Reverse Vaccinology in SHIV Infected Macaques as a Molecular Guide for HIV-1 Vaccine Design

SHIV 感染猕猴的逆向疫苗学作为 HIV-1 疫苗设计的分子指南

• 批准号: 10577775
• 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: 2021-03-11 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577775
• 关键词: Acceleration; Affinity; Amino Acid Substitution; Animal Model; Antibodies; Antibody Response; Antigens; Apical; Automobile Driving; B-Lymphocytes; Binding; Binding Sites; Biological; Biological Assay; Chemicals; Chronic; Development; Epitopes; Event; HIV-1; HIV-1 vaccine; Human; Immunization; Immunize; Immunogenetics; Immunologics; Laboratories; Macaca; Macaca mulatta; Modeling; Molecular; Monoclonal Antibodies; Pathway interactions; Pattern; Peptides; Polysaccharides; Prevalence; Primates; Reproducibility; Reverse engineering; Rhesus; Structure; Testing; Time; Vaccine Design; Virus; design; genome sequencing; innovation; insertion/deletion mutation; mimicry; neutralizing antibody; next generation sequencing; novel; pre-clinical; response; simian human immunodeficiency virus; transmission process; vaccine trial; vaccinology; Acceleration; Affinity; Amino Acid Substitution; Animal Model; Antibodies; Antibody Response; Antigens; Apical; Automobile Driving; B-Lymphocytes; Binding; Binding Sites; Biological; Biological Assay; Chemicals; Chronic; Development; Epitopes; Event; HIV-1; HIV-1 vaccine; Human; Immunization; Immunize; Immunogenetics; Immunologics; Laboratories; Macaca; Macaca mulatta; Modeling; Molecular; Monoclonal Antibodies; Pathway interactions; Pattern; Peptides; Polysaccharides; Prevalence; Primates; Reproducibility; Reverse engineering; Rhesus; Structure; Testing; Time; Vaccine Design; Virus; design; genome sequencing; innovation; insertion/deletion mutation; mimicry; neutralizing antibody; next generation sequencing; novel; pre-clinical; response; simian human immunodeficiency virus; transmission process; vaccine trial; vaccinology

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 commonly induced and the molecular, biological and immunological mechanisms responsible for eliciting such responses studied in a reproducible and iterative fashion. Recently, we demonstrated that primary HIV-1 Envs, when expressed by simian-human immunodeficiency viruses (SHIVs) in rhesus macaques (RMs), elicited patterns of Env-antibody coevolution strikingly similar to humans infected by homologous virus strains, leading to neutralization breadth. These similarities in Env-antibody coevolution in humans and rhesus 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 bNAb, capable of neutralizing 49% of a 208-strain panel, revealed a V2-apex mode of recognition like that of human bNAbs PGT145 and PCT64-35M. Another rhesus antibody bound the CD4-binding site of HIV-1 Env by CD4 mimicry mirroring human bNAbs 8ANC131, CH235 and VRC01. Based on these observations supporting the relevance of the rhesus model to bNAb induction in humans, we propose here a novel “reverse vaccinology” strategy in SHIV infected RMs as a “molecular guide” to inform and accelerate HIV-1 vaccine design in humans. Specific aims are: (i) To isolate bNAb mAbs targeting CD4bs, fusion peptide, V3 glycan and V2 apex epitopes from a subset of 150 SHIV infected RMs and to characterize their breadth, potency, immunogenetics, target epitopes and structural solutions to epitope recognition. (ii) To characterize molecular patterns of Env-Ab coevolution from rhesus germline B cell unmutated common ancestors (UCAs) to mature bNAbs and to identify key Env intermediates, or “immunotypes,” that are responsible for driving bNAb lineage affinity maturation to breadth. (iii) To design, construct and characterize novel SOSIP Env trimers that mimic key Env “immunotypes” and demonstrate that they bind preferentially to bNAb UCAs and intermediate stage Abs. (iv) To conduct a proof- of-concept preclinical vaccine trial in 24 RMs to test the hypothesis that reverse-engineered, B lineage-designed SOSIP Env trimers can prime, boost and affinity mature bNAb responses in RMs to an extent that is superior to conventional SOSIP Env immunogens and comparable to SOSIP-SHIV or SHIV-only immunizations.

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 可以通常诱导中和抗体（BNAB），分子，生物学和免疫学 负责以繁殖和迭代方式引起此类反应的机制。最近， 我们证明了原发性HIV-1 ENVS，当由Simian-Human免疫缺陷病毒（SHIVS）表达时 在恒河猕猴（RMS）中，引起抗体抗体的模式，与被感染的人类相似 同源病毒菌株，导致神经性广度。这些在Env-antibody共同进化中的相似之处 人类和恒河猴包括构成表位识别的免疫遗传，结构和化学解决方案 和精确的Env氨基酸取代，插入和缺失导致病毒持久性。结构 一个能够中和208杆面板的49％的恒河bnab揭示了一种v2-apex识别方式 像人类BNABS PGT145和PCT64-35M一样。另一种恒晶抗体结合了CD4结合位点 HIV-1 ENV由CD4模拟镜像人bnabs 8anc131，ch235和vrc01。基于这些观察 支持恒河类模型与人类BNAB归纳的相关性，我们在这里提出了一种新颖的“反向 SHIV感染RMS的疫苗接种策略作为“分子指南”，以告知和加速HIV-1疫苗设计 在人类中。具体目的是：（i）分离靶向CD4B，融合肽，V3 Glycan和V2 Apex的BNAB mABS 来自150个SHIV感染RMS的子集的表位，以表征其广度，效力，免疫原质， 靶向表位和结构解决方案以识别表位。 （ii）表征env-ab的分子模式 从恒河类系B细胞未分离的共同祖先（UCA）到成熟的bnabs的共同进化并确定 关键的ENV中间体或“免疫型”，负责推动BNAB谱系亲和力成熟 宽度。 （iii）设计，构建和表征新颖的sosip env三聚体，以模仿钥匙圈“免疫型” 并证明它们优先与BNAB UCA和中间阶段ABS结合。 （iv）进行证明 - 在24 RMS中的概念临床前疫苗试验测试了反向设计的假设B谱系设计 SOSIP ENV三聚体可以在RMS中启用，增强和亲和力成熟的BNAB响应，以至于优于 常规的SOSIP ENV免疫原子，可与SOSIP-SHIV或仅动湿免疫抑制作用相媲美。