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: 10641946
• 负责人: Steven Edward Bosinger
• 金额: $ 85.98万
• 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/10641946
• 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; Mutation; Outcome; Population; Population Heterogeneity; Positioning Attribute; Primates; Protocols documentation; R24; Reporting; Research; Resolution; Resources; T-Lymphocyte; Testing; Vaccinated; Vaccine Research; Vaccines; Variant; Virus; Work; cohort; combat; genetic information; genome resource; neutralizing antibody; novel; novel strategies; pandemic disease; pathogen; preclinical study; reference genome; response; tool; vaccine efficacy; vaccine response; vaccine strategy; 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.

项目摘要 当代艾滋病毒疫苗研究的战略优先事项是开发广泛引起的方法 中和抗体（BNAB）能够中和病毒的多样性菌株。 BNAB发现的基石 是在艾滋病毒感染者中进行抗体进化的准确，纵向研究的能力 突变并获得中和活性。目前，不可能执行类似的抗体进化 由于缺乏定义的免疫球蛋白（IG）等位基因，使用恒河猕猴（RMS）进行追踪研究。这是最好的 我们小组的最新研究大规模疫苗研究的例证，我们对从头基因组进行了测序 使用长阅读测序的RM的RM，以获得IG基因座的精确组件。此参考 显着提高了跟踪我们疫苗策略引起的种系突变的准确性。 该工具对于破译轨迹至关重 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）从免疫球蛋白库中鉴定未经未经形的种系抗体序列。这项工作有 导致鉴定数百种新型的推断IG等位基因。 该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。 在为主要艾滋病毒疫苗利益相关者服务的NHP灵长类动物中心指定RMS的艾滋病中。现在， IG基因座在RMS中的特征很差，部分原因是技术挑战。 IG基因型目前不是 将RMS纳入疫苗研究时，用作标准。相反，RMS的MHC基因分型已成为 疫苗研究的标准实践，是NPRC RM菌落遗传管理中的核心功能。这 因此 猴子中抗体的演变旨在引起中和抗体的疫苗。目标 R24提案是解决这一战略需求，并建立一种遗传信息的资源（IG HIV疫苗和NHP研究可用等位基因序列信息，单倍型和等位基因使用量） 社区。