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

• 批准号: 10437032
• 负责人: GEORGE M SHAW
• 金额: $ 80.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10437032
• 关键词: Affinity; Amino Acid Substitution; Animal Model; Animals; Antibodies; Antibody Response; Antigens; 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; Lead; 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; Ursidae Family; Vaccination; Vaccine Design; Vaccine Research; Vaccines; Variant; Viral; Virus; base; design; immunogenicity; innovation; insertion/deletion mutation; nanoparticle delivery; neutralizing antibody; novel; pre-clinical; response; simian human immunodeficiency virus; vaccine trial; vaccinology

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.

项目概要 在人类中，HIV-1 引发的中和抗体与病毒包膜以独特的模式共同进化，在某些情况下 案件的范围相当广泛。我们发现，当由猿猴表达时，初级 HIV-1 Envs 22 只恒河猴 (RM) 体内的免疫缺陷病毒 (SHIV) 引发了 Env-Ab 协同进化模式 与人类惊人相似（Science 371：eabd2638，2021）。这包括保守的免疫遗传学， 用于表位识别和精确的 Env-氨基酸取代、插入和 删除导致病毒持续存在。一种恒河猴抗体的结构，能够中和 49% 208 菌株面板揭示了类似于人类 bNAb PGT145 和 PCT64 的 V2-apex 识别模式。我们 随后扩大了这项研究，纳入了 150 名被 SHIV 感染的 RM，这些人携带 15 种不同的原发性 HIV-1 环境；其中 24 只 (16%) 动物开发出针对保守 V2 顶点、V3 聚糖、CD4b 或 融合肽表位。 V2 顶端是 RM 中最常见的 bNAb 靶向表位。我们的结论是 RM 中的 Env-Ab 协同进化概括了人类 bNAb 的发育特征，可能有助于指导和 加速人类 HIV-1 免疫原的设计。从这些临床前数据中，我们确定了 HIV-1 Q23.17 Env 作为最一致地引发 V2 尖 bNAb 的免疫原。在这里，我们建议阐明 Env-Ab HIV-1 Q23.17 Env 选择性启动、增强和亲和力成熟 V2 顶点的共同进化途径 bNAb 反应并将这些发现转化为全 SOSIP Env 三聚体疫苗方案，其中包括 针对种系的 Q23.17 Env Prime，随后通过谱系设计的 Q23.17 Env“免疫型”进行增强 能够使 B 细胞亲和力成熟以实现广度。具体目标是：（i）破译分子途径 SHIV.Q23.17 感染 RM 中的 Env-Ab 协同进化导致 V2 顶端 bNAb 的发育，包括 推断种系 bNAb 前体和谱系中间体以及相应 Env 的鉴定 与其结合的免疫型； (ii)使用哺乳动物展示饱和诱变来生成Q23.17 Env 对多种恒河猴种系 V2 apex bNAb B 细胞前体表现出增强的结合亲和力的变体 将这些 Env 设计为纳米粒子传递的 SOSIP 三聚体； (iii) 测试种系的免疫原性- V2 apex bNAb UCA 敲入小鼠和远交中的靶向和谱系设计 Q23.17 Env SOSIP 三聚体 RM 并推动最有希望的组合在 RM 中进行概念验证临床前疫苗试验；和 (iv) 在 28 个 RM 中进行适当有力的临床前疫苗试验，以检验逆转的假设 工程化、B 谱系设计的 Q23.17 SOSIP Env 三聚体可以引发、增强和亲和力成熟 V2 apex bNAb RM 中的反应程度优于传统的 SOSIP Env 免疫原并保护 RM 来自异源病毒的挑战。这些研究的意义可能是深远的：如果我们能够证明 在 RM 中使用种系靶向、谱系设计的 Q23.17 Env SOSIP 一致诱导 bNAb，它将 代表了 HIV-1 疫苗研究的新滩头堡，可以迅速转化为人体临床试验。