Probing the germlines of broadly neutralizing anti-HIV antibodies in knockin mice

探讨敲入小鼠中广泛中和抗 HIV 抗体的种系

• 批准号: 8225294
• 负责人: Dennis R. Burton
• 金额: $ 70.27万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225294
• 关键词: Adjuvant; Animals; Anti-Idiotypic Antibodies; Antibodies; Antibody Formation; Antibody Repertoire; Antigens; B-Cell Development; B-Lymphocytes; Breeding; Cellular biology; Collaborations; Complex; Development; Engineering; Enzyme-Linked Immunosorbent Assay; Epitopes; Evaluation; Failure; Frequencies; Gene Expression; Gene Targeting; Generations; Genes; Goals; HIV; HIV Antibodies; HIV vaccine; Housing; Human; Immune Tolerance; Immunization; Immunoglobulin Somatic Hypermutation; Immunoglobulins; Immunology; In Vitro; Individual; Knowledge; Laboratories; Light; Measures; Modeling; Molecular; Monitor; Mouse Strains; Mus; Nature; Outcome; Play; Principal Investigator; Protocols documentation; Reagent; Recruitment Activity; Relative (related person); Research; Role; Route; Screening procedure; Serum; Solutions; Specificity; Structure; Testing; Transgenic Mice; Transgenic Organisms; Vaccine Research; Vaccines; anergy; base; design; experience; human monoclonal antibodies; in vivo; mouse model; neutralizing antibody; novel; programs; prototype; receptor; response; scaffold; success; tool; vaccine candidate; vaccinology

DESCRIPTION (provided by applicant): The design of an immunogen able to elicit broadly neutralizing antibodies is a major, but so far elusive, goal of HIV vaccine research. The existence of such antibodies is indicated by the description of rare broadly neutralizing HIV sera and a handful of broadly neutralizing human monoclonal antibodies (bnMAbs) isolated from HIV infected individuals. To understand how to better induce broadly neutralizing HIV antibodies it is important to identify the appropriate B cell precursors and to stimulate them with effective antigens. For this reason we propose to develop mouse strains carrying B cells with "germline" versions of bnMAbs and to follow their responses to test immunogens. This approach renders visible the responses of the very B cells that we wish to recruit into the HIV antibody response and should allow rapid screening of vaccine candidates for the ability to elicit neutralizing antibodies in a context in which the appropriate precursors are present in high frequency. Failure of response in this context would not be ascribable to a deficiency in appropriate B cells unless such B cells are eliminated by immune tolerance, an outcome that can be experimentally excluded. The specific aims of the proposal are (1) to generate transgenic (knockin) mice carrying B cells expressing germline versions of the bnMAbs b12, 2G12 and 2F5 and (2) To investigate antibody responses in the transgenic mice to a wide variety of immunogens using a number of immunization strategies. The project is a close collaboration between a laboratory (Nemazee) with expertise in B cells, including knockin mice, and one (Burton) with expertise in antibodies and HIV. It is expected to generate valuable reagents and animals for the proposed UO1 consortium.

描述（由申请人提供）：一种能够引起广泛中和抗体的免疫原的设计是HIV疫苗研究的主要但难以捉摸的目标。这种抗体的存在是通过描述罕见的广泛中和艾滋病毒血清的描述，以及从HIV感染的个体中分离出的少数广泛中和的人类单克隆抗体（BNMAB）。要了解如何更好地诱导广泛中和HIV抗体，重要的是要识别适当的B细胞前体并用有效的抗原刺激它们。因此，我们建议开发带有BNMAB“种系”版本的B细胞的小鼠菌株，并遵循其反应以测试免疫原子。这种方法使我们希望将其募集到HIV抗体反应中的非常B细胞的反应可见，并应允许在高频出现适当的前体的情况下快速筛选疫苗候选者，以便在适当的前体中引起中和抗体的能力。除非通过免疫耐受性消除这种B细胞，否则在这种情况下的反应失败将无法归因于适当的B细胞的缺乏，这是可以在实验上排除的结果。该提案的具体目的是（1）生成带有B细胞的转基因（敲击蛋白）小鼠，表达BNMABS B12、2G12和2F5的种系版本，以及（2）研究转基因小鼠中的抗体反应，使用多种免疫策略进行多种免疫原子。该项目是实验室（Nemazee）之间与B细胞中专业知识（包括敲蛋白小鼠）的专业知识的密切合作，而一名（伯顿）具有抗体和艾滋病毒的专业知识。预计将为拟议的UO1财团生成有价值的试剂和动物。