Population genotyping of the germline immunoglobulin repertoire in AIDS-designated rhesus macaque breeding colonies

艾滋病指定恒河猴繁殖群种系免疫球蛋白库的群体基因分型

• 批准号: 10258937
• 负责人: Steven Edward Bosinger
• 金额: $ 79.06万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10258937
• 关键词: 2019-nCoV; AIDS Vaccines; Acquired Immunodeficiency Syndrome; Address; Alleles; Antibodies; Antigens; Applications Grants; Autologous; Benchmarking; Bioinformatics; Breeding; Catalogs; Communities; Complex; Data; Data Set; Databases; Development; Enrollment; Epitopes; Evolution; Foundations; Gene Targeting; Genetic; Genome; Genomics; Genotype; Germ-Line Mutation; Goals; HIV; HIV vaccine; Haplotypes; Human; Immunization; Immunoglobulin Genes; Immunoglobulins; Impairment; Individual; Knowledge; Longitudinal Studies; Macaca mulatta; Methodology; Modeling; Monkeys; Monoclonal Antibody R24; Mutation; Outcome; Population; Population Heterogeneity; Positioning Attribute; Primates; Protocols documentation; Reporting; Research; Resolution; Resources; Structure; T-Lymphocyte; Testing; Vaccinated; Vaccine Research; Vaccines; Variant; Virus; Work; base; cohort; combat; genetic information; neutralizing antibody; novel; novel strategies; pandemic disease; pathogen; preclinical study; reference genome; response; tool; vaccine efficacy; vaccine response; vaccine trial; web-accessible

PROJECT SUMMARY A strategic priority for contemporary HIV vaccine research is the development of approaches to elicit broadly neutralizing antibodies (bNAbs) able to neutralize diverse strains of the virus. A cornerstone of bNAb discovery is the ability to conduct accurate, longitudinal studies of antibody evolution in HIV infected individual as they gain mutations and acquire neutralization activity. Currently, it is not possible to perform analogous antibody evolution tracing studies using rhesus macaques (RMs), due to a lack of defined immunoglobulin (IG) alleles. This is best exemplified by a recent study large scale vaccine study by our group in which we sequenced a de novo genome of a RM using long-read sequencing in order to obtain accurate assemblies of the IG loci. This reference significantly enhanced the accuracy of tracking the mutations from germline elicited by our vaccine strategies. This tool was critical in deciphering trajectories that led to either autologous neutralization or immunodominance and non-neutralizing responses. In other work, we have developed novel bioinformatics methodology (germline inference) to identify the unmutated germline antibody sequence from immunoglobulin repertoire. This work has led to identification of hundreds of novel inferred IG alleles. The goal of this R24 proposal is to build on these findings by characterizing the IG alleles and haplotypes in AIDS designated RMs at NHP primate centers that serve the major HIV vaccine stakeholders. Currently, the IG loci are poorly characterized in RMs, in part due to technical challenges. IG genotypes are not currently used as criteria when enrolling RMs into vaccine studies. In contrast, MHC genotyping of RMs has become standard practice for vaccine studies and is a core function in genetic management of NPRC RM colonies. The lack of genetic data on the RM IG loci is therefore a significant knowledge gap and impairs our ability to assess the evolution of antibodies in monkeys administered vaccines that aim to elicit neutralizing antibodies. The goal of this R24 proposal is to address this strategic need and build a resource in which this genetic information (IG allele sequence information, haplotype, and allele usage) is available to the HIV vaccine and NHP research communities.

项目概要 当代艾滋病毒疫苗研究的一个战略重点是开发广泛诱导的方法 中和抗体（bNAb）能够中和不同的病毒株。 bNAb 发现的基石 是对 HIV 感染者的抗体进化进行准确、纵向研究的能力 突变并获得中和活性。目前还不可能进行类似的抗体进化 由于缺乏明确的免疫球蛋白 (IG) 等位基因，使用恒河猴 (RM) 进行追踪研究。这是最好的 我们小组最近进行的一项大规模疫苗研究就是例证，其中我们对从头基因组进行了测序 使用长读长测序的 RM 以获得 IG 位点的准确组装。这个参考 显着提高了追踪我们的疫苗策略引起的种系突变的准确性。 该工具对于破译导致自体中和或免疫优势的轨迹至关重要 和非中和反应。在其他工作中，我们开发了新颖的生物信息学方法（种系 推断）以从免疫球蛋白库中识别未突变的种系抗体序列。这部作品有 导致数百个新推断的 IG 等位基因的鉴定。 R24 提案的目标是通过表征 IG 等位基因和单倍型来建立这些发现 NHP 灵长类动物中心的 AIDS 指定 RM 为主要 HIV 疫苗利益相关者提供服务。现在， RM 中 IG 位点的表征很差，部分原因是技术挑战。目前还没有 IG 基因型 用作将 RM 纳入疫苗研究时的标准。相比之下，RM 的 MHC 基因分型已成为 疫苗研究的标准实践，是 NPRC RM 菌落遗传管理的核心功能。这 因此，缺乏 RM IG 位点的遗传数据是一个重大的知识差距，并削弱了我们评估的能力 注射疫苗的猴子体内抗体的进化旨在引发中和抗体。目标 该 R24 提案的目的是解决这一战略需求并建立一个资源，其中该遗传信息（IG 等位基因序列信息、单倍型和等位基因用途）可用于 HIV 疫苗和 NHP 研究 社区。