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.

项目总结 合理设计HIV-1疫苗的一个主要障碍是缺乏合适的灵长类模型，在这种模型中 中和抗体(BNAbs)可以被持续诱导，其潜在的分子、生物学和 以迭代的方式研究免疫学机制。由于大多数HIV-1bNAb来自人类 感染了HIV-1，我们推测在灵长类动物中诱导bnab的一种方式可能是通过感染恒河猴。 猴-人类免疫缺陷病毒(SHIV)株携带初级或 传播/创始HIV-1包膜病毒，包括那些在人类体内诱导bNAbs的包膜病毒。受SHIV感染的RMS可能会 被用来评估不同的HIV-1环境的潜力，以诱导bNAb和表征共同进化 诱导它们的bNAb谱系和同源env的途径，从而为 合理的疫苗设计。我们实验室最近在Shiv设计方面的创新已经做出了这一实验策略 可测试的。在此更新申请中，我们显示了感染SHIV的RMS中的24个，即16%，具有不同的 原代HIV-1包膜蛋白制备了针对V3糖链、V2顶端、CD4bs或融合多肽表位的bNAb。其中九个 这些动物产生了V3糖链bNAbs。从这个广泛的数据集中，我们识别出HIV-1 CH848和 BG505.N332作为免疫原在RMS中最稳定地诱导V3糖蛋白bNAbs。我们进一步展示了 通过减少V1的长度和V1中潜在的N-连接的糖链的数量(命名为CH848.dV1 和BG505.N332.dV1)，我们可以提高V3糖链bNAbs在SHIV中的诱导频率和速度 感染的RMS。基于这些发现，我们在这个项目中建议检验RMS感染的假设 通过SHIV.CH848.dV1或SHIV.BG505.N332.dV1将选择性地启动V3糖蛋白bNAb谱系B细胞前体， 并通过Env-Ab的共同进化过程，成熟这些反应以实现中和广度。 此外，通过鉴定为V3糖蛋白bNAb亲和力成熟选择的进化的Env中间体，我们可以 设计基于谱系的环境免疫原，当构建为SOSIP环境三聚体并用于免疫时 远缘繁殖的RMS，将诱导出V3糖蛋白bNAb，对异源病毒攻击具有保护作用。具体目标 是：(I)破译导致SHV感染的RMS中Env-Ab共同进化的分子途径 V3糖链bNAbs，包括对推测的胚系bNAb前体、bNAb谱系的鉴定 选择亲和力成熟和中和广度的中间体和进化的环境中间体； 评估纳米颗粒传递、生殖系靶向CH848.dV1和BG505.N332.dV1 SOSIP环境的能力 启动V3糖链bNAb谱系前体的三聚体，并用于后续同源Shiv感染的选择 亲和力成熟和中和广度；以及(Iii)进行统计支持的概念验证 RMS中的疫苗试验验证了以下假设：种系靶向、B系设计的SOSIP环境三聚体可以 启动、增强和亲和成熟的V3葡聚糖bNAb反应，其程度优于常规SOSIP 环境免疫原，保护RMS免受异源病毒的攻击。