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Project 1: Immunization strategies to elicit broadly neutralizing antibodies against HIV-1

项目 1：引发广泛中和 HIV-1 抗体的免疫策略

基本信息

批准号：
10521244
负责人：
Pamela J Bjorkman
金额：
$ 59.35万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-10 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10521244
关键词：
Abbreviations Acquired Immunodeficiency Syndrome Adjuvant Animal Model Anti-Retroviral Agents Antibodies Antibody Binding Sites Antibody Response Antigens Autologous B cell repertoire B-Lymphocytes Binding Binding Sites Biological Assay C57BL/6 Mouse Collaborations Complementarity Determining Regions Consensus Development Disease Enzyme-Linked Immunosorbent Assay Epitopes Family Frequencies Genes Genetic Engineering Genetically Engineered Mouse Goals HIV Envelope Protein gp120 HIV envelope protein HIV vaccine HIV-1 Human IgK Immune response Immunization Immunoglobulin Somatic Hypermutation Immunoglobulins Individual Infection Infection prevention Institution Knock-in Mouse Laboratories Length Letters Leukapheresis Light Link Macaca Membrane Methods Modeling Mus Passive Transfer of Immunity Persons Pharmaceutical Preparations Polysaccharides Proteins Protocols documentation Publishing Regimen Reporting Reproducibility Research Sampling Scheme Series Site Somatic Mutation Sorting Surface Plasmon Resonance Technology Testing United States National Institutes of Health V3 Loop Vaccine Clinical Trial Vaccines Virus Virus-like particle Wild Type Mouse Work base design env Gene Products experimental study glycosylation gp160 immunoglobulin light chain locus neutralizing antibody programs protein expression rational design receptor binding vaccination strategy vaccine development

项目摘要

Proj.1 Immunization strategies to elicit bNAbs against HIV-1 PI: Bjorkman, P.J./Nussenzweig, M.C. ! Summary AIDS is a preventable disease, however, according to UNAIDS, millions of people are newly infected every year. The design of a vaccine for HIV-1 is therefore highly desirable. To date, despite numerous efforts, no immunization regimen reproducibly elicits broadly neutralizing antibodies (bNAbs) against HIV-1. Recently available native-like Env trimers do elicit antibodies that neutralize autologous tier-2 viruses but these antibodies have only limited potency and breadth. The observation that most of the native-like Env proteins do not bind the inferred germline (iGL) antibody precursors of bNAbs suggested that rationally designed iGL targeting immunogens would be required to initiate bNAb responses. The Nussenzweig lab has confirmed this hypothesis in knock in mice that carry the iGL PGT121 bNAb which targets the base of the V3 loop and surrounding glycans (V3/N332). Immunization with iGL targeting proteins followed by a series of more native- looking Env trimers elicited bNAbs in iGL PGT121 bNAb knock-in mice. The long term goal of the proposed research is to extend these studies to other animal models that more closely resemble a human immune response and also to other types of bNAbs such as the IOMA-like bNAbs targeting the CD4bs. To accomplish these goals Dr. Nussenzweig will work with Dr. Bjorkman to design and test new immunogens and immunization strategies to elicit V3/N332 and IOMA-like bNAbs in knock-in mice, wild type mice and mice that carry un-rearranged human immunoglobulin loci. The Nussenzweig lab plans to: 1) optimize the previous immunization protocol designed to elicit PGT121-like bNAbs; 2) extend the use of this immunization regimen to other iGL bNAb knock-in mice targeting the V3/N332 site such as the BG18GL mice; 3) design a consensus series of immunogens that elicits the class of V3/N332 bNAbs; 4) design immunization strategies that elicit IOMA-like CD4bs antibodies in IOMAGL knock-in mice; 5) extend these immunization experiments to wild type mice and mice that carry un-rearranged human immunoglobulin loci; 6) evaluate the suitability of the new immunogens to isolate bNAb precursors from healthy donors. The proposed experiments will produce candidate immunogens for vaccine clinical trials. !

Proj.1免疫策略，以引发针对HIV-1 PI的bNAb：Bjorkman，P. J./ Nussenzweig，M.C. ! 总结艾滋病是一种可预防的疾病，但据联合国艾滋病规划署称，每年因此，非常需要设计HIV-1疫苗。迄今为止，尽管作出了许多努力，没有免疫方案可重复地产生抗HIV-1的广泛中和抗体（bNAb）。最近可用的天然样Env三聚体确实引发中和自体2级病毒的抗体，但这些抗体抗体的效力和广度有限。观察到大多数天然的类似Env蛋白不结合bNAb的推断生殖系（iGL）抗体前体，表明合理设计的iGL 启动bNAb应答需要靶向免疫原。Nussenzweig实验室已经证实了这一点在携带iGL PGT 121 bNAb的小鼠中敲除的假设，所述iGL PGT 121 bNAb靶向V3环的碱基，周围的聚糖（V3/N332）。用iGL靶向蛋白免疫，然后用一系列更天然的- 观察Env三聚体在iGL PGT 121 bNAb敲入小鼠中引发bNAb。拟议的长期目标这项研究的目的是将这些研究扩展到更类似于人类免疫系统的其他动物模型此外，这些抗体还可以针对其他类型的bNAb，例如靶向CD 4 b的IOMA样bNAb。完成 Nussenzweig博士将与Bjorkman博士合作设计和测试新的免疫原，在敲入小鼠、野生型小鼠和携带未重排的人免疫球蛋白基因座。Nussenzweig实验室计划：1）优化以前的设计用于引发PGT 121样bNAb的免疫方案; 2）将该免疫方案的使用扩展至其他靶向V3/N332位点的iGL bNAb敲入小鼠，如BG 18 GL小鼠; 3）设计共有 4）设计免疫策略， IOMAGL敲入小鼠中的IOMA样CD 4 b抗体; 5）将这些免疫实验扩展至野生型小鼠和携带未重排的人免疫球蛋白基因座的小鼠; 6）评估新的免疫球蛋白基因座的适用性。免疫原从健康供体中分离bNAb前体。这些实验将产生疫苗临床试验的候选免疫原。 !