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

• 批准号: 10368158
• 负责人: Fikri Y Avci
• 金额: $ 51.94万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-10 至 2022-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368158
• 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; 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; antibody test; 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

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.

项目摘要/摘要 艾滋病毒一直是对人类健康的主要威胁，受保护的艾滋病疫苗尚未开发。 设计可重复诱导中和和非中和保护的策略 通过疫苗接种的抗体一直是停止HIV传播的高价值靶标。但是，设计 当前一代的疫苗不利用免疫系统激活机制 最大程度地刺激参与受保护抗体的临界免疫细胞（即辅助T细胞）。一个 急需艾滋病毒疫苗研究的新观点。在这里，我们提出了一种创新的方法 建立人类CD4+ T细胞库中包含的新范式的潜力 碳水化合物特异性的T细胞（即TCARBS）识别GP120的N-聚糖屏蔽。 HIV-1表面是 用称为GP120的重糖基化的包膜蛋白装饰，其与CD4分子的相互作用 是病毒进入CD4+ T细胞的关键步骤。使用此类TCARB及其聚糖的发现 表位，我们可以设计和开发基于知识的新代艾滋病毒疫苗，这些疫苗将引起强大 和持久的适应性免疫响应，以防止艾滋病毒。我们假设招募TCARB将会 不仅引起T细胞增殖和记忆，还会引起受保护的高亲和力的产生 B细胞通过亲和力成熟和抗体类开关等机制进行的抗体。我们相信 我们提出的研究将产生一个平台，以开发新的受保护的未来艾滋病毒疫苗。