of-concept preclinical vaccine trial in RMs; and (iv) to conduct an appropriately powered preclinical vaccine trial in 28 RMs to test the hypothesis that reverse- engineered, B lineage-designed Q23.17 SOSIP Env trimers can prime, boost and affinity mature V2 apex bNAb responses in RMs to an extent that is superior to conventional SOSIP Env immunogens and that protects RMs from heterologous virus challenge. The significance of these studies could be far-reaching: if we can demonstrate consistent induction of bNAbs using germline-targeted, lineage-designed Q23.17 Env SOSIPs in RMs, it would represent a new beachhead for HIV-1 vaccine research that could be translated rapidly into human clinical trials.

项目摘要在人类中，在某些人中，HIV-1与病毒环境共同产生的中和抗体，在某些情况下案件获得了大量广度。我们发现，当由Simian-Human表达时，主要的HIV-1环境 22个恒河猕猴（RMS）中的免疫缺陷病毒（SHIVS），引起的ENV-AB协同进化模式与人类中的人非常相似（科学371：EABD2638，2021）。其中包括构成免疫遗传，表位的结构和化学解决方案识别和精确环境氨基酸取代，插入和缺失导致病毒持久性。一种恒河抗体的结构，能够中和49％ 208-STRAIN面板显示了一种V2-APEX识别方式，例如人类BNABS PGT145和PCT64。我们随后将这项研究扩展到包括15个带有15个不同主要主要中任何一种的RMS HIV-1 Envs；这些动物中有24只（16％）开发出靶向配置V2顶点，V3 Glycycan，CD4B或融合肽表位。 V2顶点是RMS中最常见的BNAB表位。我们得出结论 RMS中的Env-AB协同进化概述了人类BNAB的发展特征，并可以指导和指导和加速人类HIV-1免疫原设计。从这些临床前数据中，我们确定了HIV-1 Q23.17 env 作为最一致地引起V2 Apex BNAB的免疫原。在这里，我们建议阐明env-ab HIV-1 Q23.17 ENV有选择性地质量，增强和亲和力v2 Apex的协同进化途径 BNAB响应并将这些发现转化为全索环境触发疫苗，由A组成以种系为定位的Q23.17 Env Prime随后促进了谱系设计的Q23.17 Env“ Imunotypes” 能够亲和力培养B细胞以实现广度。具体目的是：（i）破译的分子途径 shiv.q23.17感染的RMS中的Env-ab共同进化，导致V2 Apex BNAB的发展，包括鉴定推断的种系BNAB前体和谱系中间体和相应的Env 与它们结合的免疫型；（ii）使用哺乳动物显示满意诱变生成Q23.17 env 暴露了增强结合亲和力与多个恒河类系的v2 Apex BNAB B细胞前体和以纳米颗粒递送的SOSIP三聚体为特工；（iii）测试种系的免疫原性 V2 Apex BNAB UCA敲击蛋白小鼠和近亲的靶向和谱系设计的Q23.17 ENV SOSIP三聚体 RMS并将最大的校对组合推向RMS的概念证明临床前疫苗试验；和（iv）在28 RMS中进行适当动力的临床前疫苗试验，以检验以下假设工程设计，B血管设计的Q23.17 SOSIP ENK TRIMERS可以启动，增强和亲和力成熟V2 Apex BNAB RMS的反应在一定程度上优于常规的SOSIP ENV免疫原，并且可以保护RMS 来自异源病毒挑战。这些研究的意义可能是深远的：如果我们能证明使用以种系为谱系设计的系列Q23.17 ENV SOSIP的BNAB一致地诱导BNAB，它将代表了一种用于HIV-1疫苗研究的新海滩，可以迅速转化为人类临床试验。