Immunoglobulin gene diversity in an African population and impact on antibody function in HIV infection

非洲人群的免疫球蛋白基因多样性及其对 HIV 感染中抗体功能的影响

• 批准号: 10226240
• 负责人: Lynn Morris
• 金额: $ 24.64万
• 依托单位: WITS HEALTH CONSORTIUM (PTY), LTD
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226240
• 关键词: African; Alleles; Antibodies; Antibody Diversity; Antibody Repertoire; Antibody Response; Antigens; Antiviral Agents; Autoimmunity; B-Lymphocytes; Biological; Biological Assay; Blood specimen; Cells; Communities; Complementary DNA; Data; Databases; Ethnic Origin; Fc Receptor; Frequencies; Genes; Genetic Recombination; Genetic Variation; Genome; HIV; HIV Antibodies; HIV Infections; HIV vaccine; HIV-1; Heterozygote; High Risk Woman; Human; Human Genome; IgA1; IgA2; IgG1; IgG2; IgG3; Immune; Immune response; Immunogenetics; Immunoglobulin A; Immunoglobulin Constant Region; Immunoglobulin G; Immunoglobulin Genes; Immunoglobulin Joining Region; Immunoglobulin M; Immunoglobulin Somatic Hypermutation; Immunoglobulin Variable Region; Immunoglobulins; Individual; Infection; Knowledge; Light; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Participant; Phagocytosis; Polymorphism Analysis; Population; Research; Role; Sampling; Single Nucleotide Polymorphism; Somatic Mutation; South Africa; Specificity; Testing; Vaccination; Vaccine Design; Vaccines; Variant; Woman; antibody-dependent cell cytotoxicity; antigen binding; base; bioinformatics tool; cohort; efficacy trial; improved; infection rate; insight; interest; neutralizing antibody; next generation sequencing; novel; receptor; response; vaccine efficacy; young woman

PROJECT SUMMARY Antibodies are critical components of immune defense and are mediators of vaccine-elicited protection as well as autoimmunity. The heavy and light chains that comprise an antibody molecule are encoded by germline immunoglobulin (Ig) gene fragments that recombine and undergo somatic mutation thereby generating billions of specificities able to contend with a multitude of foreign antigens. The majority of the diversity lies within the antigen-binding (Fab) portion of antibodies although variation also exists within the conserved (Fc) region of the heavy chain that interacts with cellular receptors to mediate non-neutralizing functions. Diversity within both regions impacts on antibody function. Given the protective role of antibodies in HIV and other infections, we propose to mine the depth of the antibody repertoire and study how Fc diversity impacts antiviral activity. It is well known that Africans are more genetically diverse than other populations and yet there is a scarcity of data on African genomes including Ig genes. Our preliminary data using samples from an ethnic Zulu population residing in South Africa has revealed that approximately half of the heavy chain variable (IGHV) genes as well as a significant number of single nucleotide polymorphisms (SNPs) in the Fc are not recorded in public databases. Many of these novel IGHV alleles occur at high frequency and in some cases are highly expressed. Importantly, we have shown that they are used to make functional antibodies. We hypothesize that there is significant undiscovered variability within the African Ig gene repertoire some of which will impact on the functionality of anti-HIV antibodies. To explore this, we propose to sequence the entire rearranged, antigen-naïve heavy and light variable chain gene repertoires in 40 individuals of Zulu ethnicity using Illumina MiSeq. Data will be analyzed using a new bioinformatics tool called IgDiscover that will enable the identification of novel and known germline variable and joining region gene segments from both heavy and light chains that are expressed by functional antibodies. Variability in the Fc region of IgG and IgA will be analyzed using SNP analysis in 100 Zulu individuals. Furthermore, the Fc regions from individuals with novel IgG3 SNPs will be sequenced and used to make fully native antibodies for functional studies, including antibody-dependent cellular cytotoxicity (ADCC), phagocytosis and neutralization. In this way the diversity within both the Fab and Fc regions will be analyzed and the impact on function assessed. This project will contribute new knowledge on African germline immunoglobulin genes, which is essential for a fully comprehensive immunogenetics database. These studies will be of great benefit to the HIV research community as they embark on major vaccine efficacy trials as well as to others studying the immune responses to infection, vaccination, cancer and auto-immunity in this population.

