High-resolution definition of B cell responses to HIV Env for immunogen design

用于免疫原设计的 B 细胞对 HIV 包膜反应的高分辨率定义

• 批准号: 10594411
• 负责人: Yuxing Li
• 金额: $ 35万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594411
• 关键词: Address; Affinity; Alleles; Animals; Antibodies; Antibody Affinity; Antibody Response; Antigens; B cell repertoire; B-Cell Antigen Receptor; B-Lymphocytes; Binding Sites; CD4 Antigens; Cavia; Clinical Research; Clone Cells; Complex; Development; Elements; Epitopes; Frequencies; Funding; Generations; Genes; Genetic; Glycoproteins; HIV; HIV Antibodies; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Immune response; Immunization; Immunize; Immunoglobulin Somatic Hypermutation; Individual; Infection; Knock-in Mouse; Light; Modeling; Modification; Monoclonal Antibodies; Outcome Study; Pathway interactions; Patients; Play; Process; Regimen; Resolution; Role; Serum; Specificity; Structure of germinal center of lymph node; Testing; Vaccination; Vaccines; Virus; clinical translation; cross reactivity; design; donor-specific antibody; emerging pathogen; experimental study; guinea pig model; immunogenicity; improved; innovation; mouse model; neutralizing antibody; novel; novel vaccines; pathogen; pathogenic virus; preclinical study; programs; receptor binding; response; success; vaccine candidate; vaccine development

Project Summary The elicitation of broadly neutralizing antibodies (bNAbs) against HIV Env is one of the major challenges of HIV-1 vaccine development. As a vaccine component, HIV-1 Env however elicits limited neutralizing breadth and potency in most pre-clinical and clinical studies to date. The isolation of second generation of bNAbs from HIV-infected individuals, and characterization of their cognate epitopes on Env, offer a tremendous opportunity for understanding the mechanisms underlying the elicitation of bNAb responses. As one of the most functionally conserved and accessible elements of the HIV Env, the receptor binding site, namely CD4 binding site (CD4bs), plays a crucial role for virus engagement with receptor CD4 while serves as a vulnerable target for bNAb response in natural infections. VRC01-class bNAbs, a subset of CD4bs bNAbs isolated from donor 45 and numerous other HIV-infected individuals strongly supports the premise of utilizing VRC01-class bNAbs as vaccine template. However, current Env-based immunogens are not capable of eliciting potent VRC01-class bNAb response via vaccination. The inferred VRC01- class bNAb germline precursors (gVRC01) often display weak or no apparent affinity to prototypical Env immunogens. Thus, immunogen modifications including approaches for efficiently activating, selectively expanding, and precisely shepherding bNAb germline precursors (germline targeting) are needed for CD4bs bNAb elicitation, yet met with limited success. During the last funding period, we established a panel of Env-based designer immunogens with desirable antigenicity for eliciting CD4bs bNAb response. In this proposal, we aim to extend our effort by an innovative program consisting of the following three complementary specific aims: (1) to investigate the immunogenicity of novel immunogens/regimens in bNAb germline BCR knockin mice; (2) to investigate the immunogenicity of novel immunogens in guinea pigs and OmniMouse2 model that carries un- rearranged human antibody loci; and (3) to explore a novel neutralizing epitope in the C3/V4 region of the Env as potential bNAb response target. We believe that through this study we will (i) contribute to the thorough understanding of the basic aspects of the B cell response to the HIV-1 Env following vaccination and natural infection; and (ii) contribute new immunogens, new vaccine target, and optimized vaccination regimens leading to improved neutralizing responses targeting conserved Env elements.

项目摘要 针对HIV Env的广泛中和抗体（BNAB）的启发是主要的之一 HIV-1疫苗开发的挑战。作为疫苗成分，HIV-1 Env但是引起 迄今为止，大多数临床前和临床研究中的中和广度和效力有限。这 从HIV感染的个体中隔离第二代BNAB，并进行表征 他们在Env上的同源表位，为理解 BNAB响应引起的基础机制。作为功​​能上最多的 HIV ENV的保守且可访问的元素，受体结合位点，即CD4 结合位点（CD4B），在服务时对病毒与受体CD4的互动起着至关重要的作用 作为自然感染中BNAB反应的脆弱靶标。 VRC01级BNAB，子集 从供体45和许多其他HIV感染者中分离出的CD4BS BNAB的强烈 支持将VRC01级BNAB作为疫苗模板的前提。但是，当前 基于ENV的免疫原不能通过 疫苗接种。推断的VRC01-类BNAB种系前体（GVRC01）经常显示 弱或没有明显的亲和力对原型ENV免疫原生物。因此，免疫原改变 包括有效激活，选择性扩展和精确牧羊的方法 CD4BS BNAB启发需要BNAB种系前体（种系靶），但要满足 成功有限。在上一个资金期间，我们建立了一个基于Env的小组 具有理想抗原性的设计师免疫原子可引起CD4BS BNAB反应。在这个 提案，我们旨在通过包括以下各项的创新计划来扩展我们的努力 三个补充特定的目的：（1）研究新颖的免疫原性 BNAB种系BCR敲击蛋白小鼠中的免疫剂/方案； （2）调查 新型免疫原的免疫原性在豚鼠和Omnimouse2模型中的免疫原性 重新排列的人类抗体基因座； （3）在C3/V4中探索一种新颖的中和表位 ENV的区域是潜在的BNAB响应靶标。我们相信，通过这项研究，我们将 （i）有助于彻底理解B细胞响应的基本方面 疫苗接种和自然感染后的HIV-1 Env； （ii）贡献新的免疫原， 新的疫苗靶标，并优化了疫苗接种方案，导致中和 针对保守的环境元素的响应。