Characterization of HIV-1 IgA bNAbs and ADCP function

HIV-1 IgA bNAb 的表征和 ADCP 功能

基本信息

批准号：
10529017
负责人：
Xueling Wu
金额：
$ 62.38万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-10 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10529017
关键词：
Acquired Immunodeficiency Syndrome Active Biological Transport Acute Antibodies Antibody Repertoire Antibody-Dependent Enhancement Antigen-Antibody Complex Avidity B-Cell Antigen Receptor B-Lymphocytes CD4 Positive T Lymphocytes Cameroon Cells Cohort Studies Communicable Diseases Data Dental crowns Epithelial Cells Epitopes Exclusion Excretory function Exhibits Gut Mucosa Gut associated lymphoid tissue HIV-1 Human Immune Immune system Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G In Vitro Individual Infection Knowledge Lamina Propria Macaca Macaca mulatta Mediating Membrane Memory B-Lymphocyte Modeling Monoclonal Antibodies Mucosal Immune System Mucous Membrane New York Patients Peripheral Blood Mononuclear Cell Phagocytosis Plasma Prevention therapy Primates Process Research Sampling Secretory Immunoglobulin A Site Surface Testing Time Transcript Universities Vesicular stomatitis Indiana virus Viral Virus Virus Replication antibody-dependent cellular phagocytosis arm base density dimer fight against fighting in vivo intraepithelial medical schools mucosa-associated lymphoid tissue neutralizing antibody novel particle public health relevance response simian human immunodeficiency virus tool

Acquired Immunodeficiency Syndrome Active Biological Transport Acute Antibodies Antibody Repertoire Antibody-Dependent Enhancement Antigen-Antibody Complex Avidity B-Cell Antigen Receptor B-Lymphocytes CD4 Positive T Lymphocytes Cameroon Cells Cohort Studies Communicable Diseases Data Dental crowns Epithelial Cells Epitopes Exclusion Excretory function Exhibits Gut Mucosa Gut associated lymphoid tissue HIV-1 Human Immune Immune system Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G In Vitro Individual Infection Knowledge Lamina Propria Macaca Macaca mulatta Mediating Membrane Memory B-Lymphocyte Modeling Monoclonal Antibodies Mucosal Immune System Mucous Membrane New York Patients Peripheral Blood Mononuclear Cell Phagocytosis Plasma Prevention therapy Primates Process Research Sampling Secretory Immunoglobulin A Site Surface Testing Time Transcript Universities Vesicular stomatitis Indiana virus Viral Virus Virus Replication antibody-dependent cellular phagocytosis arm base density dimer fight against fighting in vivo intraepithelial medical schools mucosa-associated lymphoid tissue neutralizing antibody novel particle public health relevance response simian human immunodeficiency virus tool

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项目摘要

PROJECT SUMMARY HIV-1 spreads mainly through mucosal exposures. Dominant in mucosal secretions, IgA has long been the class of antibodies desired at the portal of entrance to block infection. However, due to a paucity of IgA responses to HIV-1, as compared to IgG, previous antibody isolation efforts and antibody repertoire analyses have focused on IgG+ B cells and missed IgA+ B cells. With a novel vesicular stomatitis virus (VSV)-based platform, we were able to display the membrane-embedded HIV-1 envelope (Env) trimer on the surface, use it to probe Env-specific memory B cells, and isolate HIV-1 broadly neutralizing antibodies (bNAbs) from infected individuals. During this process, we included the IgA transcripts in antibody repertoire analyses and identified two HIV-1 bNAb lineages that class-switched to both IgG and IgA, thus for the first time identified IgA bNAbs produced during the course of HIV-1 natural infection. Additionally, we have isolated two HIV-1 Env-directed IgA monoclonal antibodies (mAbs) that exhibited partial virus neutralization capability; these IgAs also mediated potent antibody-dependent cellular phagocytosis (ADCP) function to eliminate HIV-1-infected cells. Supported by these scientific premises, we propose in this application to identify additional HIV-1 IgA bNAbs and ADCP IgA mAbs from clade-B and non-clade-B infected individuals, including those followed longitudinally (Aim 1), and then characterize the IgA target epitopes on HIV-1 Env (Aim 2), and test a representative IgA bNAb and ADCP IgA for protection efficacy in rhesus macaque SHIV mucosal challenge model (Aim 3). We aim to test the hypothesis that 1) significant IgA bNAbs and ADCP responses are elicited during HIV-1 infection; 2) IgA bNAbs and ADCP IgAs may target novel sites of vulnerability on HIV-1 Env; 3) an IgA bNAb is comparable to or better than its IgG bNAb counterpart at protection against SHIV mucosal challenge, and an ADCP IgA may also protect macaques from SHIV mucosal challenge. If successful, the project will unveil and validate the potential antiviral functions of IgA to fight against HIV-1.

项目摘要 HIV-1主要通过粘膜暴露传播。 Iga在粘膜分泌物中占主导地位，长期以来一直是班级入口门户的抗体以阻断感染。但是，由于IgA对 HIV-1，与IgG相比，以前的抗体隔离工作和抗体库分析已集中在IgG+ B细胞上，错过IgA+ B细胞。凭借新型的囊泡气孔病毒（VSV）的平台，我们是能够在表面上显示膜上包裹的HIV-1信封（ENV）三聚体，用它来探测特定于ENV的记忆B细胞和分离的HIV-1从感染个体中广泛中和抗体（BNAB）。在此期间过程，我们在抗体库分析中包括了IgA转录本，并确定了两个HIV-1 BNAB谱系该类别切换到IgG和IgA，因此首次确定了课程中产生的IgA bnabs HIV-1自然感染。此外，我们已经隔离了两个HIV-1 Env指导的IgA单克隆抗体（mAb）表现出部分病毒中和能力；这些IGA还介导的有效抗体依赖性细胞吞噬作用（ADCP）功能可消除HIV-1感染的细胞。在这些科学前提的支持下我们建议在此应用中识别来自进化枝B和非clade-b感染的个体，包括纵向遵循的人（AIM 1），然后表征IgA HIV-1 Env（AIM 2）上的靶向座位，并测试代表性IGA BNAB和ADCP IGA的保护功效在恒河猕猴湿粘膜挑战模型中（AIM 3）。我们旨在检验以下假设，即1）在HIV-1感染期间，引起了IgA BNAB和ADCP反应。 2）IgA bnabs和ADCP IGA可能针对 HIV-1 Env上的脆弱性新颖地点； 3）IgA BNAB与其IgG BNAB对应物相当或更好在防止Shiv Mucosal Challenge的保护下，ADCP IGA也可以保护猕猴免受Shiv Mucosal的影响挑战。如果成功，该项目将揭幕并验证IGA的潜在抗病毒功能与之抗争 HIV-1。