Glycopeptide-specific helper T cells eliciting protective humoral immunity against HIV - Resubmission

糖肽特异性辅助 T 细胞引发针对 HIV 的保护性体液免疫 - 重新提交

基本信息

批准号：
10254963
负责人：
Fikri Y Avci
金额：
$ 52.85万
依托单位：
UNIVERSITY OF GEORGIA
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：
2021-03-10 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10254963
关键词：
Acquired Immunodeficiency Syndrome Affinity Antibodies Antibody Affinity Antibody Response Antigen-Presenting Cells Antigens B Cell Proliferation B-Lymphocytes Benchmarking Biological Assay CD4 Antigens CD4 Positive T Lymphocytes Carbohydrates Cause of Death Cells Collaborations Data Data Analyses Development Disease Outbreaks Epitopes Experimental Designs Future Generations Glycopeptides Goals HIV HIV Envelope Protein gp120 HIV vaccine HIV-1 Health Helper-Inducer T-Lymphocyte Human Humoral Immunities Immune Immune response Immune system Immunity Immunization Immunoglobulin Class Switching Individual Infectious Agent Investigation Maps Mediating Membrane Glycoproteins Memory Molecular Nature Pathway interactions Peptides Peripheral Blood Mononuclear Cell Plasmids Polysaccharides Population Production Protocols documentation Reporting Research Research Design Research Institute Role Scheme Specimen Structure Surface Surface Antigens T cell receptor repertoire sequencing T cell response T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte The Sun Universities Vaccination Vaccine Design Vaccine Research Vaccines Virus adaptive immune response base cell mediated immune response design env Gene Products experimental study glycosylation immunogenic immunogenicity innovation knowledge base mouse model neutralizing antibody recruit single-cell RNA sequencing success

项目摘要

PROJECT SUMMARY/ABSTRACT HIV has been a major threat to human health and a protective AIDS vaccine has not as yet been developed. Designing strategies for reproducibly inducing the production of neutralizing and non-neutralizing protective antibodies through vaccination has been a high-value target for halting the spread of HIV. However, the design of the current generation of vaccines does not make use of immune system activation mechanisms to maximize stimulation of critical immune cells (i.e., helper T cells) involved in producing protective antibodies. A new perspective to HIV vaccine research is much needed. Here, we propose an innovative approach with the potential of establishing a new paradigm that the human CD4+ T cell repertoire contains a population of carbohydrate-specific T cells (i.e., Tcarbs) that recognize the N-glycan shield of gp120. The HIV-1 surface is decorated with a heavily glycosylated envelope protein called gp120, whose interaction with the CD4 molecule is the key step for the virus’s entry into CD4+ T cells. Using the discovery of such Tcarbs and their glycan epitopes, we can design and develop knowledge-based, new-generation HIV vaccines that will elicit a strong and long lasting adaptive immune response to protect from HIV. We hypothesize that recruitment of Tcarbs will not only induce T cell proliferation and memory, but will also induce production of protective, high-affinity antibodies by B cells through mechanisms such as affinity maturation and antibody class-switch. We believe our proposed studies will yield a platform to develop a new-generation of protective future HIV vaccines.

项目概要/摘要艾滋病毒一直是对人类健康的主要威胁，而保护性艾滋病疫苗尚未研制出来。设计可重复诱导中和和非中和保护剂产生的策略通过疫苗接种产生抗体一直是阻止艾滋病毒传播的高价值目标。当前一代疫苗没有利用免疫系统激活机制最大限度地刺激参与产生保护性抗体 A 的关键免疫细胞（即辅助 T 细胞）。艾滋病毒疫苗研究非常需要新的视角，在这里，我们提出了一种创新方法。建立人类 CD4+ T 细胞库包含一组新范例的潜力识别 gp120 的 N-聚糖屏蔽的碳水化合物特异性 T 细胞（即 Tcarb）是 HIV-1 表面的。用一种称为 gp120 的高度糖基化的包膜蛋白装饰，该蛋白与 CD4 分子相互作用是利用此类 Tcarb 及其聚糖的发现，病毒进入 CD4+ T 细胞的关键步骤。表位，我们可以设计和开发基于知识的新一代艾滋病毒疫苗，这将引发强大的我们致力于招募 Tcarbs 来预防艾滋病毒。不仅诱导 T 细胞增殖和记忆，还诱导产生保护性、高亲和力我们相信 B 细胞通过亲和力成熟和抗体类别转换等机制产生抗体。我们提出的研究将为开发新一代保护性未来艾滋病毒疫苗提供一个平台。