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Knock-in mice expressing germline-reverted broadly neutralizing HIV antibodies

表达种系恢复的广泛中和艾滋病毒抗体的敲入小鼠

基本信息

批准号：
10190786
负责人：
DAVID NEMAZEE
金额：
$ 67.91万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-05 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10190786
关键词：
Address Affinity Animal Model Animals Antibodies Antibody Binding Sites Antigens B-Lymphocytes Binding Binding Sites Cell Count Cell Line Cells Chronic Clinical Trials Data Dose Engineering Epitopes Funding Gene Mutation Gene Targeting Genes Genetic Goals HIV HIV Antibodies HIV vaccine Human Immune response Immunization Immunoglobulin Class Switching In Vitro Individual Infection Infection Control Knock-in Knock-in Mouse Knowledge Memory B-Lymphocyte Modeling Monkeys Mus Mutate Mutation Pathway interactions Patients Pattern Peptides Peripheral Blood Mononuclear Cell Physiological Plasma Cells Polysaccharides Predictive Value Primates Production Seeds Site Somatic Mutation Sorting - Cell Movement Specificity Speed Structure Study models Testing Vaccination Vaccine Design Vaccine Research Vaccines Variant Virus base competitive environment cost design engineering design env Glycoproteins global health human model improved in vivo insertion/deletion mutation insight mouse model neutralizing antibody novel vaccines optimism response simian human immunodeficiency virus tool vaccination strategy vaccine candidate vaccine trial

项目摘要

This is a renewal R01 application to exploit knock-in mouse models and hypermutating human B cell lines carrying germline-reverted broadly neutralizing antibodies (gl-bNAbs) against HIV Env with the goal to speed HIV vaccine research. Developing an HIV vaccine is a major global health objective as no effective vaccine yet exists. bnAbs to HIV Env glycoprotein can likely control infection but eliciting bnAbs by vaccination is challenging because of Env genetic variability and the fact that responses to conserved Env epitopes are weak. bnAbs are made naturally in some patients, but usually only after years of infection, when they provide no real protection. However, many individual bnAbs can provide passive protection in animal models, suggesting that elicitation of these antibodies could be protective, particularly if bnAbs to several conserved sites can be raised simultaneously. To begin to investigate the best ways to elicit bnAbs by vaccination, we have previously generated B cell lines and knock-in mice carrying inferred gl-bnAbs for VRC01, PGT121, b12, 4E10 and other specificities. gl-bnAb mouse models are valuable for antigen design and vaccination studies because they carry B cells with the potential to become bnAbs after appropriate stimulation and somatic mutation. Placement of the V(D)J genes into the physiological Ig loci allows the knock-in B cells to undergo normal H-chain class switching and V-region hypermutation. Moreover, knock-in mice allow vaccination studies in a convenient, relatively low-cost mouse model. One can seed B cells from these mice at physiologically low numbers in otherwise WT mice and assess their responses in the face of competition from non bnAb clones. In these cell lines and mice, we have been carrying out studies to evaluate whether the imputed gl-bnAbs develop normally and to assess various vaccine candidates and immunization strategies. We have tested so-called germline-targeting immunogens engineered to bind better to gl-bnAbs than immunogens derived from WT Env. In the present proposal we focus on two aspects of vaccine design: the use of validated, rather than inferred, gl-bnAb precursors and an assessment of the ease of selectability of beneficial mutations using somatically-mutating human gl-bnAb cell lines and gl-bnAb mice. We hypothesize that by taking these approaches we will identify preferred gl-bnAbs that most effectively mature to become bnAbs and preferred immunogens or selection paths that should most effectively promote bnAb production when tested in primates. Because the problem of poor precursor affinity to antigen and uncertain paths to affinity maturation by somatic mutation are limitations to all immune responses, knowledge obtained here should be applicable to a variety of vaccine targets.

这是一个更新的R01应用程序，用于开发敲入小鼠模型和超突变的人类B细胞系