Env-Ab coevolution in SHIV infected RMs leading to V3 glycan bNAbs

SHIV 感染 RM 中的 Env-Ab 共同进化导致 V3 聚糖 bNAb

• 批准号: 10370983
• 负责人: GEORGE M SHAW
• 金额: $ 140.56万
• 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 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370983
• 关键词: Affinity; Animals; Antibodies; Antibody Affinity; Antibody Response; Antigens; Autologous; B-Lymphocytes; Binding Sites; Biological; Data; Data Set; Development; Epitopes; Foundations; Frequencies; Glycopeptides; Goals; HIV-1; HIV-1 vaccine; Human; Immunization; Immunize; Immunologics; Infection; Lead; Length; Link; Macaca mulatta; Mannose; Modeling; Molecular; Molecular Analysis; Monoclonal Antibodies; Mutation; Pathway interactions; Peptides; Polysaccharides; Prevalence; Primates; Process; Program Research Project Grants; Reproducibility; Reverse engineering; Rhesus; Scheme; Scientific Advances and Accomplishments; Specificity; Speed; Structure; Testing; Ursidae Family; Vaccination; Vaccine Design; Vaccine Research; Virus; Virus Diseases; Work; arm; base; design; immunogenicity; innovation; nanoparticle delivery; neutralizing antibody; nonhuman primate; novel; response; simian human immunodeficiency virus; vaccine trial

PROJECT SUMMARY A major roadblock to rational HIV-1 vaccine design is the lack of a suitable primate model in which broadly neutralizing antibodies (bNAbs) can be consistently induced and the underlying molecular, biological and immunological mechanisms studied in an iterative fashion. Since most HIV-1 bNAbs have come from humans infected by HIV-1, we hypothesized that one means to elicit bNabs in primates might be by infecting rhesus macaques (RMs) with simian-human immunodeficiency virus (SHIV) strains that bear primary or transmitted/founder HIV-1 Envs, including those that induced bNAbs in humans. SHIV infected RMs could then be employed to assess the potential of different HIV-1 Envs to elicit bNAbs and to characterize the coevolutionary pathways of bNAb lineages and cognate Envs that elicited them, thereby serving as a “molecular guide” for rational vaccine design. Recent innovations in SHIV design by our lab have made this experimental strategy testable. In this renewal application, we show that 24 of 150, or 16%, of RMs infected by SHIVs bearing different primary HIV-1 Envs developed bNAbs targeting V3 glycan, V2 apex, CD4bs or fusion peptide epitopes. Nine of these animals developed V3 glycan bNAbs. From this extensive dataset, we identified HIV-1 CH848 and BG505.N332 Envs as immunogens that most consistently elicited V3 glycan bNAbs in RMs. We further showed that by reducing the length of V1 and the number of potential N-linked glycans in V1 (designated CH848.dV1 and BG505.N332.dV1), we could enhance the frequency and speed of induction of V3 glycan bNAbs in SHIV infected RMs. Based on these findings, we propose in this project to test the hypothesis that infection of RMs by SHIV.CH848.dV1 or SHIV.BG505.N332.dV1 will selectively prime V3 glycan bNAb lineage B cell precursors, and through a process of Env-Ab coevolution, mature these responses to achieve neutralization breadth. Moreover, by identifying evolved Env intermediates that select for V3 glycan bNAb affinity maturation, we can design lineage-based Env immunogens that, when constructed as SOSIP Env trimers and used to immunize outbred RMs, will elicit V3 glycan bNAbs that are protective against heterologous virus challenge. Specific Aims are: (i) to decipher molecular pathways of Env-Ab coevolution in SHIV-infected RMs that lead to the development of V3 glycan bNAbs, including the identification of inferred germline bNAb precursors, bNAb lineage intermediates and evolved Env intermediates that select for affinity maturation and neutralization breadth; (ii) to evaluate the ability of nanoparticle-delivered, germline-targeted CH848.dV1 and BG505.N332.dV1 SOSIP Env trimers to prime V3 glycan bNAb lineage precursors and for subsequent homologous SHIV infection to select for affinity maturation and neutralization breadth; and (iii) to conduct a statistically-powered, proof-of-concept vaccine trial in RMs testing the hypothesis that germline-targeted, B lineage-designed SOSIP Env trimers can prime, boost and affinity mature V3 glycan bNAb responses to an extent that is superior to conventional SOSIP Env immunogens and that protects RMs from heterologous virus challenge.

项目摘要 理性HIV-1疫苗设计的主要障碍是缺乏合适的私人型号 中和抗体（BNAB）可以始终诱导，并具有基本的分子，生物学和 免疫机制以迭代方式研究。由于大多数HIV-1 BNAB来自人类 受HIV-1感染，我们假设一种在私人中引起bnabs的手段可能是被感染的恒河猴 猕猴（RMS），带有原发性或主要的猿猴免疫缺陷病毒（SHIV）菌株 传输/创始人HIV-1环境，包括那些诱导人类BNAB的人。 Shiv感染的RM可以 被用来评估不同的HIV-1 ENV的潜力引起BNAB并表征协同进化 BNAB谱系和同源的途径使它们引起它们，从而作为“分子指南” 理性疫苗设计。我们实验室的Shiv Design的最新创新已经制定了这一实验策略 可测试。在此续订应用中，我们表明150个或16％的RMS中有24个被SHIV感染的RMS不同 原发性HIV-1 ENVS开发了针对V3 Glycan，V2 Apex，CD4B或融合肽表位的BNABS。九 这些动物开发了V3 Glycan bnabs。从这个广泛的数据集中，我们确定了HIV-1 CH848和 BG505.N332将其作为免疫原子，最始终如一地引起RMS中的V3 Glycycan bnabs。我们进一步显示 通过减少V1的V1长度和V1中潜在的N连接聚糖数量（指定的CH848.DV1） 和BG505.N332.DV1），我们可以提高SHIV中V3 Glycan BNAB的诱导频率和速度 感染的RMS。基于这些发现，我们在该项目中建议测试RMS感染的假设 shiv.ch848.dv1或shiv.bg505.n332.dv1将有选择地启用V3 Glycan BNAB bnab谱系B细胞前体， 通过ENV-AB协同进化的过程，这些反应成熟，以实现神经化的广度。 此外，通过确定选择V3 Glycan BNAB亲和力成熟的进化的Env中间体，我们可以 设计基于谱系的ENV免疫原，当将其构造为SOSIP ENV三聚体并用来免疫化时 杂种RMS，将引起受保护不受异源病毒挑战的V3 Glycan BNAB。具体目标 为：（i）在Shiv感染的RMS中，ENV-AB共同进化的分子途径，导致发育 V3 Glycan BNAB的bnab，包括鉴定推断的种系BNAB前体，BNAB谱系 中间体和进化的Env中间体选择亲和力成熟和中和宽。 （ii）到 评估纳米颗粒递送，靶向种系的CH848.DV1和BG505.N332.DV1 SOSIP ENV的能力 三聚体至Prime V3 Glycan BNAB谱系前体，并为随后的同源SHIV感染选择 亲和力成熟和神经刺激宽度； （iii）进行统计驱动的概念验证证明 RMS中的疫苗试验测试了以种系为定位的B谱系设计的SOSIP ENV三聚体的假设 Prime，Boost和亲和力成熟的V3 Glycan BNAB响应的范围优于常规SOSIP ENV免疫原生物并保护RMS免受异源病毒挑战。