项目总结 抗体是免疫防御的重要组成部分，也是疫苗诱导保护的媒介。 作为自身免疫力。构成抗体分子的重链和轻链由生殖系编码。 免疫球蛋白(Ig)基因片段重组并经历体细胞突变，从而产生数十亿 能够对抗多种外来抗原的特异性。大部分的多样性存在于 抗体的抗原结合(Fab)部分，尽管在保守的(Fc)区也存在变异 与细胞受体相互作用以调节非中和功能的重链。两者之间的多样性 地区对抗体功能的影响。考虑到抗体在艾滋病毒和其他感染中的保护作用，我们 建议挖掘抗体库的深度，并研究Fc多样性如何影响抗病毒 活动。 众所周知，非洲人的基因比其他人更多样化，但却缺乏 关于包括免疫球蛋白基因在内的非洲基因组的数据。我们使用祖鲁族样本的初步数据 居住在南非的人口显示，大约一半的重链可变(IGHV) Fc中的基因以及大量单核苷酸多态(SNPs)没有记录在 公共数据库。这些新的IGHV等位基因中有许多是高频出现的，在某些情况下还很高 表达。重要的是，我们已经证明它们被用来制造功能性抗体。我们假设 在非洲免疫球蛋白基因谱系中存在着重大的未被发现的变异，其中一些将 对抗HIV抗体功能的影响。 为了探索这一点，我们建议对整个重排的、抗原天真的重链和轻链进行测序 应用Illumina MiSeq对40名祖鲁族人的基因库进行分析数据将使用新的 名为IgDiscover的生物信息学工具，它将能够识别新的和已知的生殖系变量和 连接由功能性抗体表达的重链和轻链的区域基因片段。 将对100名祖鲁族人进行SNP分析，以分析Ig G和Ig A Fc区的变异性。 此外，来自具有新的IgG3 SNPs的个体的Fc区域将被测序并用于完全 用于功能研究的天然抗体，包括抗体依赖的细胞毒性(ADCC)， 吞噬和中和作用。通过这种方式，将分析FAB和FC区域内的多样性 以及对功能的影响评估。 该项目将提供有关非洲生殖系免疫球蛋白基因的新知识，这对 全面的免疫遗传学数据库。这些研究将对艾滋病的研究大有裨益。 社区正在进行主要的疫苗效力试验，以及其他研究免疫反应的人 感染、疫苗接种、癌症和自身免疫。

项目成果

Dependence on a variable residue limits the breadth of an HIV MPER neutralizing antibody, despite convergent evolution with broadly neutralizing antibodies.

• DOI: 10.1371/journal.ppat.1010450
• 发表时间: 2022-09
• 期刊: PLoS pathogens
• 影响因子: 6.7

Antibody class-switching as a strategy to improve HIV-1 neutralization.

• DOI: 10.1016/j.molmed.2022.08.010
• 发表时间: 2022-11
• 期刊: TRENDS IN MOLECULAR MEDICINE
• 影响因子: 13.6
• 作者: Scheepers, Cathrine;Richardson, Simone I.;Moyo-Gwete, Thandeka;Moore, Penny L.
• 通讯作者: Moore, Penny L.

The antibody response in HIV-1-infected donors.

HIV-1 感染捐赠者的抗体反应。

• DOI: 10.1097/coh.0000000000000559
• 发表时间: 2019
• 期刊: Current opinion in HIV and AIDS
• 影响因子: 4.1
• 作者: Richardson,SimoneI;Moore,PennyL
• 通讯作者: Moore,PennyL