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.

项目概要 合理设计 HIV-1 疫苗的一个主要障碍是缺乏合适的灵长类动物模型，在该模型中广泛 中和抗体（bNAb）可以持续诱导，并且潜在的分子、生物学和 以迭代方式研究免疫机制。由于大多数 HIV-1 bNAb 来自人类 感染 HIV-1 后，我们假设在灵长类动物中引发 bNab 的一种方法可能是感染恒河猴 携带猿猴人类免疫缺陷病毒 (SHIV) 毒株的猕猴 (RM)，这些毒株携带原发性或 传播/创始人 HIV-1 包膜，包括那些在人类中诱导 bNAb 的包膜。感染 SHIV 的 RM 可以 用于评估不同 HIV-1 Env 引发 bNAb 的潜力并表征共同进化 bNAb 谱系和引发它们的同源环境的途径，从而充当 合理的疫苗设计。我们实验室最近在 SHIV 设计方面的创新使这一实验策略成为可能 可测试的。在此续订申请中，我们表明，在 150 名感染 SHIV 的 RM 中，有 24 名（即 16%）携带不同的基因。 初级 HIV-1 Envs 开发了针对 V3 聚糖、V2 顶点、CD4b 或融合肽表位的 bNAb。九个 这些动物产生了 V3 聚糖 bNAb。从这个广泛的数据集中，我们识别出 HIV-1 CH848 和 BG505.N332 Envs 作为免疫原，最一致地在 RM 中引发 V3 聚糖 bNAb。我们进一步展示了 通过减少 V1 的长度和 V1 中潜在的 N 连接聚糖的数量（称为 CH848.dV1 和 BG505.N332.dV1)，我们可以提高 SHIV 中 V3 聚糖 bNAb 的诱导频率和速度 受感染的 RM。基于这些发现，我们建议在这个项目中检验 RM 感染的假设 SHIV.CH848.dV1 或 SHIV.BG505.N332.dV1 将选择性地引发 V3 聚糖 bNAb 谱系 B 细胞前体， 并通过 Env-Ab 协同进化过程，使这些反应成熟以实现中和广度。 此外，通过鉴定选择 V3 聚糖 bNAb 亲和力成熟的进化 Env 中间体，我们可以 设计基于谱系的 Env 免疫原，当构建为 SOSIP Env 三聚体并用于免疫时 近亲繁殖的 RM 将引发 V3 聚糖 bNAb，可抵御异源病毒的攻击。具体目标 是：（i）破译 SHIV 感染 RM 中 Env-Ab 协同进化的分子途径，从而导致发育 V3 聚糖 bNAb，包括推断种系 bNAb 前体、bNAb 谱系的鉴定 选择亲和力成熟和中和宽度的中间体和进化的 Env 中间体； (二) 至 评估纳米颗粒递送的、种系靶向的 CH848.dV1 和 BG505.N332.dV1 SOSIP Env 的能力 启动 V3 聚糖 bNAb 谱系前体的三聚体，并用于随后的同源 SHIV 感染选择 亲和力成熟和中和广度； (iii) 进行统计支持的概念验证 RM 中的疫苗试验测试了以下假设：针对种系的 B 谱系设计的 SOSIP Env 三聚体可以 初免、加强和亲和力成熟的 V3 聚糖 bNAb 反应程度优于传统 SOSIP Env 免疫原可保护 RM 免受异源病毒的攻击。